Chapter 13

555
Allergy and Hypersensitivity

13
The adaptive immune response is a critical component of host defense

against infection and is essential for normal health. Unfortunately, adaptive
immune responses are also sometimes elicited by antigens not associated
with infectious agents, and this can cause serious disease. One circumstance
in which this occurs is when harmful immune reactions known generally as
hypersensitivity reactions are made in response to inherently harmless
‘environmental’ antigens such as pollen, food, and drugs.
Hypersensitivity reactions were classified into four types by Coombs and Gell
(Fig. 13.1). Allergy, the commonest type of hypersensitivity, is often equated
with type I hypersensitivity reactions, which are immediate-type hypersen-
sitivity reactions mediated by IgE antibodies, but many of the allergic
diseases discussed below also have features characteristic of other types of
hypersensitivity, particularly of T cell-mediated type IV hypersensitivity
reactions. In the majority of allergies, such as those to food, pollen, and house
dust, reactions occur because of the individual has become sensitized to an
innocuous antigen—the allergen—by producing IgE antibodies against it.
Subsequent exposure to the allergen triggers the activation of IgE-binding
cells, including mast cells and basophils, in the exposed tissue, leading to a
series of responses that are characteristic of allergy and are known as allergic
reactions. Allergic reactions can, however, be independent of IgE; T lympho-
cytes have the predominant role in allergic contact dermatitis.
© Garland Science 2008

556 Chapter 13: Allergy and Hypersensitivity
Type I Type II Type III Type IV
Immune IgE IgG IgG TH 1 cells TH 2 cells CTL

reactant
Soluble Cell- or matrix- Cell-surface Soluble Soluble Soluble Cell-associated

Antigen antigen associated receptor antigen antigen antigen antigen
antigen
Complement, IgE production,

Effector Mast-cell Antibody
FcR+ cells alters
Complement, Macrophage eosinophil Cytotoxicity
mechanism activation (phagocytes, phagocytes activation activation,
signaling
NK cells) mastocytosis
immune complex
platelets
blood
vessel
+ TH 1 TH2
complement IFN-
+ IL-4 CTL
complement IL-5 eotaxin
Ag
chemokines, cytotoxins,
cytokines, cytotoxins inflammatory mediators
Example of Allergic rhinitis, Some drug Chronic urticaria Chronic asthma,

Serum sickness, Contact dermatitis, Graft
hypersensitivity asthma, systemic allergies (antibody against chronic allergic
Arthus reaction tuberculin reaction rejection
reaction anaphylaxis (e.g. penicillin) FCRI) rhinitis
Fig. 13.1 Hypersensitivity reactions are mediated by damage involved is caused by responses triggered by immune
immunological mechanisms that cause tissue damage. Four complexes. A special category of type II responses involves IgG
types of hypersensitivity reactions are generally recognized. Types antibodies against cell-surface receptors that disrupt the normal
I–III are antibody-mediated and are distinguished by the different functions of the receptor, either by causing uncontrollable
types of antigens recognized and the different classes of antibody activation or by blocking receptor function. Type IV
involved. Type I responses are mediated by IgE, which induces hypersensitivity reactions are T-cell mediated and can be
mast-cell activation, whereas types II and III are mediated by IgG, subdivided into three groups. In the first group, tissue damage is
which can engage complement-mediated and phagocytic effector caused by the activation of macrophages by TH1 cells, which
mechanisms to varying degrees, depending on the subclass of results in an inflammatory response. In the second, damage is
IgG and the nature of the antigen involved. Type II responses are caused by the activation by TH2 cells of inflammatory responses
directed against cell-surface or matrix antigens, whereas type III in which eosinophils predominate; in the third, damage is caused
responses are directed against soluble antigens, and the tissue directly by cytotoxic T cells (CTL).
The biological role of IgE is in protective immunity, especially in response to

parasitic worms, which are prevalent in less developed countries. In the
industrialized countries, allergic IgE responses to innocuous antigens pre-
dominate and are an important cause of disease (Fig. 13.2). Almost half the
population of North America and Europe have allergies to one or more com-
mon environmental antigens and, although rarely life-threatening, these
cause much distress and lost time from school and work. Much more is
known about the pathophysiology of IgE-mediated responses than about the
normal physiological role of IgE, probably because the prevalence of allergy
in industrialized societies has doubled in the past 10–15 years.
In this chapter we first consider the mechanisms that favor the sensitization
of an individual to an allergen through the production of IgE. We then
describe the allergic reaction itself—the pathological consequences of the
interaction between allergen and the IgE bound to the high-affinity Fce
receptor on mast cells and basophils. Finally, we consider the causes and con-
sequences of other types of immunological hypersensitivity reactions.

Sensitization and the production of IgE 557
Fig. 13.2 IgE-mediated reactions to

IgE-mediated allergic reactions extrinsic antigens. All IgE-mediated
responses involve mast-cell
Syndrome Common allergens Route of entry Response degranulation, but the symptoms
experienced by the patient can be
Edema very different depending on whether
Drugs Intravenous (either Increased vascular the allergen is injected, inhaled,
Systemic Serum directly or following permeability
anaphylaxis or eaten, and depending also on
Venoms oral absorption Laryngeal edema
Food, e.g. peanuts into the blood) Circulatory collapse
the dose of the allergen.
Death
Acute urticaria Animal hair Local increase in

Through skin
(wheal-and-flare) Insect bites blood flow and
Systemic
Allergy testing vascular permeability
Seasonal Pollens (ragweed, Edema of nasal

rhinoconjunctivitis trees, grasses) Inhalation mucosa
(hay fever) Dust-mite feces Sneezing
Bronchial constriction
Danders (cat)
Increased mucus
Asthma Pollens Inhalation production
Dust-mite feces
Airway inflammation
Tree nuts
Shellfish
Vomiting
Peanuts
Diarrhea
Milk
Food allergy Oral Pruritis (itching)
Eggs
Urticaria (hives)
Fish
Anaphylaxis (rarely)
Soy
Wheat
Sensitization and the production of IgE.

Features of inhaled allergens that may
promote the priming of TH2 cells
IgE is produced both by plasma cells in lymph nodes draining the site of that drive IgE responses
antigen entry and by plasma cells at the site of the allergic reaction, where Protein, often with
germinal centers develop within the inflamed tissue. IgE differs from other Only proteins induce
carbohydrate
T-cell responses
antibody isotypes in being predominantly localized in tissues, where it is side chains
tightly bound to mast-cell surfaces through the high-affinity IgE receptor Enzymatically Allergens are often
FceRI (see Section 9-22). Binding of antigen to IgE cross-links these recep- active proteases
tors, causing the release of chemical mediators from the mast cells that can
lead to a type I hypersensitivity reaction. Basophils also express FceRI and Favors activation of IL-4-
Low dose
so can display surface-bound IgE and take part in type I hypersensitivity producing CD4 T cells
reactions. How an initial antibody response comes to be dominated by IgE is
still being worked out. In this part of the chapter we describe the current Low molecular Allergen can diffuse
weight out of particle into mucus
understanding of the factors that contribute to this process.
Allergen can be readily
Highly soluble
13-1 Allergens are often delivered transmucosally at low dose, a route eluted from particle
that favors IgE production.
Allergen can survive in
Stable
desiccated particle
Certain antigens and routes of antigen presentation to the immune system
favor the production of IgE, which is driven by CD4 TH2 cells (see Section Contains peptides
Required for
9-9). Much human allergy is caused by a limited number of small inhaled that bind host
T-cell priming
MHC class II
proteins that reproducibly elicit IgE production in susceptible individuals.
We inhale many different proteins that do not induce IgE production; this
raises the question of what is unusual about those proteins that are common Fig. 13.3 Properties of inhaled allergens.
allergens. Although we do not yet have a complete answer, some general The typical characteristics of inhaled
properties have emerged (Fig. 13.3). Most allergens are relatively small, allergens are described in this table.

highly soluble proteins that are carried on dry particles such as pollen grains
or mite feces. On contact with the mucosa of the airways, for example, the
soluble allergen elutes from the particle and diffuses into the mucosa.
Allergens are typically presented to the immune system at very low doses. It
has been estimated that the maximum exposure of a person to the common
pollen allergens in ragweed (Ambrosia species) does not exceed 1 mg per year.
Yet many people develop irritating and even life-threatening TH2-driven IgE
antibody responses to these minute doses of allergen. It should be empha-
sized, however, that only some people who are exposed to these substances
make IgE antibodies against them.
It seems likely that presenting an antigen across a mucosal epithelium and at
very low doses is a particularly efficient way of inducing TH2-driven IgE
responses. IgE antibody production requires help from TH2 cells that produce
interleukin-4 (IL-4) and IL-13, and it can be inhibited by TH1 cells that
produce interferon-g (IFN-g) (see Fig. 9.13). Low doses of antigen can favor
the activation of TH2 cells over TH1 cells (see Section 10-5), and many
common allergens are delivered to the respiratory mucosa by the inhalation
of a low dose. In the respiratory mucosa these allergens encounter dendritic
Fig. 13.4 The enzymatic activity of
cells that take up and process protein antigens very efficiently and thus
some allergens enables the
penetration of epithelial barriers. The
become activated. In some circumstances, mast cells and eosinophils can
epithelial barrier of the airways is formed also present antigen to T cells and promote the differentiation of TH2 cells.
by tight junctions between the epithelial
cells. Fecal pellets from the house dust
mite, Dermatophagoides pteronyssimus, 13-2 Enzymes are frequent triggers of allergy.
contain a proteolytic enzyme, Der p 1,
that acts as an allergen. It cleaves Several lines of evidence suggest that the natural role of IgE is in the defense
occludin, a protein that helps to maintain against parasitic worms (see Section 11-16). Many of these invade their hosts
the tight junctions, and thus destroys the by secreting proteolytic enzymes that break down connective tissue and allow
barrier function of the epithelium. Mite the parasite access to internal tissues, and it has been proposed that these
fecal antigens can then pass through and
be taken up by dendritic cells in
enzymes are particularly active at promoting TH2 responses. This idea
subepithelial tissue. Der p 1 is taken up receives some support from the many examples of allergens that are enzymes.
by dendritic cells, which are activated and The major allergen in the feces of the house dust mite (Dermatophagoides
move to lymph nodes (not shown), where pteronyssimus), which is responsible for allergy in about 20% of the North
they act as antigen-presenting cells, American population, is a cysteine protease known as Der p 1. This enzyme
inducing the production of TH2 cells has been found to cleave occludin, a protein component of intercellular tight
specific for Der p 1 and the production of
junctions. This reveals one possible reason for the allergenicity of certain
Der p 1-specific IgE. Der p 1 can then
bind directly to specific IgE on the enzymes. By destroying the integrity of the tight junctions between epithelial
resident mast cells, triggering mast-cell cells, Der p 1 may gain abnormal access to subepithelial antigen-presenting
activation. cells, resident mast cells, and eosinophils (Fig. 13.4).
Der p 1 is taken up by dendritic Der p 1-specific IgE binds to

Tight junctions seal the barrier The enzyme Der p 1 cleaves mast cell; Der p 1 triggers
cells for antigen presentation and
of airway epithelium occludin in tight junction mast-cell degranulation
TH2 priming
Airway Der p 1
tight
junction
dendritic cell mast cell antigen presentation degranulation

The tendency of proteases to induce IgE production is highlighted by indi-

viduals with Netherton’s disease (Fig. 13.5), which is characterized by high
levels of IgE and multiple allergies. The defect in this disease is the lack of a
protease inhibitor called SPINK5, which is thought to inhibit the proteases
released by bacteria such as Staphylococcus aureus, thus raising the possibil-
ity that protease inhibitors might be novel therapeutic targets in some aller- Allergic Asthma
gic disorders. The cysteine protease papain, derived from the papaya fruit, is
used as a meat tenderizer and causes allergy in workers preparing the
enzyme; such allergies are called occupational allergies. Not all allergens are
enzymes, however; two allergens identified from filarial worms are enzyme
inhibitors, for example. Many protein allergens derived from plants have
been identified and sequenced, but their biochemical functions are currently
obscure. Thus, there seems to be no systematic association between enzy-
matic activity and allergenicity.
Knowledge of the identity of allergenic proteins can be important to public
health and can have economic significance, as illustrated by the following
cautionary tale. Some years ago, the gene for a protein from brazil nuts that
encodes a protein rich in methionine and cysteine was transferred by genetic
engineering into soy beans intended for animal feed. This was done to
improve the nutritional value of soy beans, which are intrinsically poor in
these sulfur-containing amino acids. This experiment led to the discovery
that the protein, 2S albumin, was the major brazil nut allergen. Injection of
extracts of the genetically modified soy beans into the epidermis triggered an
allergic skin response in people with an allergy to brazil nuts. As there could
be no guarantee that the modified soy beans could be kept out of the human
food chain if they were produced on a large scale, development of this genet-
ically modified food was abandoned.
13-3 Class switching to IgE in B lymphocytes is favored by

specific signals. Epidermis
The immune response leading to IgE production is driven by two main

groups of signals. The first consists of the signals that favor the differentiation
of naive T cells to a TH2 phenotype. The second comprises the action of
cytokines and co-stimulatory signals from TH2 cells that stimulate B cells to
switch to the production of IgE antibodies. Dermis
The fate of a naive CD4 T cell responding to a peptide presented by a den-

dritic cell is determined by the cytokines it is exposed to before and during Fig. 13.5 Netherton’s syndrome
this response, and by the intrinsic properties of the antigen, the antigen dose, illustrates the association of proteases
and the route of presentation. Exposure to IL-4, IL-5, IL-9, and IL-13 favors with the development of high levels of
the development of TH2 cells, whereas IFN-g and IL-12 (and its relatives IL-23 IgE and allergy. This 26-year-old man
and IL-27) favor TH1-cell development (see Section 8-19). Immune defenses with Netherton’s syndome, caused by a
against multicellular parasites are found mainly at the sites of parasite deficiency in the protease inhibitor
SPINK5, had persistent erythroderma,
entry—under the skin and in the mucosal-associated lymphoid tissues of the
recurrent infections of the skin and
airways and the gut. Cells of the innate and adaptive immune systems at elsewhere, and multiple food allergies
these sites are specialized to secrete cytokines that promote a TH2-cell associated with high serum IgE levels.
response. Dendritic cells taking up antigen in these tissues migrate to In the top photograph, large
regional lymph nodes, where they tend to drive antigen-specific naive CD4 erythematous plaques covered with
T cells to become effector TH2 cells; TH2 cells themselves secrete IL-4, IL-5, scales and erosions are visible over the
upper trunk. The lower panel shows a
IL-9, and IL-13, thus maintaining an environment in which further differen-
section through the skin of the same
tiation of TH2 cells is favored. patient. Note the psoriasis-like
There is evidence that the mix of cytokines and chemokines in the environment hyperplasia of the epidermis. Neutrophils
are also present in the epidermis. In the
polarizes both dendritic cells and T cells in respect of TH2 differentiation. The
dermis, a perivascular infiltrate containing
chemokines CCL2, CCL7, and CCL13, for example, act on activated monocytes both mononuclear cells and neutrophils
to suppress their production of IL-12, and thereby promote TH2 responses. In is evident. Source: Sprecher, E., et al.:
general, however, it seems that an interaction between antigen-presenting Clin. Exp. Dermatol. 2004, 29:513–517.

dendritic cells and naive T cells in the absence of inflammatory stimuli

induced by bacterial or viral infection tends to polarize T-cell differentiation
toward TH2 cells. In contrast, if antigen is encountered by dendritic cells in
the context of pro-inflammatory signals, then the dendritic cells are stimu-
lated to produce TH1-polarizing cytokines such as IL-12, IL-23, and IL-27.
The cytokines and chemokines produced by TH2 cells both amplify the TH2
response and stimulate the class switching of B cells to IgE production. As we
saw in Chapter 9, IL-4 or IL-13 provide the first signal that switches B cells to
IgE production. Cytokines IL-4 and IL-13 activate the Janus-family tyrosine
kinases Jak1 and Jak3 (see Section 6-23), which ultimately leads to phospho-
rylation of the transcriptional regulator STAT6 in T and B lymphocytes. Mice
lacking functional IL-4, IL-13, or STAT6 have impaired TH2 responses and
impaired IgE switching, demonstrating the key importance of these cytokines
and their signaling pathways. The second signal is a co-stimulatory interac-
tion between CD40 ligand on the T-cell surface and CD40 on the B-cell sur-
face. This interaction is essential for all antibody class switching; patients
with the X-linked hyper IgM syndrome have a deficiency of CD40 ligand and
produce no IgG, IgA, or IgE (see Section 12-10).
The IgE response, once initiated, can be amplified by mast cells and
basophils, which also drive IgE production (Fig. 13.6). These cells express
FceRI, and when they are activated by antigen cross-linking their FceRI-
bound IgE, they express cell-surface CD40 ligand and secrete IL-4. Like TH2
cells, therefore, they can drive class switching and IgE production by B cells.
The interaction between these specialized granulocytes and B cells can occur
at the site of the allergic reaction, because B cells are observed to form ger-
minal centers at inflammatory foci. One goal of therapy for allergies is to
block this amplification process and thus prevent allergic reactions from
becoming self-sustaining.
13-4 Both genetic and environmental factors contribute to the

development of IgE-mediated allergy.
Studies have found that as many as 40% of people in the populations of

Western industrialized countries show an exaggerated tendency to mount IgE
responses to a wide variety of common environmental allergens. This state is
called atopy, has a strong familial basis, and is influenced by several genetic
loci. Atopic individuals have higher total levels of IgE in the circulation and
higher levels of eosinophils than their normal counterparts and are more sus-
ceptible to allergic diseases such as hay fever and asthma. Environment and
genetic variation each account for about 50% of the risk of allergic diseases
such as asthma. Genome-wide linkage scans have uncovered a number of
distinct susceptibility genes for the allergic diseases atopic dermatitis and
Fig. 13.6 Antigen binding to IgE on
mast cells leads to amplification of IgE
production. Left panel: IgE secreted by IgE secreted by plasma cells binds to a Activated mast cells provide contact and secreted
plasma cells binds to the high-affinity IgE high-affinity Fc receptor FcRI on mast cells signals to B cells to stimulate IgE production
receptor on mast cells (illustrated here)
and basophils. Right panel: when the
surface-bound IgE is cross-linked by
antigen, these cells express CD40 ligand
IgE
(CD40L) and secrete IL-4, which in turn
binds to IL-4 receptors (IL-4R) on the CD40
activated B cell, stimulating class
switching by B cells and the production CD40L
of more IgE. These interactions can occur IL-4R
FcRI
in vivo at the site of allergen-triggered
inflammation, for example in bronchus- IL-4
associated lymphoid tissue.

asthma, although there is little overlap between the two, suggesting that the
genetic predisposition differs somewhat (Fig. 13.7). In addition, there are Allergic Asthma
many ethnic differences in the susceptibility genes for the same disease.
Several of the chromosome regions associated with allergy or asthma are also
associated with the inflammatory disease psoriasis and autoimmune dis-
eases, suggesting the presence of genes that are involved in exacerbating
inflammation (see Fig. 13.7).
One candidate susceptibility gene for asthma and atopic dermatitis, at chro-
mosome 11q12–13, encodes the b subunit of the high-affinity IgE receptor
(FceRI). Another region of the genome associated with disease, 5q31–33, con- Atopic Dermatitis
tains at least four types of candidate gene that might be responsible for
increased susceptibility. First, there is a cluster of tightly linked genes for
cytokines that promote TH2 responses by enhancing IgE class switching,
eosinophil survival, and mast-cell proliferation. This cluster includes the
genes for IL-3, IL-4, IL-5, IL-9, IL-13, and granulocyte–macrophage colony-
stimulating factor (GM-CSF). In particular, genetic variation in the promoter
region of the IL-4 gene has been associated with raised IgE levels in atopic
individuals. The variant promoter directs increased expression of a reporter
gene in experimental systems and thus might produce increased IL-4 in vivo.
Atopy has also been associated with a gain-of-function mutation of the a
subunit of the IL-4 receptor that causes increased signaling after ligation of
the receptor.
A second set of genes in this region of chromosome 5 is the TIM family (for
T cell, immunoglobulin domain and mucin domain), which encode T-cell
Fig. 13.7 Susceptibility loci identified by genome screens for dermatitis, suggesting that specific genetic factors are involved
asthma, atopic dermatitis, and other immune disorders. Only in both. There is also some overlap between susceptibility genes
loci with significant linkages are indicated. Clustering of disease- for asthma and those for autoimmune diseases, and between
susceptibility genes is found for the MHC on chromosome 6p21, those for the inflammatory skin disease psoriasis and atopic
and also in several other genomic regions. There is in fact little dermatitis. Adapted from Cookson, W.: Nat. Rev. Immunol. 2004,
overlap between susceptibility genes for asthma and atopic 4:978–988.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y
Asthma Atopic dermatitis Psoriasis Autoimmune diseases

surface proteins. In mice, Tim-3 protein is specifically expressed on TH1 cells

and negatively regulates TH1 responses, whereas Tim-2 (and to a lesser extent
Tim-1) is preferentially expressed in, and negatively regulates, TH2 cells.
Mouse strains that carry different variants of the TIM genes differ both in
their susceptibility to allergic inflammation of the airways and in the produc-
tion of IL-4 and IL-13 by their T cells. Inherited variation in the TIM genes in
humans has been correlated with levels of airway hyperreactivity, the condi-
tion in which a nonspecific irritant causes contraction of bronchial smooth
muscle similar to that seen in asthma. The third candidate susceptibility gene
in this part of the genome encodes p40, one of the two subunits of IL-12. This
cytokine promotes TH1 responses, and genetic variation in p40 expression
that could cause reduced production of IL-12 was found to be associated with
more severe asthma. A fourth candidate susceptibility gene, that encoding
the b-adrenergic receptor, is encoded in this region. Variation in this receptor
might be associated with alteration in smooth muscle responsiveness to
endogenous and pharmacological ligands.
This complexity illustrates a common challenge in identifying the genetic
basis of complex disease traits. Relatively small regions of the genome, iden-
tified as containing genes for altered disease susceptibility, may contain
many good candidates, judging by their known physiological activities.
Identifying the correct gene, or genes, may require studies of several very
large populations of patients and controls. For chromosome 5q31–33, for
example, it is still too early to know how important each of the different poly-
morphisms is in the complex genetics of atopy.
A second type of inherited variation in IgE responses is linked to the HLA
class II region (the human MHC class II region) and affects responses to spe-
cific allergens, rather than a general susceptibility to atopy. IgE production in
response to particular allergens is associated with certain HLA class II alleles,
implying that particular peptide:MHC combinations might favor a strong TH2
response; for example, IgE responses to several ragweed pollen allergens are
associated with haplotypes containing the HLA class II allele DRB1*1501.
Many people are therefore generally predisposed to make TH2 responses and
are specifically predisposed to respond to some allergens more than others.
However, allergies to drugs such as penicillin show no association with HLA
class II or the presence or absence of atopy.
There are also likely to be genes that affect only particular aspects of allergic
disease. In asthma, for example, there is evidence that different genes affect
at least three aspects of the disease—IgE production, the inflammatory
response, and clinical responses to particular treatments. Polymorphism of
the gene on chromosome 20 encoding ADAM33, a metalloproteinase
expressed by bronchial smooth muscle cells and lung fibroblasts, has been
associated with asthma and bronchial hyperreactivity. This is likely to be an
example of genetic variation in the pulmonary inflammatory response and in
the pathological anatomical changes that occur in the airways (airway
remodeling), leading to increased susceptibility to asthma. Some of the best-
characterized genetic polymorphisms of candidate genes associated with
asthma are shown in Fig. 13.8, together with possible ways in which the
genetic variation might affect the type of disease that develops and its
response to drugs.
The prevalence of atopic allergy, and of asthma in particular, is increasing in
economically advanced regions of the world, an observation that is best
explained by environmental factors. The four main candidate environmental
factors are changes in exposure to infectious diseases in early childhood,
environmental pollution, allergen levels, and dietary changes. Pollution has
been blamed for an increase in the incidence of non-allergic cardiopul-
monary diseases such as chronic bronchitis, but an association with allergy

Fig. 13.8 Candidate susceptibility

Gene Nature of polymorphism Possible mechanism of association genes for asthma. *May also affect
response to bronchodilator therapy with
IL-4 Promoter variant Variation in expression of IL-4 b2-adrenergic agonists. †Patients with
alleles associated with reduced enzyme
production failed to show a beneficial
IL-4 receptor chain Structural variant Increased signaling in response to IL-4 response to a drug inhibitor of
5-lipoxygenase. This is an example of a
High-affinity IgE Variation in consequences of IgE
pharmacogenetic effect, in which
Structural variant genetic variation affects the response
receptor chain ligation by antigen
to medication.
Enhanced presentation of particular

MHC class II genes Structural variants
allergen-derived peptides
Enhanced T-cell recognition of certain

T-cell receptor locus Microsatellite markers
allergen-derived peptides
ADAM33 Structural variants Variation in airway remodeling
2-Adrenergic receptor Structural variants Increased bronchial hyperreactivity*
5-Lipoxygenase Promoter variant Variation in leukotriene production†
Promoter and structural

TIM gene family Regulation of the TH1/TH2 balance
variants
has been less easy to demonstrate. There is, however, increasing evidence for
an interaction between allergens and pollution, particularly in genetically
sensitive individuals. Diesel exhaust particles are the best-studied pollutant
in this context; they increase IgE production 20–50-fold when combined with
allergen, with an accompanying shift to TH2 cytokine production. Reactive
oxidant chemicals seem to be generated and individuals less able to deal with
this onslaught may be at increased risk of allergic disease. Genes that might
be governing this susceptibility are GSTP1 and GSTM, the members of the
glutathione-S-transferase superfamily, as people with variant alleles of these
genes showed airway hyperreactivity when exposed to allergen. Indeed,
genetic factors may explain why the epidemiological evidence for an associ-
ation between pollution and allergy remains moderate at best, as it may only
apply to genetically sensitive individuals.
A decrease in exposure to microbial pathogens as a possible cause of the
increase in allergy has also received much attention since the idea was first
mooted in 1989. This is known as the ‘hygiene hypothesis’ (Fig. 13.9). The
proposition is that less hygienic environments, specifically environments
that predispose to infections early in childhood, help to protect against atopy
and asthma. This implies that TH2 responses predominate over TH1
responses by default in early childhood, and that the immune system is
reprogrammed toward more TH1-dominated responses by the cytokine
response to early infections.
There is much evidence in support of this hypothesis, but also some obser-
vations that are difficult to reconcile with it. In favor, there is evidence for a
bias toward TH2 responses in newborn infants, in whom dendritic cells pro-
duce less IL-12 and T cells produce less IFN-g than in older children and
adults. There is also evidence that exposure to childhood infections, with the
important exception of some respiratory infections that we consider below,
helps to protect against the development of atopic allergic disease. Younger

children from families with three or more older siblings, and children aged
Genetic
susceptibility
Environment less than 6 months who are exposed to other children in daycare facilities—
situations linked to a greater exposure to infections—are somewhat
protected against atopy and asthma. Furthermore, early colonization of the
gut by commensal bacteria such as lactobacilli and bifidobacteria, or infec-
tion by gut pathogens such as Toxoplasma gondii (which stimulates a TH1
response) or Helicobacter pylori are associated with a reduced prevalence of
allergic disease.
A history of infection with measles or hepatitis A virus, or a positive tuber-
culin skin test (suggesting previous exposure and an immune response to
Mycobacterium tuberculosis), also seem to have a negative association with
atopy. The human counterpart of the murine Tim-1 protein, which might be
important in determining airway hyperreactivity and the production of IL-4
and IL-13 by T cells, is the cellular receptor for hepatitis A virus. The infection
of T cells by hepatitis A virus could thus directly influence their differentiation
High Hygienic Low Unhygienic and cytokine production, limiting the development of TH2 responses.
In contrast to these negative associations between childhood infection and
Atopic Non-atopic the development of atopy and asthma, there is evidence that children who
have had attacks of bronchiolitis associated with respiratory syncytial virus
Conjunctivitis Hepatitis A virus (RSV) infection are more prone to developing asthma later on. This effect of
Rhinitis Primary tuberculosis RSV may depend on the age at first infection. Infection of neonatal mice with
Eczema Measles
Asthma Early bowel RSV was followed by a decreased IFN-g response compared with mice chal-
colonization with lenged at 4 or 8 weeks of age. When these mice were rechallenged at 12 weeks
commensal bacteria of age with RSV infection, animals that had been primarily infected as
neonates suffered from more severe lung inflammation than animals infected
at 4 or 8 weeks of age (Fig. 13.10). Similarly, children hospitalized with RSV
Fig. 13.9 Genes, the environment, and
infection have a skewed ratio of cytokine production away from IFN-g toward
atopic allergic diseases. Both inherited
and environmental factors are important IL-4, the cytokine that induces TH2 responses. All these findings suggest that
determinants of the likelihood of an infection that evokes a TH1 immune response early in life might reduce the
developing atopic allergic disease. Some likelihood of TH2 responses later in life, and vice versa.
known genes that influence the
development of asthma are shown in The biggest ‘fly in the ointment’ for the hygiene theory, however, is the strong
Fig. 13.8. The postulate of the ‘hygiene negative correlation between infection by helminths (such as hookworm and
hypothesis’ is that exposure to some schistosomes) and the development of allergy. A study in Venezuela showed
infectious agents in childhood drives the that children treated for a prolonged period with antihelminthic agents had a
immune system toward a general state higher prevalence of atopy compared with untreated and heavily parasitized
of TH1 responsiveness and non-atopy.
children. As we have seen, however, helminths are strong drivers of TH2
In contrast, children with genetic
susceptibility to atopy and who live in
responses, and it is difficult to reconcile this with the idea that the polariza-
an environment with low exposure to tion of T-cell responses toward TH1 is a general mechanism by which infec-
infectious disease tend to mount TH2 tion protects against atopy.
responses, which naturally predominate
in the neonatal period of life. It is these These observations have led to a modification of the hygiene hypothesis
children who are thought to be most known as the counter-regulation hypothesis. This proposes that all types of
susceptible to the development of atopic infection might protect against the development of atopy by driving the pro-
allergic disease. duction of cytokines such as IL-10 and transforming growth factor (TGF)-b,
which downregulate both TH1 and TH2 responses (see Section 8-19). In
hygienic environments, children suffer fewer infections, resulting in a
reduced production of these cytokines. Neither the molecular pathways
induced by microbial exposure nor the tolerance-inducing responses in the
host have yet been identified, but there are a variety of microbial products
with immunoregulatory potential. For instance, exposure of dendritic cells to
various Toll-like receptor (TLR) ligands, such as bacterial lipopolysaccharide
(the ligand for TLR-4), CpG DNA (the ligand for TLR-9), or pro-inflammatory
mediators such as IFN-g can stimulate the production of indoleamine
2,3-dioxygenase (IDO), an enzyme that degrades the essential amino acid
tryptophan. Dendritic cells expressing IDO can suppress TH2-driven inflam-
mation and promote the differentiation of regulatory T cells, providing both
immediate and long-term protective effects against allergy. Genetic factors

IFN- production (relative level)
Percentage of original weight

Infect mice intranasally with 10 Reinfect mice with 100
Eosinophils ++
RSV up to 7 days postnatally RSV as adult
Neutrophils ++
1 90
IFN- +
0.1 80 IL-4 ++
0 7 14 21 0 7
Days after infection Days after infection
IFN- production (relative level)
Percentage of original weight

Infect mice intranasally with 10 100
Eosinophils –
RSV at 4 or 8 weeks postnatally
Neutrophils +
1 90
IFN- ++
0.1 80 IL-4 +
–
0 7 14 21 0 7
Days after infection Days after infection
may also have a bearing on this type of regulation because newborn infants Fig. 13.10 Response to infection and
with a genetic predisposition to allergy have been found to have impaired rechallenge of mice with respiratory
syncytial virus (RSV) according to the
regulatory T-cell function.
age of primary infection. Mice respond
to infection with RSV in different ways
13-5 Regulatory T cells can control allergic responses. according to the age of primary infection.
The graphs on the left show the IFN-g
response after either neonatal infection
Peripheral blood mononuclear cells (PBMCs) from atopic individuals have a (upper panel) or infection at 4 or 8 weeks
tendency to secrete TH2 cytokines after nonspecific stimulation via the T-cell of age (lower panel). Mice infected
receptor, whereas those from non-atopic individuals do not. This has led to neonatally fail to produce IFN-g. The right-
the suggestion that regulatory mechanisms have an important role in hand panels show the consequences of
preventing IgE responses to allergens. Regulatory T cells, in particular, are reinfection with RSV of the two cohorts of
mice when adult. The mice that had the
receiving considerable attention with regard to all types of immunologically
primary infection as neonates show
mediated disease. The different types of regulatory T cells (see Section 8-17) weight loss and a severe inflammatory
may all have a role in modulating allergy. Natural regulatory T cells (CD4 response to reinfection, with infiltration of
CD25 Treg cells) from atopic individuals are defective in suppressing TH2 the lungs by eosinophils and neutrophils,
cytokine production compared with those from non-atopic individuals, and accompanied by production of the TH2
this defect is even more pronounced during the pollen season. More evidence cytokine IL-4. In contrast, mice that had
comes from mice deficient in the transcription factor FoxP3, the master the primary infection at 4 or 8 weeks of
age show no weight loss, mild neutrophil
switch for producing CD4 CD25 Treg cells, which develop manifestations of
infiltration, and production of the TH1
allergy including eosinophilia, hyper IgE, and allergic airway inflammation, cytokine IFN-g.
suggesting that these result from the absence of regulatory T cells. This syn-
drome could be partially reversed by a concomitant deficiency in STAT6,
which independently prevents the development of the TH2 response (see
Section 13-3).
Regulatory T cells might also be induced by IDO secreted by a variety of cell
types (see Section 13-4). Dendritic cells secrete IDO on activation through
stimulation of the receptor TLR-9 by ligands containing unmethylated CpG
DNA. IDO secretion from resident lung cells stimulated in this way has been
shown to ameliorate experimental asthma in mice.
Summary.
Allergic reactions are the result of the production of specific IgE antibody
against common, innocuous antigens. Allergens are small antigens that com-
monly provoke an IgE antibody response. Such antigens normally enter the
body at very low doses by diffusion across mucosal surfaces and therefore
trigger a TH2 response. The differentiation of naive allergen-specific T cells

into TH2 cells is also favored by cytokines such as IL-4 and IL-13. Allergen-
specific TH2 cells producing IL-4 and IL-13 drive allergen-specific B cells to
produce IgE. The specific IgE produced in response to the allergen binds to
the high-affinity receptor for IgE on mast cells, basophils, and activated
eosinophils. IgE production can be amplified by these cells because, upon
activation, they produce IL-4 and CD40 ligand. The tendency to IgE overpro-
duction is influenced by genetic and environmental factors. Once IgE is pro-
duced in response to an allergen, reexposure to the allergen triggers an
allergic response. Immunoregulation is critical in the control of allergic dis-
ease through a variety of mechanisms, including regulatory T cells. We
describe the mechanism and pathology of the allergic responses themselves
in the next part of the chapter.
Effector mechanisms in allergic reactions.
Allergic reactions are triggered when allergens cross-link preformed IgE

bound to the high-affinity receptor FceRI on mast cells. Mast cells line the
body surfaces and serve to alert the immune system to local infection. Once
activated, they induce inflammatory reactions by secreting chemical media-
tors stored in preformed granules and by synthesizing prostaglandins,
leukotrienes, and cytokines after activation occurs. In allergy, they provoke
very unpleasant reactions to innocuous antigens that are not associated with
invading pathogens that need to be expelled. The consequences of IgE-medi-
ated mast-cell activation depend on the dose of antigen and its route of entry;
symptoms range from the irritating sniffles of hay fever when pollen is
inhaled, to the life-threatening circulatory collapse that occurs in systemic
anaphylaxis (Fig. 13.11). The immediate allergic reaction caused by mast-cell
degranulation is followed by a more sustained inflammation, known as the
late-phase response. This late response involves the recruitment of other
Fig. 13.11 Mast-cell activation has

different effects on different tissues. Mast-cell activation
and granule release
Gastrointestinal tract Airways Blood vessels
Increased fluid secretion, Decreased diameter, Increased blood flow,

increased peristalsis increased mucus secretion increased permeability
Congestion and blockage of Increased fluid in tissues

airways (wheezing, coughing, causing increased flow of
Expulsion of gastrointestinal
phlegm) lymph to lymph nodes,
tract contents
increased cells and protein
(diarrhea, vomiting)
Swelling and mucus secretion in tissues, increased effector
in nasal passages response in tissues

Effector mechanisms in allergic reactions 567
effector cells, notably TH2 lymphocytes, eosinophils, and basophils, which

contribute significantly to the immunopathology of an allergic response.
13-6 Most IgE is cell-bound and engages effector mechanisms of the

immune system by different pathways from other antibody isotypes.
Antibodies engage effector cells such as mast cells by binding to receptors

specific for the Fc constant regions. Most antibodies engage Fc receptors only
after the antibody variable region has bound specific antigen, forming an
immune complex of antigen and antibody. IgE is an exception, because it is
captured by the high-affinity Fce receptor in the absence of bound antigen.
This means that, unlike other antibodies, which are found mainly in body
fluids, IgE is mostly found fixed in the tissues on mast cells that bear this
receptor as well as on circulating basophils and activated eosinophils. The
ligation of the cell-bound IgE antibody by specific antigen triggers the activa-
tion of these cells at the sites of antigen entry into the tissues. The release of
inflammatory lipid mediators, cytokines, and chemokines at sites of IgE-
triggered reactions recruits eosinophils and basophils to augment the type I
hypersensitivity response. It also recruits other effector cells, including
T lymphocytes, that can mediate a local type IV hypersensitivity response.
There are two types of IgE-binding Fc receptor. The first, FceRI, is a high-
affinity receptor of the immunoglobulin superfamily that binds IgE on mast
cells, basophils, and activated eosinophils (see Section 9-24). When the cell-
bound IgE is cross-linked by specific antigen, FceRI transduces an activating
signal. High levels of IgE, such as those that exist in people with allergic dis-
eases or parasite infections, can result in a marked increase in FceRI on the
surface of mast cells, an enhanced sensitivity of such cells to activation by low
concentrations of specific antigen, and a markedly increased IgE-dependent
release of chemical mediators and cytokines.
The second IgE receptor, FceRII, usually known as CD23, is a C-type lectin
and is structurally unrelated to FceRI; it binds IgE with low affinity. CD23 is
present on many cell types, including B cells, activated T cells, monocytes,
eosinophils, platelets, follicular dendritic cells, and some thymic epithelial
cells. This receptor was thought to be crucial for the regulation of IgE levels,
but mouse strains in which the CD23 gene has been inactivated still develop
relatively normal polyclonal IgE responses. Nevertheless, CD23 does seem to
be involved in enhancing IgE antibody levels in some situations. Responses
against a specific antigen are known to be increased in the presence of the
same antigen complexed with IgE, but such enhancement fails to occur in
mice that lack the CD23 gene. This has been interpreted to indicate that
CD23 on antigen-presenting cells has a role in the capture of antigen com-
plexed with IgG.
13-7 Mast cells reside in tissues and orchestrate allergic reactions.
Mast cells were described by Ehrlich in the mesentery of rabbits and named
Mastzellen (‘fattened cells’). Like basophils, mast cells contain granules rich in
acidic proteoglycans that take up basic dyes. Mast cells are derived from
hematopoietic stem cells but mature locally, often residing near surfaces
exposed to pathogens and allergens. The major factors for mast-cell growth
and development include stem-cell factor (the ligand for the receptor tyrosine
kinase Kit), IL-3, and TH2-associated cytokines such as IL-4 and IL-9. Mice
with defective Kit lack differentiated mast cells, and although they produce
IgE they cannot make IgE-mediated inflammatory responses. This shows that
such responses depend almost exclusively on mast cells. Mast-cell activation
depends on the activation of phosphatidylinositol 3-kinase (PI 3-kinase) in

mast cells by Kit, and pharmacological inactivation of the p110d isoform of PI

3-kinase protects mice against allergic responses. p110d is thus a potential
target for therapy in allergy and other mast-cell related pathologies.
Mast cells express FceRI constitutively on their surface and are activated
when antigens cross-link IgE bound to these receptors (see Fig. 9.35).
Different levels of stimulation result in varied responses; for instance, low
levels of allergen resulting in low receptor occupancy provide a strong
signal leading to allergic inflammation. Conversely, higher levels of antigen
occupancy can induce the production of immunoregulatory cytokines such
as IL-10. Thus, mast cells display various responses depending upon the
signals they receive.
Mast cell degranulation begins within seconds, releasing an array of pre-
formed and newly generated inflammatory mediators (Fig. 13.12). Among
these are histamine—a short-lived vasoactive amine that causes an immedi-
ate increase in local blood flow and vessel permeability—and enzymes such
as mast-cell chymase, tryptase, and serine esterases. These enzymes can
in turn activate matrix metalloproteinases, which break down tissue matrix
proteins, causing tissue destruction. Large amounts of the cytokine tumor
necrosis factor (TNF)-a are also released by mast cells after activation. Some
comes from stores in mast-cell granules; some is newly synthesized by the
activated mast cells. TNF-a activates endothelial cells, causing an increased
expression of adhesion molecules, which promotes the influx of inflamma-
tory leukocytes and lymphocytes into tissues (see Chapter 2).
On activation, mast cells also synthesize and release chemokines, lipid medi-
ators such as prostaglandins, leukotrienes, and platelet-activating factor
(PAF), and cytokines such as IL-4 and IL-13, which perpetuate the TH2
response. These mediators contribute to both the acute and the chronic
inflammatory responses. The lipid mediators, in particular, act rapidly to
cause smooth muscle contraction, increased vascular permeability, and the
Fig. 13.12 Molecules released by mast

cells on activation. Mast cells produce a Class of product Examples Biological effects
wide variety of biologically active proteins
and other chemical mediators. The Tryptase, chymase,
enzymes and toxic mediators listed in the Enzyme cathepsin G, Remodel connective tissue matrix
first two rows are released from the carboxypeptidase
preformed granules. The cytokines,
chemokines, and lipid mediators are Toxic to parasites
Toxic mediator Histamine, heparin Increase vascular permeability
synthesized after activation. Cause smooth muscle contraction
IL-4, IL-13 Stimulate and amplify TH2-cell response
IL-3, IL-5, GM-CSF Promote eosinophil production and activation

Cytokine
Promotes inflammation, stimulates cytokine

TNF- (some stored
production by many cell types,
preformed in granules)
activates endothelium
Chemokine Attracts monocytes, macrophages,

CCL3
and neutrophils
Cause smooth muscle contraction

Prostaglandins D2, E2
Increase vascular permeability
Leukotrienes B4, C4
Stimulate mucus secretion
Lipid mediator
Attracts leukocytes
Platelet-activating factor Amplifies production of lipid mediators
Activates neutrophils, eosinophils, and platelets

secretion of mucus, and also induce the influx and activation of leukocytes,
which contribute to the late phase of the allergic response. The lipid media-
tors derive from membrane phospholipids, which are cleaved to release the
precursor molecule arachidonic acid. This molecule can be modified via two
pathways to give rise to prostaglandins, thromboxanes, and leukotrienes.
Prostaglandin D2 is the major prostaglandin produced by mast cells and
recruits TH2 cells, eosinophils, and basophils, all of which express its receptor
protein (PTGDR). Prostaglandin D2 is critical to the development of allergic
diseases such as asthma, and polymorphisms in PTGDR have been linked to
an increased risk of developing asthma. The leukotrienes, especially B4 and
C4, are also important in sustaining inflammatory responses in tissues. Many
anti-inflammatory drugs are inhibitors of arachidonic acid metabolism.
Aspirin, for example, is an inhibitor of the enzyme cyclooxygenase and blocks
the production of prostaglandins.
IgE-mediated activation of mast cells thus orchestrates an important inflam-
matory cascade that is amplified by the recruitment of several cell types
including eosinophils, basophils, TH2 lymphocytes, B cells, and dendritic cells.
The physiological importance of this reaction is as a defense against parasite
infection (see Section 9-25). In allergy, however, the acute and chronic inflam-
matory reactions triggered by mast-cell activation have important pathophys-
iological consequences, as seen in the diseases associated with allergic
responses to environmental antigens. Increasingly, mast cells are also consid-
ered to have a role in immunoregulation as well as being drivers of pro-inflam-
matory reactions. High concentrations of allergen, leading to high occupancy
of the receptor IgE, produce immunoregulatory rather than inflammatory
consequences. Mast cells can also participate in autoimmune reactions.
13-8 Eosinophils are normally under tight control to prevent inappropriate

toxic responses.
Eosinophils are granulocytic leukocytes that originate in bone marrow. They

are so called because their granules, which contain arginine-rich basic
proteins, are colored bright orange by the acidic stain eosin. Only very small
numbers of these cells are normally present in the circulation; most
eosinophils are found in tissues, especially in the connective tissue immedi-
ately underneath respiratory, gut, and urogenital epithelium, implying a
likely role for these cells in defense against invading organisms. Eosinophils
have two kinds of effector functions. First, on activation they release highly
toxic granule proteins and free radicals, which can kill microorganisms and
parasites but also cause significant tissue damage in allergic reactions.
Second, activation induces the synthesis of chemical mediators such as
prostaglandins, leukotrienes, and cytokines. These amplify the inflammatory
response by activating epithelial cells and recruiting and activating more
eosinophils and leukocytes (Fig. 13.13). Eosinophils also secrete a number of
proteins involved in airway tissue remodeling.
The activation and degranulation of eosinophils is strictly regulated, as their
inappropriate activation would be harmful to the host. The first level of con-
trol acts on the production of eosinophils by the bone marrow. Few
eosinophils are produced in the absence of infection or other immune stimu-
lation. But when TH2 cells are activated, cytokines such as IL-5 are released
that increase the production of eosinophils in the bone marrow and their
release into the circulation. However, transgenic animals overexpressing IL-5
have increased numbers of eosinophils (eosinophilia) in the circulation but
not in their tissues, indicating that the migration of eosinophils from the cir-
culation into tissues is regulated separately, by a second set of controls. The
key molecules in this case are CC chemokines. Most of these cause chemotaxis

Fig. 13.13 Eosinophils secrete a range

of highly toxic granule proteins and Class of product Examples Biological effects
other inflammatory mediators.
Eosinophil peroxidase Toxic to targets by catalyzing halogenation
Triggers histamine release from mast cells
Enzyme Eosinophil collagenase Remodels connective tissue matrix
Matrix metalloproteinase-9 Matrix protein degradation
Major basic protein Toxic to parasites and mammalian cells

Triggers histamine release from mast cells
Toxic protein Eosinophil cationic protein Toxic to parasites

Neurotoxin
Eosinophil-derived neurotoxin Neurotoxin
IL-3, IL-5, GM-CSF Amplify eosinophil production by bone marrow

Cause eosinophil activation
Cytokine
TGF-, TGF- Epithelial proliferation,
myofibroblast formation
Chemokine CXCL8 (IL-8) Promotes influx of leukocytes
Cause smooth muscle contraction

Leukotrienes C4, D4, E4 Increase vascular permeability
Increase mucus secretion
Lipid mediator
Attracts leukocytes
Platelet-activating factor Amplifies production of lipid mediators
Activates neutrophils, eosinophils, and platelets
of several types of leukocytes, but three are particularly important in attract-

ing and activating eosinophils, and have been named the eotaxins: CCL11
(eotaxin 1), CCL24 (eotaxin 2), and CCL26 (eotaxin 3).
The eotaxin receptor on eosinophils, CCR3, is quite promiscuous and binds
other CC chemokines, including CCL7, CCL13, and CCL5, which also induce
eosinophil chemotaxis and activation. Identical or similar chemokines stim-
ulate mast cells and basophils. For example, eotaxins attract basophils and
cause their degranulation, and CCL2, which binds to CCR2, similarly acti-
vates mast cells in both the presence and the absence of antigen. CCL2 can
also promote the differentiation of naive T cells to TH2 cells; TH2 cells also
carry the receptor CCR3 and migrate toward eotaxins. It is striking that these
interactions between different chemokines and their receptors show a high
degree of overlap and redundancy; we do not understand the significance of
this complexity. However, these findings show that families of chemokines, as
well as cytokines, can coordinate certain kinds of immune response.
A third set of controls regulates the state of eosinophil activation. In their
nonactivated state, eosinophils do not express high-affinity IgE receptors and
have a high threshold for release of their granule contents. After activation by
cytokines and chemokines this threshold drops, FceRI is expressed, and the
number of Fcg receptors and complement receptors on the cell surface also
increases. The eosinophil is now primed to carry out its effector activity—
degranulation in response to antigen that cross-links specific IgE bound to
FceRI on the eosinophil surface.

13-9 Eosinophils and basophils cause inflammation and tissue damage in

allergic reactions.
What were later to be defined as eosinophils were observed in the 19th cen-
tury in the first pathological description of fatal status asthmaticus, but the Fig. 13.14 Allergic reactions can be
precise role of these cells in allergic disease is still unclear. In a local allergic divided into an immediate response
and a late-phase response. Left panel:
reaction, mast-cell degranulation and TH2 activation cause eosinophils to the response to an inhaled antigen can be
accumulate in large numbers and to become activated. Eosinophils can also divided into early and late responses. An
present antigens to T cells and secrete TH2 cytokines. Eosinophils seem to asthmatic response in the lungs with
promote the apoptosis of TH1 cells, and their promotion of TH2-cell expan- narrowing of the airways caused by the
sion may be partly due to a relative reduction in TH1-cell numbers. Their constriction of bronchial smooth muscle
continued presence is characteristic of chronic allergic inflammation and can be measured as a fall in the peak
expiratory flow rate (PEFR). The
they are thought to be major contributors to tissue damage.
immediate response peaks within minutes
Basophils are also present at the site of an inflammatory reaction and growth after antigen inhalation and then
factors for basophils are very similar to those for eosinophils; they include subsides. Six to eight hours after antigen
challenge, there is a late-phase response
IL-3, IL-5, and GM-CSF. There is evidence for reciprocal control of the matu- that also results in a fall in the PEFR. The
ration of the stem-cell population into basophils or eosinophils. For example, immediate response is caused by the
TGF-b in the presence of IL-3 suppresses eosinophil differentiation and direct effects on blood vessels and
enhances that of basophils. Basophils are normally present in very low num- smooth muscle of rapidly metabolized
bers in the circulation and seem to have a similar role to that of eosinophils mediators such as histamine and lipid
in defense against pathogens. Like eosinophils, they are recruited to the sites mediators released by mast cells. The
late-phase response is caused by the
of allergic reactions. Basophils express FceRI on the cell surface and, on acti-
effects of an influx of inflammatory
vation by cytokines or antigen, they release histamine from the basophilic leukocytes attracted by chemokines and
granules after which they are named; they also produce IL-4 and IL-13. other mediators released by mast cells
during and after the immediate response.
Eosinophils, mast cells, and basophils can interact with each other.
Right panel: a wheal-and-flare allergic
Eosinophil degranulation releases major basic protein, which in turn causes reaction develops within a minute or two
degranulation of mast cells and basophils. This effect is augmented by any of of superficial injection of antigen into the
the cytokines that affect eosinophil and basophil growth, differentiation, and epidermis and lasts for up to 30 minutes.
activation, such as IL-3, IL-5, and GM-CSF. The more widespread edematous
response characteristic of the late phase
develops approximately 6 hours later and
13-10 Allergic reactions can be divided into immediate and can persist for some hours. The
late-phase responses. photograph shows an intradermal skin
challenge with allergen showing a
15-minute wheal and flare (early-phase)
The inflammatory response after IgE-mediated mast-cell activation occurs as
reaction (left) and a 6-hour late-phase
an immediate reaction, starting within seconds, and a late reaction, which reaction (right). The allergen was grass
takes up to 8–12 hours to develop. These reactions can be distinguished clin- pollen extract. Photograph courtesy of
ically (Fig. 13.14). The immediate reaction is due to the activity of histamine, S.R. Durham.
Immediate Late phase

PFER
(liters/s) 400
Antigen
300 challenge
Immediate Late phase

200
100
0
0 30 60 6 8 10 12 Time
minutes hours

prostaglandins, and other preformed or rapidly synthesized mediators that

cause a rapid increase in vascular permeability and the contraction of
smooth muscle. The late-phase reaction, which occurs in about 50% of
patients with an early-phase response, is caused by the induced synthesis and
release of mediators including prostaglandins, leukotrienes, chemokines,
and cytokines such as IL-5 and IL-13 from the activated mast cells and
basophils (see Fig. 13.12). These recruit other leukocytes, including
eosinophils and TH2 lymphocytes, to the site of inflammation. Late-phase
reactions are associated with a second phase of smooth muscle contraction
mediated by T cells, with sustained edema, and with tissue remodeling such
as smooth muscle hypertrophy (an increase in size due to cell growth) and
hyperplasia (an increase in the number of cells).
The late-phase reaction and its long-term sequel, chronic allergic inflam-
mation, which is in essence a type IV hypersensitivity reaction (see Fig.
Allergic Asthma 13.1), contribute to much serious long-term illness, such as chronic asthma.
The chronic phase of asthma is characterized by the presence of both TH1
cytokines (such as IFN-g) and TH2 cytokines, though the latter seem to pre-
dominate.
13-11 The clinical effects of allergic reactions vary according to the site of
mast-cell activation.
When reexposure to allergen triggers an allergic reaction, the effects are

focused on the site at which mast-cell degranulation occurs. In the immedi-
ate response, the preformed mediators released are short-lived, and their
potent effects on blood vessels and smooth muscles are therefore confined to
the vicinity of the activated mast cell. The more sustained effects of the
late-phase response are also focused on the site of initial allergen-triggered
activation, and the particular anatomy of this site may determine how read-
ily the inflammation can be resolved. Thus, the clinical syndrome produced
by an allergic reaction depends critically on three variables: the amount of
allergen-specific IgE present; the route by which the allergen is introduced;
and the dose of allergen (Fig. 13.15).
If an allergen is introduced directly into the bloodstream or is rapidly
absorbed from the gut, the connective tissue mast cells associated with all
blood vessels can become activated. This activation causes a very dangerous
syndrome called systemic anaphylaxis. Disseminated mast-cell activation
has a variety of potentially fatal effects: the widespread increase in vascular
permeability leads to a catastrophic loss of blood pressure; airways constrict,
Acute Systematic causing difficulty in breathing; and swelling of the epiglottis can cause suffo-
Anaphylaxis cation. This potentially fatal syndrome is called anaphylactic shock. It can
occur if drugs are administered to people who have IgE specific for that drug,
or after an insect bite in individuals allergic to insect venom. Some foods, for
example peanuts or brazil nuts, can cause systemic anaphylaxis in suscepti-
ble individuals. This syndrome can be rapidly fatal but can usually be con-
trolled by the immediate injection of epinephrine, which relaxes the smooth
muscle and inhibits the cardiovascular effects of anaphylaxis.
The most frequent allergic reactions to drugs occur with penicillin and its
relatives. In people with IgE antibodies against penicillin, administration of
the drug by injection can cause anaphylaxis and even death. Great care
should be taken to avoid giving a drug to patients with a past history of
allergy to that drug or one that is closely related structurally. Penicillin acts as
a hapten (see Appendix I, Section A-1); it is a small molecule with a highly
reactive b-lactam ring that is crucial for its antibacterial activity. This ring
reacts with amino groups on host proteins to form covalent conjugates.
When penicillin is ingested or injected, it forms conjugates with self proteins,

and the penicillin-modified self peptides provoke a TH2 response in some

individuals. These TH2 cells then activate penicillin-binding B cells to pro-
duce IgE antibody against the penicillin hapten. Thus, penicillin acts both as
the B-cell antigen and, by modifying self peptides, as the T-cell antigen.
When penicillin is injected intravenously into an allergic individual, the
penicillin-modified proteins can cross-link IgE molecules on tissue mast
cells and circulating basophils and thus cause anaphylaxis.
Fig. 13.15 The dose and route of allergen administration of allergen activates only local connective tissue mast cells,
determine the type of IgE-mediated allergic reaction that leading to a local inflammatory reaction. Inhaled allergen,
results. There are two main anatomical distributions of mast penetrating across epithelia, activates mainly mucosal mast cells,
cells: those associated with vascularized connective tissues, causing smooth muscle contraction in the lower airways; this
called connective tissue mast cells, and those found in leads to bronchoconstriction and difficulty in expelling inhaled air.
submucosal layers of the gut and respiratory tract, called Mucosal mast-cell activation also increases the local secretion of
mucosal mast cells. In an allergic individual, all of these are mucus by epithelial cells and causes irritation. Similarly, ingested
loaded with IgE directed against specific allergens. The overall allergen penetrates across gut epithelia, causing vomiting due to
response to an allergen then depends on which mast cells are intestinal smooth muscle contraction and diarrhea due to outflow
activated. Allergen in the bloodstream activates connective tissue of fluid across the gut epithelium. Food allergens can also be
mast cells throughout the body, resulting in the systemic release disseminated in the bloodstream, causing urticaria (hives) when
of histamine and other mediators. Subcutaneous administration the allergen reaches the skin.
Connective tissue mast cells Mucosal mast cells
Route of allergen entry
Intravenous: high dose Subcutaneous: low dose Inhalation: low dose Ingestion
IgE-coated mast cells
blood capillary bronchial smooth muscle intestinal smooth muscle
Mast-cell activation
respiratory tract intestinal epithelium
Allergic rhinitis (upper airway), Contraction of intestinal smooth

General release of histamine, Local release of histamine, caused by increased mucus muscle induces vomiting. Outflow of
causes systemic anaphylaxis causes wheal-and-flare reaction production and nasal irritation. fluid into gut causes diarrhea.
Asthma (lower airway) due to Antigen diffuses into blood vessels
contraction of bronchial smooth muscle and is widely disseminated causing
and increased mucus secretion urticaria (hives) or anaphylaxis.

13-12 Allergen inhalation is associated with the development of rhinitis

and asthma.
Inhalation is the most common route of allergen entry. Many people have
mild allergies to inhaled antigens, manifesting as sneezing and a runny nose.
This is called allergic rhinitis and results from the activation of mucosal mast
cells beneath the nasal epithelium by allergens such as pollens that release
their protein contents, which can then diffuse across the mucous membranes
of the nasal passages. Allergic rhinitis is characterized by intense itching and
Allergic Asthma sneezing, local edema leading to blocked nasal passages, a nasal discharge,
which is typically rich in eosinophils, and irritation of the nose as a result of
histamine release. A similar reaction to airborne allergens deposited on the
conjunctiva of the eye is called allergic conjunctivitis. Allergic rhinitis and
conjunctivitis are commonly caused by environmental allergens that are
present only during certain seasons of the year. For example, hay fever
(known clinically as seasonal rhinoconjunctivitis) is caused by a variety of
allergens, including certain grass and tree pollens. Summer and autumnal
symptoms may be caused by weed pollen, such as that of ragweed or the
spores of fungi such as Alternaria. Perennial allergens such as cat dander and
house dust mites can be a cause of year-round misery.
A more serious syndrome is allergic asthma, which is triggered by allergen-
induced activation of submucosal mast cells in the lower airways (Fig. 13.16).
Fig. 13.16 The acute response in
This leads within seconds to bronchial constriction and an increased secre-
allergic asthma leads to TH2-mediated tion of fluid and mucus, making breathing more difficult by trapping inhaled
chronic inflammation of the airways. In air in the lungs. Patients with allergic asthma usually need treatment, and
sensitized individuals, cross-linking of asthmatic attacks can be life threatening. The same allergens that cause aller-
specific IgE on the surface of mast cells gic rhinitis and conjunctivitis commonly cause asthma attacks. For example,
by an inhaled allergen triggers them to respiratory arrest caused by severe attacks of asthma in the summer or
secrete inflammatory mediators, causing
autumn has been associated with the inhalation of spores of Alternaria. An
increased vascular permeability,
contraction of bronchial smooth muscle, important feature of asthma is chronic inflammation of the airways, which is
and increased secretion of mucus. There characterized by the continued presence of increased numbers of TH2 lym-
is an influx of inflammatory cells, phocytes, eosinophils, neutrophils, and other leukocytes (Fig. 13.17). These
including eosinophils and TH2 cells, from cells conspire to cause airway remodeling—a thickening of the airway walls
the blood. Activated mast cells and TH2 due to hyperplasia and hypertrophy of the smooth muscle layer and mucous
cells secrete cytokines that augment glands, with the eventual development of fibrosis. This remodeling leads to a
eosinophil activation and degranulation,
which causes further tissue injury and the
permanent narrowing of the airways accompanied by increased secretion of
entry of more inflammatory cells. The mucus, and is responsible for many of the clinical manifestations of asthma.
result is chronic inflammation, which can In chronic asthmatics, a general hyperresponsiveness or hyperreactivity of
cause irreversible damage to the airways. the airways to non-immunological stimuli also often develops.
Acute responses Chronic response
Inflammatory mediators cause increased Chronic response caused by cytokines

mucus secretion and smooth muscle Recruitment of cells from the circulation and eosinophil products
contraction leading to airway obstruction
eosinophil granule
airway cytokines proteins
TH2
T H2
blood
vessel

The direct action of TH2 cytokines such as IL-9 and IL-13 on airway epithelial
cells may have a dominant role in one of the major features of the disease, the
induction of goblet-cell metaplasia, which is the increased differentiation of
epithelial cells as goblet cells, and the consequent increase in secretion of
mucus. Lung epithelial cells can also produce the chemokine receptor CCR3
and at least two of the ligands for this receptor—CCL5 and CCL11. These
chemokines enhance the TH2 response by attracting more TH2 cells and
eosinophils to the damaged lungs. The direct effects of TH2 cytokines and
chemokines on airway smooth muscle cells and lung fibroblasts cause the a
apoptosis of epithelial cells and airway remodeling, induced in part by the
production of TGF-b, which has numerous effects on the epithelium, ranging
from inducing apoptosis to stimulating cell proliferation.
A disease resembling human asthma develops in mice that lack the tran-
scription factor T-bet, which is required for TH1 differentiation (see Section
8-19), and in which T-cell responses are thought to be skewed to TH2. These
mice have increased levels of the TH2 cytokines IL-4, IL-5, and IL-13 and
develop airway inflammation involving lymphocytes and eosinophils (Fig.
13.18). They also develop nonspecific airway hyperreactivity to non-
immunological stimuli, similar to that seen in human asthma. These changes b
occur in the absence of any exogenous inflammatory stimulus and show that,
in extreme circumstances, a genetic imbalance toward TH2 responses can
Fig. 13.17 Morphological evidence of
cause allergic disease. The involvement of eosinophils in asthma seems chronic inflammation in the airways of
somewhat different in humans and in mice. In human asthma patients, the an asthmatic patient. Panel a shows a
number of eosinophils is directly associated with the severity of asthma. In section through a bronchus of a patient
mice deficient in eosinophils, however, the only consistent finding relevant to who died of asthma; there is almost total
asthma pathophysiology is a reduction in airway remodeling without a occlusion of the airway by a mucous
plug. In panel b, a close-up view of the
reduction in airway hyperreactivity.
bronchial wall shows injury to the
epithelium lining the bronchus,
accompanied by a dense inflammatory
infiltrate that includes eosinophils,
T-bet+/+ T-bet–/– neutrophils, and lymphocytes.
Photographs courtesy of T. Krausz.
Normal lung biopsy Airway inflammation with lymphocytes

and eosinophils
Fig. 13.18 Mice lacking the

transcription factor T-bet develop
Airway remodeling with increased asthma and T-cell responses polarized
Normal airway
collagen deposited around airway
toward TH2. T-bet binds to the promoter
of the gene encoding IL-2 and is present
in TH1 but not TH2 cells. Mice with a
gene-targeted deletion of T-bet (T-bet–/–)
developed a spontaneous asthma-like
phenotype in the lungs. Left-hand panels:
lung and airways in normal mice. Right-
hand panels: T-bet-deficient mice showed
lung inflammation, with lymphocytes and
eosinophils around the airway and blood
vessels (top) and airway remodeling with
increased collagen around the airway
(bottom). Photographs courtesy of
L. Glimcher.

Although allergic asthma is initially driven by a response to a specific aller-

gen, the subsequent chronic inflammation seems to be perpetuated even in
the apparent absence of exposure to allergen. The airways become charac-
teristically hyperreactive, and factors other than antigen can trigger asthma
attacks. Asthmatics characteristically show hyperresponsiveness to environ-
mental chemical irritants such as cigarette smoke and sulfur dioxide. Viral or,
to a smaller extent, bacterial respiratory tract infections can also exacerbate
the disease by inducing a TH2-dominated local response.
13-13 Skin allergy is manifested as urticaria or chronic eczema.
The same dichotomy between immediate and delayed responses is seen in

cutaneous allergic responses. The skin forms an effective barrier to the entry
of most allergens but it can be breached by the local injection of small
amounts of allergen, for example by a stinging insect. The entry of allergen
into the epidermis or dermis causes a localized allergic reaction. Local mast-
cell activation in the skin leads immediately to a local increase in vascular
permeability, which causes extravasation of fluid and swelling. Mast-cell acti-
vation also stimulates the release of chemicals from local nerve endings by a
nerve axon reflex, causing the vasodilation of surrounding cutaneous blood
vessels, which causes redness of the surrounding skin. The resulting skin
lesion is called a wheal-and-flare reaction. About 8 hours later, a more wide-
spread and sustained edematous response appears in some individuals as a
consequence of the late-phase response (see Fig. 13.14). A disseminated form
of the wheal-and-flare reaction, known as urticaria or hives, sometimes
appears when ingested allergens enter the bloodstream and reach the skin.
Histamine released by mast cells activated by allergen in the skin causes
large, itchy, red swellings of the skin.
Allergists take advantage of the immediate response to test for allergy by
injecting minute amounts of potential allergens into the epidermal layer of
the skin. Although the reaction after the administration of antigen by
intraepidermal injection is usually very localized, there is a small risk of
inducing systemic anaphylaxis. Another standard test for allergy is to meas-
ure levels of IgE antibody specific for a particular allergen in a sandwich
ELISA (see Appendix I, Section A-6).
Although acute urticaria is commonly caused by allergens, the causes of chronic
urticaria, in which the urticarial rash can recur over long periods, are less well
understood. It seems likely that up to one-third of cases of chronic urticaria are
caused by autoantibodies against the a chain of FceRI, and are thus due to
autoimmunity. This is an example of a type II hypersensitivity reaction (see Fig.
13.1) in which an autoantibody against a cellular receptor triggers cellular acti-
vation, in this case causing mast-cell degranulation with resulting urticaria.
A more prolonged inflammatory response is sometimes seen in the skin,
most often in atopic children. They develop a persistent skin rash called
eczema or atopic dermatitis, due to a chronic inflammatory response with
features of tissue remodeling and fibrosis similar to those seen in the
bronchial walls of patients with asthma. Although allergy is often considered
Atopic Dermatitis solely in the context of a TH2 phenotype, in human disease (as opposed to
murine models) both TH1 and TH2 cytokines can contribute to the
immunopathogenesis. Atopic dermatitis is an excellent example of this.
About one-third of patients show minimal, if any, elevation of IgE in their
sera, and TH1-cell development is preferentially observed in the lesions of
atopic dermatitis patients with a persistent history of the disease.
Innate immune responses due to activation of TLRs by microbial products
can exacerbate atopic dermatitis. Activation of these receptors usually
initiates a TH1-cell response by stimulating the production of IL-12 and IL-18.

KCASP1Tg Genotypes Dermatitis IgE Mast cells
Wild type — control control

Hematoxylin
and eosin
staining KCASP1Tg +++ +++ +++
Stat6–/–KCASP1Tg +++ ND +
Toluidine blue IL-18–/–KCASP1Tg — + control

staining
KIL-18Tg +++* +++ +++
After birth 4 weeks 16 weeks *Onset is delayed
An experimental situation in which these cytokines are overproduced is in Fig. 13.19 A deficiency of IL-18 prevents
mutant mice that overexpress the enzyme caspase-1 specifically in their the development of atopic dermatitis in
susceptible mice. KCASP1Tg mice
keratinocytes (KCASP1Tg mice). These mice are born healthy but develop
overexpress the enzyme caspase-1 in
cutaneous changes similar to human atopic dermatitis and start frequent their keratinocytes and develop a
scratching at around 8–10 weeks after birth. Serum IgE and IgG levels also condition similar to human atopic
begin to rise at that time. The overexpression of caspase-1 leads to increased dermatitis. Left panel: in skin sections
apoptosis of keratinocytes, but also to increased levels of IL-1 and IL-18, stained by hematoxylin and eosin (HE)
because caspase-1 is required to activate these cytokines. As the mice grow, (top row), the lesions are characterized
the skin lesions expand and the disease becomes more severe. The mice are, by hyperkeratosis and dense infiltration
with leukocytes and lymphocytes. When
however, completely protected from developing the condition when they are
stained by toluidine blue (bottom row), a
made deficient in IL-18, and thus do not develop a strong TH1 response. They dense accumulation of mast cells can be
are not protected when made deficient in STAT6, which leads to a lack of a seen. The dark-purple stained
TH2-cell response (Fig. 13.19). This type of allergy has been classified as cells are mast cells. Far greater numbers
innate-type allergy, in contrast to TH2-dependent classical allergy. of mast cells (indicated by arrows) are
present in the lesion at 16 weeks
TH2 responses are, however, important in natural atopic dermatitis and may compared with 4 weeks. Right panel:
lead indirectly to exacerbation of the disease by making the individual more KCASP1Tg mice deficient in STAT6 have
susceptible to certain infections. For example, individuals with atopic serum IgE concentrations below
dermatitis are more susceptible to cutaneous inflammation after vaccination detectable levels, but still suffer from
similar changes in the skin, whereas
with vaccinia virus. The increased susceptibility results from the spread of the
KCASP1Tg mice deficient in IL-18 are
vaccinia virus due to the actions of the TH2 cytokines IL-4 and IL-13. The TH2 free from dermatitis. This suggests that
response also inhibits the production of the antimicrobial peptide catheli- TH2 cytokines are not important in this
cidin, which is normally induced as a result of stimulation of TLR-3. Thus, one model. KIL-18Tg mice, which overexpress
could envisage a vicious circle of infection triggering atopic dermatitis result- mature IL-18 in their keratinocytes, show
ing in increased susceptibility to further infection. the same symptoms as KCASP1Tg mice
except for the delay in disease onset.
KCASP1Tg, keratinocyte-specific
13-14 Allergy to foods causes systemic reactions as well as symptoms caspase-1-transgenic mice; KIL-18Tg,
limited to the gut. keratinocyte-specific mature
IL-18-transgenic mice; ND, not
detectable. Photographs courtesy of
Genuine food allergy affects about 1–4% of American and European popula- Tsutsui, H., et al.: Immunol. Rev. 2004,
tions, although food intolerances and dislikes are ubiquitous and often 202: 115–138.
misnamed ‘allergy’ by the sufferer. About one-quarter of true food allergy in
the United States and Europe is accounted for by allergy to peanuts, which is
increasing in incidence—tripling in the past 5 years. Food allergy causes
approximately 30,000 anaphylactic reactions each year in the United States,
including 200 deaths. This is a significant public-health problem, especially
in school, where children may be unwittingly exposed to peanuts, which are
present in many different foods. Fig. 13.20 illustrates the risk factors for the
development of food allergy.

One of the characteristic features of food allergens is a high degree of resist-

Risk factors for the development
of food allergy ance to digestion by pepsin in the stomach. This allows them to reach the
mucosal surface of the small intestine as intact allergens. When an allergen is
Immature mucosal immune system eaten, two types of allergic responses are seen. Activation of mucosal mast
cells associated with the gastrointestinal tract leads to transepithelial fluid
Early introduction of solid food loss and smooth muscle contraction, causing diarrhea and vomiting. For rea-
sons that are not fully understood, connective tissue mast cells in the dermis
and subcutaneous tissues can also be activated after ingestion of allergen,
Hereditary increase in mucosal permeability
presumably by allergen that has been absorbed into the bloodstream, and
this results in urticaria. Urticaria is a common reaction when penicillin is
IgA deficiency or delayed IgA production
given orally to a patient who already has penicillin-specific IgE antibodies.
Ingestion of food allergens can also lead to the development of asthma and of
Inadequate challenge of the intestinal immune generalized anaphylaxis, accompanied by cardiovascular collapse. Certain
system with commensal flora
foods, most importantly peanuts, tree nuts, and shellfish, are particularly
associated with this type of life-threatening response. Food allergy can be
Genetically determined bias toward a
TH2 environment either IgE mediated, as in asthma or systemic anaphylaxis, or non-IgE medi-
ated. An important example of the latter is celiac disease.
Polymorphisms of TH2 cytokine or
IgE receptor genes 13-15 Celiac disease is a model of antigen-specific immunopathology.
Impaired enteric nervous system Celiac disease is a chronic condition of the upper small intestine caused by
an immune response directed at gluten, a complex of proteins present in
Immune alterations (e.g., low levels of TGF-) wheat, oats, and barley. Elimination of gluten from the diet restores normal
gut function, but must be continued throughout life. The pathology of celiac
Gastrointestinal infections disease is characterized by the loss of the slender, finger-like villi formed by
the intestinal epithelium (a condition termed villous atrophy), together with
an increase in the size of the sites in which epithelial cells are renewed (crypt
Fig. 13.20 Risk factors for the hyperplasia) (Fig. 13.21). These pathological changes result in the loss of the
development of food allergy. mature epithelial cells that cover the villi and which normally absorb and
digest food, and is accompanied by severe inflammation of the intestinal
wall, with increased numbers of T cells, macrophages, and plasma cells in the
lamina propria, as well as increased numbers of lymphocytes in the epithelial
layer. Gluten seems to be the only food protein that provokes intestinal
inflammation in this way, a property that reflects gluten’s ability to stimulate
both specific and innate immunity in genetically susceptible individuals.
Celiac disease shows an extremely strong genetic predisposition, with more
than 95% of patients expressing the HLA-DQ2 class II MHC allele, and there
is an 80% concordance in monozygotic twins (that is, if one twin develops it,
Celiac Disease
there is an 80% probability that the other will), but only a 10% concordance
in dizygotic twins. Nevertheless, most individuals expressing HLA-DQ2 do
not develop celiac disease despite the almost universal presence of gluten in
the Western diet. Thus, other genetic factors must make important contribu-
tions to susceptibility.
Most evidence indicates that celiac disease requires the aberrant priming of
IFN-g-producing CD4 T cells by antigenic peptides present in a-gliadin, one
of the major proteins in gluten. It is generally accepted that only a limited
number of peptides can provoke an immune response leading to celiac dis-
ease. This is likely to be due to the unusual structure of the peptide-binding
groove of the HLA-DQ2 molecule. The key step in the immune recognition of
a-gliadin is the deamidation of its peptides by the enzyme tissue transgluta-
minase (tTG), which converts selected glutamine residues to negatively
charged glutamic acid. Only peptides containing negatively charged
residues in certain positions bind strongly to HLA-DQ2, and thus the
transamination reaction promotes the formation of peptide:HLA-DQ2 com-
plexes, which can activate antigen-specific CD4 T cells (Fig. 13.22). Multiple
peptide epitopes can be generated from gliadin. Activated gliadin-specific

Figure 13.21 The pathological features

Normal jejunum Celiac jejunum of celiac disease. Left: the surface of the
normal small intestine is folded into
finger-like villi, which provide an extensive
surface for nutrient absorption. Right: The
local immune response against the food
protein a-gliadin provokes destruction of
the villi. In parallel, there is lengthening
and increased mitotic activity in the
underlying crypts where new epithelial
cells are produced. There is also a
marked inflammatory infiltrate in the
intestinal mucosa, with increased
numbers of lymphocytes in the epithelial
layer and accumulation of CD4 T cells,
plasma cells, and macrophages in the
deeper layer, the lamina propria. Because
the villi contain all the mature epithelial
cells that digest and absorb foodstuffs,
their loss results in life-threatening
malabsorption and diarrhea. Photographs
courtesy of Allan Mowat.
Fig. 13.22 Molecular basis of immune

CD4 T cells accumulate in the lamina propria, producing IFN-g, a cytokine recognition of gluten in celiac disease.
that leads to intestinal inflammation. After the digestion of gluten by gut
digestive enzymes, deamidation of
Celiac disease is entirely dependent on the presence of a foreign antigen epitopes by tissue transglutaminase leads
(gluten) and is not associated with a specific immune response against anti- to their binding to HLA-DQ molecules and
gens in the tissue—the intestinal epithelium—that is damaged during the priming of the immune system.
An enzyme, tissue transglutaminase The activated T cells can kill

Peptides naturally produced from
(tTG) modifies the peptides so The bound peptide activates mucosal epithelial cells by binding
gluten do not bind to MHC
they now can bind to the gluten-specific CD4 T cells Fas. They also secrete IFN-␥,
class II molecules
MHC class II molecules which activates the epithelial cell
tTG
Fas
FasL IFN-

immune response. It is therefore not considered an autoimmune disease.

gluten-specific
T cell Nevertheless, autoantibodies against tissue transglutaminase are found in all
gluten–tTG
complex
patients with celiac disease; indeed, the presence of serum IgA antibodies
CD4+ against this enzyme is used as a sensitive and specific test for the disease.
Interestingly, no tTG-specific T cells have been found and it has been pro-
posed that gluten-reactive T cells provide help to B cells reactive to tissue
B cell
transglutaminase. In support of this hypothesis, gluten can complex with the
T-cell help
enzyme and therefore could be taken up by tTG-reactive B cells (Fig. 13.23).
There is no evidence that these autoantibodies contribute to tissue damage.
anti-tTG antibodies
Chronic T-cell responses against food proteins are normally prevented by the
development of oral tolerance (see Section 11-13). Why this breaks down in
Fig. 13.23 A hypothesis to explain patients with celiac disease is unknown. The properties of the HLA-DQ2 mol-
antibody production against tissue
transglutaminase (tTG) in the absence
ecule provide a partial explanation, but there must be additional factors
of T cells specific for tTG in celiac because most HLA-DQ2-positive individuals do not develop celiac disease
patients. tTG-reactive B cells endocytose and the high concordance rates in monozygotic twins indicate a role for addi-
gluten–tTG complexes and present gluten tional genetic factors. Polymorphisms in the gene for CTLA-4 or in other
peptides to the gluten-specific T cells. immunoregulatory genes may be associated with susceptibility. There could
The stimulated T cells can now provide also be differences in how individuals digest gliadin in the intestine, so that
help to these B cells, which produce
differing amounts survive for deamidation and presentation to T cells.
autoantibodies against tTG.
The gluten protein also seems to have several properties that contribute to
pathogenesis. As well as its relative resistance to digestion, there is mounting
evidence that some gliadin-derived peptides stimulate the innate immune
system by inducing the release of IL-15 by intestinal epithelial cells. This
process is antigen-nonspecific and involves peptides that cannot be bound
by HLA-DQ2 molecules or recognized by CD4 T cells. IL-15 release leads to
the activation of dendritic cells in the lamina propria, as well as the upregu-
Intraepithelial lation of MIC-A expression by epithelial cells. CD8 T cells in the mucosal
Gluten peptides lymphocytes (IELs) epithelium can be activated via their NKG2D receptors, which recognize
activate mucosal express NKG2D,
which binds to MIC
MIC-A, and they can kill MIC-A-expressing epithelial cells via these same
epithelial cells to
express MIC molecules and NKG2D receptors (Fig. 13.24). Triggering of these innate immune responses
molecules activates the IELs to by a-gliadin may create some intestinal damage on its own and also induce
kill the epithelial cell
some of the co-stimulatory events necessary for initiating an antigen-specific
CD4 T-cell response to other parts of the a-gliadin molecule. The ability of
gluten to stimulate both innate and adaptive immune responses may thus
explain its unique ability to induce celiac disease.
13-16 Allergy can be treated by inhibiting either IgE production or the

effector pathways activated by the cross-linking of cell-surface IgE.
Current drug treatments for allergic disease either treat the symptoms only,
as do the antihistamines, or are general immunosuppressants such as the
corticosteroids used for the long-term treatment of asthma and other chronic
MIC CD8 T cell allergic diseases. They are largely palliative, rather than curative, often need
(IEL)
to be taken for life, and consequently incur a wide range of side effects, which
NKG2D we discuss in Chapter 15. Anaphylactic reactions are treated with
epinephrine, which stimulates the re-formation of endothelial tight junc-
Fig. 13.24 The activation of cytotoxic tions, promotes the relaxation of constricted bronchial smooth muscle, and
T cells by the innate immune system in also stimulates the heart. Inhaled bronchodilators that act on b-adrenergic
celiac disease. Gluten peptides can receptors to relax constricted muscle are used to relieve acute asthma attacks.
induce the expression of the MHC class Antihistamines that block the histamine H1 receptor reduce the urticaria that
Ib molecules MIC-A and MIC-B on gut follows the release of histamine from mast cells and basophils. Relevant H1
epithelial cells. Intraepithelial lymphocytes
receptors include those on blood vessels that cause increased permeability of
(IELs), many of which are CD8 cytotoxic
T cells, recognize these proteins via the the vessel wall, and those on unmyelinated nerve fibers that are thought to
receptor NKG2D, which activates the IELs mediate the itching sensation. In chronic allergic disease it is extremely
to kill the MIC-bearing cells, leading to important to treat and prevent the chronic inflammatory injury to tissues.
destruction of the gut epithelium. Topical or systemic corticosteroids (see Section 15-1) are used to suppress the

chronic inflammatory changes seen in asthma, rhinitis, and eczema. What is

really needed, however, is a means of regulating the T-cell response to the
allergenic peptide antigen in an antigen-specific manner.
Some of the newer approaches to the treatment and prevention of allergy
that attempt to do this are set out in Fig. 13.25. Two treatments are com-
monly used in clinical practice—one is desensitization or specific allergen
immunotherapy and the other is blockade of the effector pathways. There
are also several approaches still in the experimental stage. In desensitization
the aim is to restore tolerance to the allergen by reducing its tendency to
induce IgE production. The key to this therapy seems to be the induction of
regulatory T cells secreting IL-10 and/or TGF-b, which skew the response
away from IgE (see Section 13-3). Beekeepers exposed to multiple stings are
often naturally protected from severe allergic reactions such as anaphylaxis
through a mechanism involving IL-10-secreting T cells. Similarly, specific
allergen immunotherapy for sensitivity to insect venom and airborne aller-
gens induces the increased production of IL-10 and in some cases TGF-b, as
well as the induction of IgG isotypes, particularly IgG4, an isotype selectively
promoted by IL-10. Patients are desensitized by injection with escalating
doses of allergen, starting with tiny amounts, an injection schedule that
gradually decreases the IgE-dominated response. Allergen injection
immunotherapy in fact seems to downregulate both TH1- and TH2-driven
hypersensitivity disease, in line with its presumed induction of Treg cells.
Recent evidence shows that desensitization is also associated with a reduc-
tion in the numbers of late-phase inflammatory cells at the site of the
allergic reaction. A potential complication of the desensitization approach
is the risk of inducing IgE-mediated allergic responses. This strategy is not
always successful, for example in treating severe reactions against food
allergens such as peanut allergy.
An alternative, and still experimental, approach to desensitization is vaccina-
tion with peptides derived from common allergens. This procedure induces
Fig. 13.25 Approaches to the treatment

Target step Mechanism of treatment Specific approach of allergy. Possible methods of inhibiting
allergic reactions are shown. Two
Injection of specific antigen approaches are in regular clinical use.
or peptides The first is the injection of specific
Administration of cytokines, antigen in desensitization regimes, which
TH2 activation Induce regulatory T cells e.g., IFN-, IL-10, IL-12, TGF- is believed to restore tolerance to the
Use of adjuvants such as CpG allergen—perhaps through the production
oligodeoxynucleotides to of regulatory T cells. The second clinically
stimulate TH1 response useful approach is the use of specific
inhibitors to block the synthesis or effects
Activation of B cell to Block co-stimulation Inhibit CD40L of inflammatory mediators produced by
produce IgE Inhibit TH2 cytokines Inhibit IL-4 or IL-13 mast cells.
Inhibit effects of IgE Blockade of IgE receptor

Mast-cell activation binding to mast cell
Inhibit effects of mediators Antihistamine drugs

on specific receptors
Mediator action
Inhibit synthesis of Lipooxygenase inhibitors
specific mediators
Block cytokine and

Eosinophil-dependent chemokine receptors that Inhibit IL-5
inflammation mediate eosinophil Block CCR3
recruitment and activation

T-cell anergy (see Section 8-15), which is associated with multiple changes in
T-cell phenotype, including the production of IL-10 and upregulation of the
cell-surface protein CD5. IgE-mediated responses are not induced by the
peptides because IgE, in contrast to T cells, can recognize only the intact anti-
gen. A difficulty with this approach is that an individual’s responses to
peptides are restricted by their MHC class II alleles; patients with different
MHC class II molecules therefore respond to different allergen-derived
peptides. One possible solution is the use of peptides that contain short
sequences with multiple overlapping MHC-binding motifs that would
provide coverage for the majority of the population.
Another vaccination strategy that shows promise in experimental models of
allergy is the use of oligodeoxynucleotides rich in unmethylated CpG as adju-
vants for desensitization regimes. These oligonucleotides mimic the CpG
motifs in bacterial DNA and strongly promote TH1 responses, probably
through the stimulation of TLR-9 in dendritic cells (see Section 8-7). The
mechanism of action of adjuvants is discussed in Appendix I, Section A-4.
The signaling pathways that enhance the IgE response in allergic disease are
also potential targets for therapy. Inhibitors of IL-4, IL-5, and IL-13 would be
predicted to reduce IgE responses, but redundancy between some of the
activities of these cytokines might make this approach difficult to implement
in practice. A second approach to manipulating the response is to give
cytokines that promote TH1-type responses. IFN-g, IFN-a, and IL-12 have
each been shown to reduce IL-4-stimulated IgE synthesis in vitro, and IFN-g
and IFN-a have been shown to reduce IgE synthesis in vivo. Administration
of IL-12 to patients with mild allergic asthma caused a decrease in the num-
ber of eosinophils in blood and sputum but had no effect on immediate or
late-phase responses to inhaled allergen. The treatment with IL-12 was
accompanied by quite severe flu-like symptoms in most patients, which is
likely to limit its possible therapeutic value.
Another target for therapeutic intervention might be the high-affinity IgE
receptor. An effective competitor for IgE at this receptor could prevent the
binding of IgE to the surfaces of mast cells, basophils, and eosinophils.
Clinical trials have taken place of a humanized mouse anti-IgE monoclonal
antibody named omalizumab, which binds to the portion of IgE that ligates
the high-affinity IgE receptor. Because IgE is present in plasma at low levels
it was possible to give a large molar excess of omalizumab that caused a
decrease in IgE levels of more than 95%. This was accompanied by down-
regulation of the numbers of high-affinity IgE receptors on basophils and
mast cells. This antibody blocked both the immediate and late-phase
responses to experimentally inhaled allergen. Patients with asthma and
allergic rhinitis receiving omalizumab in clinical trials had fewer exacerba-
tions than patients on the placebo, and were able to reduce their use of cor-
ticosteroids. The efficacy of this agent, which has led to its being licensed for
use to treat patients with asthma, provides a clear-cut demonstration of the
importance of IgE in the atopic allergic diseases. Targeting the inhibitory
receptor FcgRIIb is a potential new therapy for allergy to cat’s dander. A
chimeric fusion protein consisting of human Fcg and the cat allergen Fel d 1
blocked the skin reaction in a mouse model of cat allergy and inhibited the
release of inflammatory mediators from basophils. This inhibition is specific
to the allergen.
A further approach to treatment would be to block the recruitment of
eosinophils to sites of allergic inflammation. The eotaxin receptor CCR3 is a
potential target in this context. The production of eosinophils in bone mar-
row and their exit into the circulation might also be reduced by a blockade of
IL-5 action. Studies using anti-IL-5 treatment have not been encouraging,

Hypersensitivity diseases 583
however: anti-IL-5 did reduce the numbers of eosinophils in blood and

sputum but did not alter immediate and late-phase responses to inhaled
allergen or airway hyperreactivity to histamine.
Summary.
The allergic response to innocuous antigens reflects the pathophysiological

aspects of a defensive immune response whose physiological role is to pro-
tect against helminth parasites. It is triggered by the binding of antigen to IgE
antibodies bound to the high-affinity IgE receptor FceRI on mast cells. Mast
cells are strategically distributed beneath the mucosal surfaces of the body
and in connective tissue. Antigen cross-linking the IgE on their surface causes
them to release large amounts of inflammatory mediators. The resulting
inflammation can be divided into early events, characterized by short-lived
mediators such as histamine, and later events that involve leukotrienes,
cytokines, and chemokines, which recruit and activate eosinophils and
basophils. The late phase of this response can evolve into chronic inflamma-
tion, characterized by the presence of effector T cells and eosinophils, which
is most clearly seen in chronic allergic asthma.
Hypersensitivity diseases.
In this part of the chapter we focus on immunological responses involving

IgG antibodies or specific T cells that cause adverse hypersensitivity
reactions. Although these effector arms of the immune response normally
participate in protective immunity to infection, they occasionally react with
noninfectious antigens to produce acute or chronic hypersensitivity reac-
tions. Although the mechanisms initiating the various forms of hypersensi-
tivity are different, much of the pathology is due to the same immunological
effector mechanisms. We also consider here a newly characterized category of
hypersensitivity disease, in which certain variants of the genes regulating
inflammatory responses cause the inappropriate triggering of inflammation,
leading to severe disease.
13-17 Innocuous antigens can cause type II hypersensitivity reactions

in susceptible individuals by binding to the surfaces of circulating
blood cells.
Antibody-mediated destruction of red blood cells (hemolytic anemia) or

platelets (thrombocytopenia) can be caused by some drugs, including the
antibiotics penicillin and cephalosporin. These are examples of type II
hypersensitivity reactions in which the drug binds to the cell surface and
serves as a target for anti-drug IgG antibodies that cause destruction of the
cell (see Fig. 13.1). The anti-drug antibodies are made in only a minority of
people and it is not clear why these individuals make them. The cell-bound
antibody triggers the clearance of the cell from the circulation, predomi-
nantly by tissue macrophages in the spleen, which bear Fcg receptors.
13-18 Systemic disease caused by immune-complex formation can follow

the administration of large quantities of poorly catabolized antigens.
Type III hypersensitivity reactions can arise with soluble antigens (see Fig.
13.1). The pathology is caused by the deposition of antigen:antibody

aggregates, or immune complexes, in particular tissues and sites. Immune

complexes are generated in all antibody responses, but their pathogenic
Drug-Induced
Serum Sickness potential is determined, in part, by their size and by the amount, affinity, and
isotype of the responding antibody. Larger aggregates fix complement and
are readily cleared from the circulation by the mononuclear phagocyte
system. However, the small complexes that form when antigen is in excess
tend to be deposited in blood vessel walls. There they can ligate Fc receptors
on leukocytes, leading to leukocyte activation and tissue injury.
A local type III hypersensitivity reaction called an Arthus reaction (Fig. 13.26)
can be triggered in the skin of sensitized individuals who possess IgG anti-
bodies against the sensitizing antigen. When antigen is injected into the skin,
circulating IgG antibody that has diffused into the skin forms immune com-
plexes locally. The immune complexes bind Fc receptors such as FcgRIII on
mast cells and other leukocytes, generating a local inflammatory response
and increased vascular permeability. Fluid and cells, especially polymor-
phonuclear leukocytes, then enter the site of inflammation from local blood
vessels. The immune complexes also activate complement, leading to the
Fig. 13.26 The deposition of immune
complexes in tissues causes a local
production of the complement fragment C5a. This is a key participant in the
inflammatory response known as an inflammatory reaction because it interacts with C5a receptors on leukocytes
Arthus reaction (type III hypersensitivity to activate these cells and attract them to the site of inflammation (see
reaction). In individuals who have Section 2-5). Both C5a and FcgRIII have been shown to be required for the
already made IgG antibody against an experimental induction of an Arthus reaction in the lung by macrophages in
antigen, the same antigen injected into the walls of the alveoli, and they are probably required for the same reaction
the skin forms immune complexes with
induced by mast cells in the skin and the linings of joints (synovia).
IgG antibody that has diffused out of
the capillaries. Because the dose of A systemic type III hypersensitivity reaction, known as serum sickness, can
antigen is low, the immune complexes result from the injection of large quantities of a poorly catabolized foreign
are only formed close to the site of
injection, where they activate mast cells
antigen. This illness was so named because it frequently followed the admin-
bearing Fcg receptors (FcgRIII). The istration of therapeutic horse antiserum. In the pre-antibiotic era, antiserum
complement component C5a seems made by immunizing horses was often used to treat pneumococcal pneumo-
important in sensitizing the mast cell to nia; the specific anti-pneumococcal antibodies in the horse serum would
respond to immune complexes. As a help the patient to clear the infection. In much the same way, antivenin
result of mast-cell activation, (serum from horses immunized with snake venoms) is still used today as a
inflammatory cells invade the site, and
source of neutralizing antibodies to treat people suffering from the bites of
blood vessel permeability and blood flow
are increased. Platelets also accumulate poisonous snakes. The increasing use of monoclonal antibodies in the treat-
inside the vessel at the site, ultimately ment of disease (for example, anti-TNF-a in rheumatoid arthritis) has led to
leading to vessel occlusion. the development of serum sickness in a small minority of patients.
Local immune-complex formation

Locally injected antigen activates complement. C5a binds Local inflammation, increased fluid
Activation of FcRIII on mast cells
in immune individual to and sensitizes the mast cell to and protein release, phagocytosis,
induces their degranulation
with IgG antibody respond to immune complexes and blood vessel occlusion
C5a
1– 2 hours

Serum sickness occurs 7–10 days after the injection of horse serum, an inter-
antigen:antibody
val that corresponds to the time required to mount an IgG-switched primary complexes
antibody
immune response against the foreign antigens. The clinical features of serum
Level in plasma
against foreign
foreign serum serum proteins
sickness are chills, fever, rash, arthritis, and sometimes glomerulonephritis proteins
(inflammation of the glomeruli of the kidneys). Urticaria is a prominent fea-
ture of the rash, implying a role for histamine derived from mast-cell degran-
ulation. In this case, the mast-cell degranulation is triggered by the ligation of
cell-surface FcgRIII by IgG-containing immune complexes.
Time
The course of serum sickness is illustrated in Fig. 13.27. The onset of disease foreign serum Fever, vasculitis, (days)
coincides with the development of antibodies against the abundant soluble injection arthritis, nephritis
proteins in the foreign serum; these antibodies form immune complexes with
their antigens throughout the body. These immune complexes fix comple-
Fig. 13.27 Serum sickness is a classic
ment and can bind to and activate leukocytes bearing Fc and complement
example of a transient immune
receptors; these in turn cause widespread tissue damage. The formation of complex-mediated syndrome.
immune complexes causes clearance of the foreign antigen, so serum sick- An injection of a foreign protein or
ness is usually a self-limiting disease. Serum sickness after a second dose of proteins leads to an antibody response.
antigen follows the kinetics of a secondary antibody response (see Section These antibodies form immune
10-14), with symptoms typically appearing within a day or two. complexes with the circulating foreign
proteins. The complexes are deposited
Pathological immune-complex deposition is seen in other situations in which in small vessels and activate complement
antigen persists. One is when an adaptive antibody response fails to clear the and phagocytes, inducing fever and the
infecting pathogen, as occurs in subacute bacterial endocarditis or chronic symptoms of vasculitis, nephritis, and
arthritis. All these effects are transient
viral hepatitis. In these situations, the replicating pathogen is continuously
and resolve when the foreign protein
generating new antigen in the presence of a persistent antibody response, is cleared.
with the consequent formation of abundant immune complexes. These are
deposited within small blood vessels, with consequent injury in many tissues
and organs, including the skin, kidneys, and nerves.
Immune-complex disease also occurs when inhaled allergens provoke IgG
rather than IgE antibody responses, perhaps because they are present at
relatively high levels in the air. When a person is reexposed to high doses of
such allergens, immune complexes form in the walls of alveoli in the lung.
This leads to the accumulation of fluid, protein, and cells in the alveolar wall,
slowing blood–gas interchange and compromising lung function. This type of
reaction is more likely to occur in occupations such as farming, where there
is repeated exposure to hay dust or mold spores, and the resulting disease is
known as farmer’s lung. If exposure to antigen is sustained, the lining of the
lungs can be permanently damaged.
13-19 Delayed-type hypersensitivity reactions are mediated by TH1 cells and

CD8 cytotoxic T cells.
Unlike the immediate hypersensitivity reactions described so far, which are

mediated by antibodies, delayed-type hypersensitivity or type IV hypersen-
sitivity reactions are mediated by antigen-specific effector T cells. These
function in essentially the same way as they do in a response to a pathogen,
as described in Chapter 8. The causes and consequences of some syndromes
in which type IV hypersensitivity responses predominate are listed in Fig.
13.28. These responses can be transferred between experimental animals by
purified T cells or cloned T-cell lines. Much of the inflammation seen in some
of the allergic diseases described in the earlier parts of this chapter is in fact
due to delayed-type hypersensitivity.
The prototypic delayed-type hypersensitivity reaction is an artifact of mod-
ern medicine—the tuberculin test (see Appendix I, Section A-38). This is used
to determine whether an individual has previously been infected with
M. tuberculosis. Small amounts of tuberculin—a complex mixture of peptides
and carbohydrates derived from M. tuberculosis—are injected intradermally.
In people who have been exposed to the bacterium, either by infection or by

Fig. 13.28 Type IV hypersensitivity

responses. These reactions are mediated Type IV hypersensitivity reactions are mediated by antigen-specific effector T cells
by T cells and all take some time to
develop. They can be grouped into three Syndrome Antigen Consequence
syndromes, according to the route by
which antigen passes into the body. In Local skin swelling:
delayed-type hypersensitivity the antigen Proteins:
Delayed-type Erythema
Insect venom
is injected into the skin; in contact hypersensitivity Induration
Mycobacterial proteins
hypersensitivity it is absorbed into the Cellular infiltrate
(tuberculin, lepromin)
Dermatitis
skin; and in gluten-sensitive enteropathy
it is absorbed by the gut. DNFB,
dinitrofluorobenzene. Haptens: Local epidermal reaction:
Pentadecacatechol (poison ivy) Erythema
Contact DNFB
hypersensitivity Cellular infiltrate
Small metal ions: Vesicles
Nickel Intraepidermal abscesses
Chromate
Gluten-sensitive enteropathy Villous atrophy in small bowel

(celiac disease) Gliadin Malabsorption
immunization with the BCG vaccine (an attenuated form of M. tuberculosis),

a local T cell-mediated inflammatory reaction evolves over 24–72 hours. The
response is caused by TH1 cells, which enter the site of antigen injection, rec-
ognize complexes of peptide:MHC class II molecules on antigen-presenting
cells, and release inflammatory cytokines such as IFN-g and TNF-b. These
stimulate the expression of adhesion molecules on endothelium and increase
local blood vessel permeability, allowing plasma and accessory cells to enter
the site, thus causing a visible swelling (Fig. 13.29). Each of these phases takes
several hours and so the fully developed response only appears 24–48 hours
after challenge. The cytokines produced by the activated TH1 cells and their
actions are shown in Fig. 13.30.
Very similar reactions are observed in several cutaneous hypersensitivity
responses. These can be elicited by either CD4 or CD8 T cells, depending on
the pathway by which the antigen is processed. Typical antigens that cause
cutaneous hypersensitivity responses are highly reactive small molecules that
can easily penetrate intact skin, especially if they cause itching that leads to
scratching. These chemicals then react with self proteins, creating
Fig. 13.29 The stages of a delayed-type

Antigen is injected into A TH1 effector cell recognizes
hypersensitivity reaction. The first phase Recruitment of phagocytes
subcutaneous tissue and antigen and releases
involves uptake, processing, and and plasma to site of antigen
processed by local cytokines, which act on
presentation of the antigen by local injection causes visible lesion
antigen-presenting cells vascular endothelium
antigen-presenting cells. In the second
phase, TH1 cells that were primed by a
previous exposure to the antigen migrate
into the site of injection and become
activated. Because these specific cells
are rare, and because there is little
inflammation to attract cells into the site,
it can take several hours for a T cell of the
correct specificity to arrive. These cells
release mediators that activate local
endothelial cells, recruiting an
inflammatory cell infiltrate dominated
by macrophages and causing the
accumulation of fluid and protein. At
this point the lesion becomes apparent.
24–72 hours

Fig. 13.30 The delayed-type (type IV)

Antigen is processed by tissue macrophages hypersensitivity response is directed by
and stimulates TH1 cells
chemokines and cytokines released by
antigen-stimulated TH1 cells. Antigen in
the local tissues is processed by antigen-
presenting cells and presented on MHC
class II molecules. Antigen-specific TH1
cells that recognize the antigen locally at
the site of injection release chemokines
and cytokines that recruit macrophages
to the site of antigen deposition. Antigen
presentation by the newly recruited
TH1 macrophages then amplifies the
response. T cells can also affect local
blood vessels through the release of
TNF-a and TNF-b, and stimulate the
production of macrophages through the
chemokines cytokines cytotoxins
release of IL-3 and GM-CSF. TH1 cells
activate macrophages through the release
of IFN-g and TNF-a, and kill macrophages
and other sensitive cells through the cell-
surface expression of the Fas ligand.
Chemokines IFN- and TNF-
TNF- lL-3/GM-CSF
Induces expression of Cause local tissue

Recruit vascular adhesion destruction. Stimulate monocyte
macrophages to molecules. Increase expression of production by bone
site of antigen Activates macrophages, adhesion molecules on marrow stem cells
deposition increasing release of local blood vesssels
inflammatory mediators
hapten:protein complexes that can be processed to hapten:peptide com-

plexes capable of being presented by MHC molecules and recognized by
T cells as foreign antigens. There are two phases to a cutaneous hypersensi-
tivity response: sensitization and elicitation. During the sensitization phase,
cutaneous Langerhans cells take up and process antigen, and migrate to
regional lymph nodes, where they activate T cells (see Fig. 8.13) with the
consequent production of memory T cells, which end up in the dermis. In the
elicitation phase, a subsequent exposure to the sensitizing chemical leads to
antigen presentation to memory T cells in the dermis, with the release of
T-cell cytokines such as IFN-g and IL-17. This stimulates the keratinocytes of
the epidermis to release IL-1, IL-6, TNF-a, GM-CSF, the chemokine CXCL8,
and the interferon-inducible chemokines CXCL11 (IP-9), CXCL10 (IP-10), and
CXCL9 (Mig; monokine induced by IFN-g). The cytokines and chemokines
enhance the inflammatory response by inducing the migration of monocytes
into the lesion and their maturation into macrophages, and by attracting
more T cells (Fig. 13.31).
The rash produced by contact with poison ivy (Fig. 13.32) is caused by a CD8
T-cell response to a chemical in the poison ivy leaf called pentadecacatechol.
This compound is lipid-soluble and can therefore cross the cell membrane
and modify intracellular proteins. The modified proteins generate modified
peptides within the cytosol, and these are translocated into the endoplasmic
reticulum and delivered to the cell surface bound to MHC class I molecules. Contact Sensitivity
CD8 T cells recognizing the peptides cause damage either by killing the elic- to Poison Ivy
iting cell or by secreting cytokines such as IFN-g. The well-studied chemical
picryl chloride produces a CD4 T-cell hypersensitivity reaction. It modifies
extracellular self proteins, which are then processed by the exogenous path-
way (see Section 5-5) into modified self peptides that bind to self-MHC class
II molecules and are recognized by TH1 cells. When sensitized TH1 cells
recognize these complexes, they produce extensive inflammation by activat-
ing macrophages (see Fig. 13.31). Because the chemicals in these examples

Contact-sensitizing agent Langerhans cells present self Activated keratinocytes secrete The products of keratinocytes
penetrates the skin and binds to peptides haptenated with the cytokines such as IL-1 and and TH1 cells activate
self proteins, which are taken up contact-sensitizing agent to TH1 TNF- and chemokines such macrophages to secrete
by Langerhans cells cells, which secrete IFN- and as CXCL8, CXCL11, and mediators of inflammation
other cytokines CXCL9
TNF- CXCL8 IL-1 CXCL11 CXCL9 IL-1

TH1 IFN-
TNF-
TH1 NO
Fig. 13.31 Elicitation of a delayed-type hypersensitivity must have been previously primed in lymph nodes and then have
response to a contact-sensitizing agent. A contact-sensitizing traveled back to the skin). These then secrete cytokines such as
agent is a small highly reactive molecule that can easily penetrate IFN-g that stimulate keratinocytes to secrete further cytokines
intact skin. It binds covalently as a hapten to a variety of and chemokines. These in turn attract monocytes and induce
endogenous proteins, which are taken up and processed by their maturation into activated tissue macrophages, which
Langerhans cells, the major antigen-presenting cells of skin. contribute to the inflammatory lesions depicted in Fig. 13.32.
These present haptenated peptides to effector TH1 cells (which NO, nitric oxide.
are delivered by contact with the skin, the rash that follows is called a contact
hypersensitivity reaction.
Some insect proteins also elicit a delayed-type hypersensitivity response.
However, the early phases of the host reaction to an insect bite are often IgE-
mediated or result from the direct effects of insect venoms. Important
delayed-type hypersensitivity responses to divalent cations such as nickel
have also been observed. These divalent cations can alter the conformation
or the peptide binding of MHC class II molecules, and thus provoke a T-cell
response. Finally, although this section has focused on the role of T cells in
inducing delayed-type hypersensitivity reactions, there is evidence that anti-
body and complement might also have a role. Mice deficient in B cells,
antibody, or complement show impaired contact hypersensitivity reactions.
In particular, IgM antibodies (produced in part by B1 cells), which activate
the complement cascade, facilitate the initiation of these reactions.
13-20 Mutation in the molecular regulators of inflammation can cause

hypersensitive inflammatory responses resulting in
‘autoinflammatory disease.’
We have seen throughout this book that host defense against infection
depends on the engagement by the immune system of effector mechanisms
that limit the spread of infection and kill the infectious agent. In this chapter
we have seen how inappropriate responses to noninfectious immunological
stimuli may cause diseases as diverse as asthma and hypersensitivity to
nickel. There is a very fine balance between host underresponsiveness to
infectious stimuli, allowing the uncontrolled spread of infection, and overre-
sponsiveness, killing not only the infection but potentially also the host.
Fig. 13.32 Blistering skin lesions on
hand of patient with poison ivy contact There are a small number of diseases in which mutations in genes that con-
dermatitis. Photograph courtesy of trol the life, death, and activities of inflammatory cells are associated with
R. Geha. severe inflammatory disease. These conditions represent a failure to limit

damage during inflammation and immune responses to infection and are

known as autoinflammatory diseases (Fig. 13.33).
The name familial Mediterranean fever (FMF) describes the key features of
one such severe inflammatory illness, inherited as an autosomal recessive
disorder. The pathogenesis of FMF was a total mystery until its cause was dis-
covered to be mutations in the gene encoding the protein pyrin, named to Hereditary Periodic
reflect its association with fever. This gene was also discovered by a second Fever Syndromes
group of researchers at much the same time and named marenostrin, after
the Latin name mare nostrum for the Mediterranean sea. The name pyrin has
stuck and has been extended to describe a domain in this protein that is the
prototype of ‘pyrin domains’ found in some proteins involved in apoptosis.
A disease with similar clinical manifestations is familial Hibernian fever
(FHF) (also known as TNF-receptor associated periodic syndrome
(TRAPS)). Although inherited as an autosomal dominant disease, it was
romantically thought to have been a variant of FMF brought to Ireland by
sailors of the Spanish Armada, until genetic analysis showed it to be caused
by mutations in a completely different gene, that encoding the TNFR-I recep-
tor (a receptor for TNF-a). Patients have reduced levels of TNFR-1, which
leads to increased levels of TNF-a in the circulation because it is not mopped
up by receptors. The disease responds to therapeutic blockade with anti-TNF
agents such as etanercept, a soluble TNF receptor fortuitously developed to
treat patients with rheumatoid arthritis (see Section 15-8). Both FMF and
FHF are characterized by episodic attacks of severe inflammation associated
with fever, an acute-phase response, severe malaise and, in FMF, attacks of
pleural or peritoneal inflammation known as pleurisy and peritonitis,
respectively. Mutations in the gene encoding CD2-binding protein 1
(CD2BP1), a pyrin-interacting protein, are associated with another domi-
nantly inherited autoinflammatory syndrome—pyogenic arthritis, pyo-
derma gangrenosum, and acne (PAPA). These mutations accentuate the Fig. 13.33 The autoinflammatory
interaction between pyrin and CD2BP1. diseases.
Disease Clinical features Inheritance Mutated gene Protein

(common abbreviation) (alternative name)
Familial Mediterranean fever Periodic fever, serositis (inflammation of the pleural Autosomal recessive MEFV Pyrin (marenostrin)
(FMF) and/or peritoneal cavity), arthritis, acute-phase response
TNF-receptor associated periodic

syndrome (TRAPS) (also known Autosomal dominant TNF- 55 kDa receptor
TNFRSF1A (TNFR-I)
as familial Hibernian fever)
Periodic fever, myalgia, rash, acute-phase response
Pyogenic arthritis,
pyoderma gangrenosum Autosomal dominant PTSTPIP CD2-binding protein 1
and acne (PAPA)
Muckle–Wells syndrome Periodic fever, urticarial rash, joint pains,

conjunctivitis, progressive deafness
CIAS1 Cryopyrin
Familial cold autoinflammatory
syndrome (FCAS) Cold-induced periodic fever, urticarial rash, Autosomal dominant
(familial cold urticaria) joint pains, conjunctivitis
Chronic infantile neurologic, Neonatal onset recurrent fever, urticarial rash, chronic CIAS1 Cryopyrin
cutanean articular syndrome arthropathy, facial dysmorphia, neurologic involvement
(CINCA)
Hyper-IgD syndrome (HIDS) Periodic fever, elevated IgD levels, lymphadenopathy Autosomal recessive MVK Mevalonate synthase
Blau syndrome Granulomatous inflammation of skin, eye, and joints Autosomal dominant
NOD2 (CARD15) NOD2 (CARD15)

Crohn’s disease Granulomatous inflammatory bowel disease, Complex trait
sometimes eye, skin, and joint granulomata

How mutations in pyrin cause FMF is not known, but the pyrin domain is
found in proteins that participate in pathways leading to the activation of
caspases involved in the proteolytic processing and activation of the inflam-
matory cytokines pro-1b and pro-IL-18, and in apoptosis. It is not difficult to
envisage how unregulated cytokine activity and defective apoptosis could
result in a failure to control inflammation. In mice, an absence of pyrin causes
an increased sensitivity to lipopolysaccharide and a defect in macrophage
apoptosis. A related protein, named cryopyrin, encoded by the gene CIAS1, is
mutated in the episodic inflammatory diseases Muckle–Wells syndrome and
familial cold autoinflammatory syndrome (FCAS). These dominantly inher-
ited syndromes present with episodes of fever—which is induced by exposure
to cold in the case of FCAS—as well as urticarial rash, joint pains, and con-
junctivitis. Mutations in CIAS1 are also associated with the autoinflammatory
disorder chronic infantile neurologic cutaneous and articular syndrome
(CINCA), in which short recurrent fever episodes are common, although
severe arthropathic, neurologic, and dermatologic symptoms predominate.
Both pyrin and cryopyrin are predominantly expressed in leukocytes and in
cells that act as barriers to pathogens, such as intestinal epithelial cells. The
stimuli that modulate pyrin and related molecules include inflammatory
cytokines and lipopolysaccharide. The mechanism underlying these diseases
is not fully understood but is thought to be a failure to regulate NFkB and IL-1
production. Indeed, Muckle–Wells syndrome responds dramatically to the
drug anakinra, an antagonist of the receptor for IL-1.
Not all autoinflammatory diseases are caused by mutations in genes involved
in the regulation of apoptosis. Hyper IgD syndrome (HIDS), which is associ-
ated with attacks of fever starting in infancy, high levels of IgD in serum, and
lymphadenopathy, is caused by mutations that result in a partial deficiency
of mevalonate kinase, an enzyme in the pathway for the synthesis of
isoprenoids and cholesterol. It is not yet clear how this enzyme deficiency
causes the autoinflammatory disease.
13-21 Crohn’s disease is a relatively common inflammatory disease with a

complex etiology.
The heritable autoinflammatory diseases just described are fortunately rare,

although they illustrate well the importance of the precise regulation of
inflammatory responses. A much commoner inflammatory disease is Crohn’s
disease, an intestinal disorder of the type known generally as inflammatory
bowel disease. The other main inflammatory bowel disease is ulcerative coli-
tis. Crohn’s disease is thought to result from an abnormal overresponsiveness
to the normal commensal gut flora; unlike the autoinflammatory diseases
discussed previously, it has multiple genetic risk factors. Patients have
episodes of severe inflammation that commonly affect the terminal ileum—
hence the alternative name of regional ileitis for this disease—but any part of
the gastrointestinal tract can be involved. The disease is characterized by a
chronic inflammation of the mucosa and submucosa of the intestine that
includes the prominent development of granulomatous lesions (Fig. 13.34)
similar to those seen in the type IV hypersensitivity responses discussed in
Section 13-19. Genetic analysis of patients with Crohn’s disease and their
families has identified a disease-susceptibility gene named NOD2 (also
known as CARD15) that is expressed predominantly in monocytes, dendritic
Fig. 13.34 Granulomatous inflammation cells, and the Paneth cells of the small intestine. Mutations and uncommon
in Crohn’s disease. A section of bowel
polymorphic variants of the NOD2 protein are strongly associated with the
wall from a patient with Crohn’s disease.
The arrow marks a giant cell granuloma. presence of Crohn’s disease, with around 30% of patients carrying a loss-of-
There is a dense infiltrate of lymphocytes function mutation in NOD2. Mutations in the same gene are also the cause of
throughout the bowel submucosa. a dominantly inherited granulomatous disease named Blau syndrome, in
Photograph courtesy of H.T. Cook. which granulomas typically develop in the skin, eyes, and joints. Whereas

Summary to Chapter 13 591
Crohn’s disease represents a loss of function of NOD2, it is thought that Blau

syndrome represents a gain of function.
NOD2 serves as an intracellular receptor for the muramyl dipeptide derived
from bacterial peptidoglycan, and its stimulation leads to activation of the
transcription factor NFkB and the induction of genes encoding pro-inflam-
matory cytokines (see Section 2-10). This pro-inflammatory response is
believed to be important for the clearance of gut bacteria whose presence
would otherwise lead to sustained chronic inflammation (see Section 11-11).
The mutant forms of NOD2 have lost this function, and it is thought that this
allows the development of chronic inflammation.
A further complication to the story is the identification of a deficiency in
innate immunity in patients with Crohn’s disease, in which a failure to clear
pathogenic bacteria was found to be due to defective CXCL8 production and
defective neutrophil accumulation. This may not lead to abnormal bowel
pathology unless there is also a defect in NOD2, thereby promoting abnormal
inflammation. Thus, it has been proposed that defects in innate immunity
and in the regulation of inflammation act synergistically to promote the
pathology of Crohn’s disease.
Analysis of the autoinflammatory diseases has opened a new field of study in
the medical sciences; it is likely that many other diseases will turn out to be
caused by or modified by polymorphic genetic variants or mutants in the
genes that regulate innate immune responses and the control of inflamma-
tion. A minor infection or physiological stress with no adverse consequences
in most people might turn out to have devastating effects in a minority of
genetically predisposed people. A second important message from these
illnesses is that a more robust classification of diseases will be possible when
we understand their underlying molecular basis.
Summary.
Hypersensitivity diseases reflect normal immune mechanisms that are inap-

propriately directed against innocuous antigens or inflammatory stimuli.
They can be mediated by IgG antibodies bound to modified cell surfaces, or
by complexes of antibodies bound to poorly catabolized antigens, as occurs
in serum sickness. Hypersensitivity reactions mediated by T cells can be acti-
vated by modified self proteins or by injected proteins such as those in the
mycobacterial extract tuberculin. These T cell-mediated responses require
the induced synthesis of effector molecules and develop more slowly, which
is why they are termed delayed-type hypersensitivity. A genetic failure to reg-
ulate inflammation gives rise to rare autoinflammatory syndromes, whereas
Crohn’s disease is associated with a failure to control commensal gut bacteria
and prevent them from causing chronic inflammation.
Summary to Chapter 13.
In some people, immune responses to otherwise innocuous antigens

produce allergic or hypersensitivity reactions upon reexposure to the same
antigen. Most allergies involve the production of IgE antibody against com-
mon environmental allergens. Some people are intrinsically prone to making
IgE antibodies against many allergens, and such people are said to be atopic.
IgE production is driven by antigen-specific TH2 cells; the response is polar-
ized toward TH2 by an array of chemokines and cytokines that engage specific
signaling pathways. The IgE produced binds to the high-affinity IgE receptor
FceRI on mast cells and basophils. Specific effector T cells, mast cells, and
eosinophils, in combination with TH1 and TH2 cytokines and chemokines,

orchestrate chronic allergic inflammation, which is the major cause of the

chronic morbidity of asthma. Failure to regulate these responses can occur at
many levels of the immune system, including defects in regulatory T cells.
Antibodies of other isotypes and antigen-specific effector T cells contribute
to hypersensitivity to other antigens. The autoinflammatory syndromes are
due to uncontrolled inflammation in the absence of disease, whereas Crohn’s
disease is thought to represent a failure to control the numbers of commen-
sal gut bacteria.
Questions.
13.1 List three hypersensitivities that involve IgE and three that involve other
mechanisms.
13.2 Describe how a person becomes sensitized to an allergen.
13.3 Discuss the factors predisposing to the production of IgE.
13.4 What are the key features that differentiate acute and chronic allergic
reactions?
13.5 How can the innate immune system contribute to allergy?
13.6 How do infectious agents modulate allergy?
13.7 Which types of white blood cells participate in allergic responses, and what
do they do?
13.8 Describe how an ingested food allergen can give rise to the allergic skin
reaction urticaria.
13.9 How does desensitization therapy work?
13.10 What are the main features of (a) type II hypersensitivity disease; (b) type
III hypersensitivity disease; and (c) type IV hypersensitivity disease? Give
an example of each type.
13.11 How does autoinflammatory disease differ from allergy?
13.12 How is the regulation of cell death and autoinflammatory disease linked?

References 593
Sehgal, N., A. Custovic, and Woodcock, A.: Potential roles in rhinitis for pro-
General references. tease and other enzymatic activities of allergens. Curr. Allergy Asthma Rep. 2005,
5:221–226.
Johansson, S.G., Bieber, T., Dahl, R., Friedmann, P.S., Lanier, B.Q., Lockey, R.F.,
Motala, C., Ortega Martell, J.A., Platts-Mills, T.A., Ring, J., et al.: Revised nomen- Sprecher, E., Tesfaye-Kedjela, A., Ratajczak, P., Bergman, R., and Richard, G.:
clature for allergy for global use: Report of the Nomenclature Review Deleterious mutations in SPINK5 in a patient with congenital ichthyosiform ery-
Committee of the World Allergy Organization, October 2003. J. Allergy Clin. throderma: molecular testing as a helpful diagnostic tool for Netherton syn-
Immunol. 2004, 113:832–836. drome. Clin. Exp. Dermatol. 2004, 29:513–517.
Kay, A.B.: Allergy and Allergic Diseases. Oxford, Blackwell Science, 1997. Thomas, W.R., Smith, W., and Hales, B.J.: House dust mite allergen charac-
terisation: implications for T-cell responses and immunotherapy. Int. Arch.
Kay, A.B.: Allergy and allergic diseases. First of two parts. N. Engl. J. Med. Allergy Immunol. 1998, 115:9–14.
2001, 344:30–37.
Wan, H., Winton, H.L., Soeller, C., Tovey, E.R., Gruenert, D.C., Thompson, P.J.,
Kay, A.B.: Allergy and allergic diseases. Second of two parts. N. Engl. J. Med. Stewart, G.A., Taylor, G.W., Garrod, D.R., Cannell, M.B., et al.: Der p 1 facilitates
2001, 344:109–113. transepithelial allergen delivery by disruption of tight junctions. J. Clin. Invest.
1999, 104:123–133.
Kay, A.B.: The role of T lymphocytes in asthma. Chem. Immunol. Allergy 2006,
91:59–75.
Maddox, L., and Schwartz, D.A.: The pathophysiology of asthma. Annu. Rev. 13-3 Class switching to IgE in B lymphocytes is favored by specific signals.
Med. 2002, 53:477–498.
Chen, Z., Lund, R., Aittokallio, T., Kosonen, M., Nevalainen, O., and Lahesmaa,
Papageorgiou, P.S.: Clinical aspects of food allergy. Biochem. Soc.Trans. 2002, R.: Identification of novel IL-4/Stat6-regulated genes in T lymphocytes.
30:901–906. J. Immunol. 2003, 171:3627–3635.
Ring, J., Kramer, U., Schafer, T., and Behrendt, H.: Why are allergies increasing? Gauchat, J.F., Henchoz, S., Mazzei, G., Aubry, J.P., Brunner, T., Blasey, H., Life,
Curr. Opin. Immunol. 2001, 13:701–708. P., Talabot, D., Flores Romo, L., Thompson, J., et al.: Induction of human IgE
synthesis in B cells by mast cells and basophils. Nature 1993, 365:340–343.
Romagnani, S.: The role of lymphocytes in allergic disease. J. Allergy Clin.
Immunol. 2000, 105:399–408. Geha, R.S., Jabara, H.H., and Brodeur, S.R.: The regulation of immuno-
globulin E class-switch recombination. Nat. Rev. Immunol. 2003, 3:721–732.
Rosen, F.S.: Urticaria, angioedema, and anaphylaxis. Pediatr. Rev. 1992,
13:387–390. Hoey, T., and Grusby, M.J.: STATs as mediators of cytokine-induced
responses. Adv. Immunol. 1999, 71:145–162.
Pease, J.E.: Asthma, allergy and chemokines. Curr. Drug Targets 2006, 7:3–12.
Section references. Robinson, D.S.: The Th1 and Th2 concept in atopic allergic disease. Chem
Immunol. 2000, 78:50–61.
Romagnani, S.: Cytokines and chemoattractants in allergic inflammation.

13-1 Allergens are often delivered transmucosally at low dose, a route that
Mol. Immunol. 2002, 38:881–885.
favors IgE production.
Shimoda, K., van Deursen, J., Sangster, M.Y., Sarawar, S.R., Carson, R.T., Tripp,
Holt, P.G.: The role of airway dendritic cell populations in regulation of T-cell R.A., Chu, C., Quelle, F.W., Nosaka, T., Vignali, D.A., et al.: Lack of IL-4-induced Th2
responses to inhaled antigens: atopic asthma as a paradigm. J. Aerosol Med. response and IgE class switching in mice with disrupted Stat6 gene. Nature
2002, 15:161–168. 1996, 380:630–633.
Lambrecht, B.N., De Veerman, M., Coyle, A.J., Gutierrez-Ramos, J.C., Urban, J.F., Jr., Noben-Trauth, N., Donaldson, D.D., Madden, K.B., Morris, S.C.,
Thielemans, K., and Pauwels, R.A.: Myeloid dendritic cells induce Th2 responses Collins, M., and Finkelman, F.D.: IL-13, IL-4Ra, and Stat6 are required for the
to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. expulsion of the gastrointestinal nematode parasite Nippostrongylus brasilien-
2000, 106:551–559. sis. Immunity 1998, 8:255–264.
O’Hehir, R.E., Garman, R.D., Greenstein, J.L., and Lamb, J.R.: The specificity and Zhu, J., Guo, L., Watson, C.J., Hu-Li, J., and Paul, W.E.: Stat6 is necessary and
regulation of T-cell responsiveness to allergens. Annu. Rev. Immunol. 1991, 9:67–95. sufficient for IL-4’s role in Th2 differentiation and cell expansion. J. Immunol.
2001, 166:7276–7281.
13-2 Enzymes are frequent triggers of allergy.
13-4 Both genetic and environmental factors contribute to the development
Grunstein, M.M., Veler, H., Shan, X., Larson, J., Grunstein, J.S., and Chuang, S.: of IgE-mediated allergy.
Proasthmatic effects and mechanisms of action of the dust mite allergen, Der
p 1, in airway smooth muscle. J. Allergy Clin. Immunol. 2005, 116:94–101. Cookson, W.: The immunogenetics of asthma and eczema: a new focus on
the epithelium. Nat. Rev. Immunol. 2004, 4:978–988.
Kauffman, H.F., Tomee, J.F., van de Riet, M.A., Timmerman, A.J., and Borger, P.:
Protease-dependent activation of epithelial cells by fungal allergens leads to Culley, F.J., Pollott, J., and Openshaw, P.J.: Age at first viral infection deter-
morphologic changes and cytokine production. J. Allergy Clin. Immunol. 2000, mines the pattern of T cell-mediated disease during reinfection in adulthood.
105:1185–1193. J. Exp. Med. 2002, 196:1381–1386.
Nordlee, J.A., Taylor, S.L., Townsend, J.A., Thomas, L.A., and Bush, R.K.: Dunne, D.W., and Cooke, A.: Opinion: a worm’s eye view of the immune
Identification of a Brazil-nut allergen in transgenic soybeans. N. Engl. J. Med. system: consequences for evolution of human autoimmune disease. Nat. Rev.
1996, 334:688–692. Immunol. 2005, 5:420-426.

Eder, W., and von Mutius, E.: Hygiene hypothesis and endotoxin: what is the Wills-Karp, M., Santeliz, J., and Karp, C.L.: The germless theory of allergic dis-
evidence? Curr. Opin. Allergy Clin. Immunol. 2004, 4:113–117. ease: revisiting the hygiene hypothesis. Nat. Rev. Immunol. 2001, 1:69–75.
Gilliland, F.D., Li, Y.F., Saxon, A., and Diaz-Sanchez, D.: Effect of glutathione-
S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic 13-5 Regulatory T cells can control allergic responses.
responses: randomised, placebo-controlled crossover study. Lancet 2004,
363:119–125. Akdis, M., Blaser, K., and Akdis, C.A.: T regulatory cells in allergy: novel con-
cepts in the pathogenesis, prevention, and treatment of allergic diseases.
Hershey, G.K., Friedrich, M.F., Esswein, L.A., Thomas, M.L., and Chatila, T.A.: J. Allergy Clin. Immunol. 2005, 116:961–968.
The association of atopy with a gain-of-function mutation in the a subunit of
the interleukin-4 receptor. N. Engl. J. Med. 1997, 337:1720–1725. Haddeland, U., Karstensen, A.B., Farkas, L., Bo, K.O., Pirhonen, J., Karlsson, M.,
Kvavik, W., Brandtzaeg, P., and Nakstad, B.: Putative regulatory T cells are
Lynch, N.R., Hagel, I., Perez, M., Di Prisco, M.C., Lopez, R., and Alvarez, N.: impaired in cord blood from neonates with hereditary allergy risk. Pediatr.
Effect of antihelminthic treatment on the allergic reactivity of children in a trop- Allergy Immunol. 2005, 16:104–112.
ical slum. J. Allergy Clin. Immunol. 1993, 92:404–411.
Hawrylowicz, C.M.: Regulatory T cells and IL-10 in allergic inflammation.
Matricardi, P.M., Rosmini, F., Ferrigno, L., Nisini, R., Rapicetta, M., Chionne, P., J. Exp. Med. 2005, 202:1459–1463.
Stroffolini, T., Pasquini, P., and D’Amelio, R.: Cross sectional retrospective study of
prevalence of atopy among Italian military students with antibodies against Hayashi, T., Beck, L., Rossetto, C., Gong, X., Takikawa, O., Takabayashi, K.,
hepatitis A virus. BMJ 1997, 314:999–1003. Broide, D.H., Carson, D.A., and Raz, E.: Inhibition of experimental asthma by
indoleamine 2,3-dioxygenase. J. Clin. Invest. 2004, 114:270–279.
McIntire, J.J., Umetsu, S.E., Akbari, O., Potter, M., Kuchroo, V.K., Barsh, G.S.,
Freeman, G.J., Umetsu, D.T., and DeKruyff, R.H.: Identification of Tapr (an airway Kuipers, H., and Lambrecht, B.N.: The interplay of dendritic cells, Th2 cells
hyperreactivity regulatory locus) and the linked Tim gene family. Nat. Immunol. and regulatory T cells in asthma. Curr. Opin. Immunol. 2004, 16:702–708.
2001, 2:1109–1116. Lin, W., Truong, N., Grossman, W.J., Haribhai, D., Williams, C.B., Wang, J., Martin,
Mitsuyasu, H., Yanagihara, Y., Mao, X.Q., Gao, P.S., Arinobu, Y., Ihara, K., M.G., and Chatila, T.A.: Allergic dysregulation and hyperimmunoglobulinemia E
Takabayashi, A., Hara, T., Enomoto, T., Sasaki, S., et al.: Cutting edge: dominant in Foxp3 mutant mice. J. Allergy Clin. Immunol. 2005, 116:1106–1115.
effect of Ile50Val variant of the human IL-4 receptor a-chain in IgE synthesis. Mellor, A.L., and Munn, D.H.: IDO expression by dendritic cells: tolerance and
J. Immunol. 1999, 162:1227–1231. tryptophan catabolism. Nat. Rev. Immunol. 2004, 4:762–774.
Morahan, G., Huang, D., Wu, M., Holt, B.J., White, G.P., Kendall, G.E., Sly, P.D.,
and Holt, P.G.: Association of IL12B promoter polymorphism with severity of
13-6 Most IgE is cell-bound and engages effector mechanisms of the
atopic and non-atopic asthma in children. Lancet 2002, 360:455–459.
immune system by different pathways from other antibody isotypes.
Palmer, L.J., Silverman, E.S., Weiss, S.T., and Drazen, J.M.: Pharmacogenetics
of asthma. Am. J. Respir. Crit. Care Med. 2002, 165:861–866. Conner, E.R., and Saini, S.S.: The immunoglobulin E receptor: expression
and regulation. Curr. Allergy Asthma Rep. 2005, 5:191–196.
Raitala, A., Karjalainen, J., Oja, S.S., Kosunen, T.U., and Hurme, M.: Indoleamine
2,3-dioxygenase (IDO) activity is lower in atopic than in non-atopic individuals Gilfillan, A.M., and Tkaczyk, C.: Integrated signalling pathways for mast-cell
and is enhanced by environmental factors protecting from atopy. Mol. Immunol. activation. Nat. Rev. Immunol. 2006, 6:218–230.
2006, 43:1054–1056. Heyman, B.: Regulation of antibody responses via antibodies, complement,
Saxon, A., and Diaz-Sanchez, D. Air pollution and allergy: you are what you and Fc receptors. Annu. Rev. Immunol. 2000, 18:709–737.
breathe. Nat. Immunol. 2005, 6:223–226. Kinet, J.P.: The high-affinity IgE receptor (FceRI): from physiology to pathol-
Shaheen, S.O., Aaby, P., Hall, A.J., Barker, D.J., Heyes, C.B., Shiell, A.W., and ogy. Annu. Rev. Immunol. 1999, 17:931–972.
Goudiaby, A.: Measles and atopy in Guinea-Bissau. Lancet 1996, 347:1792–1796. Payet, M., and Conrad, D.H.: IgE regulation in CD23 knockout and transgenic
Shapiro, S.D., and Owen, C.A.: ADAM-33 surfaces as an asthma gene. N. Engl. mice. Allergy 1999, 54:1125–1129.
J. Med. 2002, 347:936–938.
Strachan, D.P.: Hay fever, hygiene, and household size. BMJ 1989, 13-7 Mast cells reside in tissues and orchestrate allergic reactions.
299:1259–1260.
Ali, K., Bilancio, A., Thomas, M., Pearce, W., Gilfillan, A.M., Tkaczyk, C., Kuehn,
Summers, R.W., Elliott, D.E., Urban, J.F., Jr., Thompson, R.A., and Weinstock, N., Gray, A., Giddings, J., Peskett, E., et al.: Essential role for the p110dd phospho-
J.V.: Trichuris suis therapy for active ulcerative colitis: a randomized controlled inositide 3-kinase in the allergic response. Nature 2004, 431:1007–1011.
trial. Gastroenterology 2005, 128:825–832.
Austen, K.F.: The Paul Kallos Memorial Lecture. From slow-reacting sub-
Umetsu, D.T., McIntire, J.J., Akbari, O., Macaubas, C., and DeKruyff, R.H.: stance of anaphylaxis to leukotriene C4 synthase. Int. Arch. Allergy Immunol.
Asthma: an epidemic of dysregulated immunity. Nat. Immunol. 2002, 3:715–720. 1995, 107:19–24.
Van Eerdewegh, P., Little, R.D., Dupuis, J., Del Mastro, R.G., Falls, K., Simon, J., Torrey, Bingham, C.O., and Austen, K.F.: Mast-cell responses in the development of
D., Pandit, S., McKenny, J., Braunschweiger, K., et al.: Association of the ADAM33 asthma. J. Allergy Clin. Immunol. 2000, 105:S527–S534.
gene with asthma and bronchial hyperresponsiveness. Nature 2002, 418:426–430.
Galli, S.J., Nakae, S., and Tsai, M.: Mast cells in the development of adaptive
von Mutius, E., Martinez, F.D., Fritzsch, C., Nicolai, T., Roell, G., and Thiemann, immune responses. Nat. Immunol. 2005, 6:135–142.
H.H.: Prevalence of asthma and atopy in two areas of West and East Germany.
Gonzalez-Espinosa, C., Odom, S., Olivera, A., Hobson, J.P., Martinez, M.E., Oliveira-
Am. J. Respir. Crit Care Med. 1994, 149:358–364.
Dos-Santos, A., Barra, L., Spiegel, S., Penninger, J.M., and Rivera, J.: Preferential sig-
Wills-Karp, M.: Asthma genetics: not for the TIMid? Nat. Immunol. 2001, naling and induction of allergy-promoting lymphokines upon weak stimulation of
2:1095–1096. the high affinity IgE receptor on mast cells. J. Exp. Med. 2003,197:1453–1465.

References 595
Luster, A.D., and Tager, A.M.: T-cell trafficking in asthma: lipid mediators Macfarlane, A.J., Kon, O.M., Smith, S.J., Zeibecoglou, K., Khan, L.N., Barata,
grease the way. Nat Rev Immunol. 2004, 4:711–724. L.T., McEuen, A.R., Buckley, M.G., Walls, A.F., Meng, Q., et al.: Basophils,
eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase
Mekori, Y.A., and Metcalfe, D.D.: Mast cell–T cell interactions. J. Allergy Clin.
allergic reactions in the lung and skin. J. Allergy Clin. Immunol. 2000, 105:99–107.
Immunol. 1999, 104:517–523.
Pearlman, D.S.: Pathophysiology of the inflammatory response. J. Allergy
Oguma, T., Palmer, L.J., Birben, E., Sonna, L.A., Asano, K., and Lilly, C.M.: Role
Clin. Immunol. 1999, 104:S132–S137.
of prostanoid DP receptor variants in susceptibility to asthma. N. Engl. J. Med.
2004, 351:1752–1763. Taube, C., Duez, C., Cui, Z.H., Takeda, K., Rha, Y.H., Park, J.W., Balhorn, A.,
Donaldson, D.D., Dakhama, A., and Gelfand, E.W.: The role of IL-13 in established
Taube, C., Miyahara, N., Ott, V., Swanson, B., Takeda, K., Loader, J., Shultz, L.D.,
allergic airway disease. J. Immunol. 2002, 169:6482-6489.
Tager, A.M., Luster, A.D., Dakhama, A., et al.: The leukotriene B4 receptor (BLT1)
is required for effector CD8+ T cell-mediated, mast cell-dependent airway
hyperresponsiveness. J. Immunol. 2006, 176:3157–3164. 13-11 The clinical effects of allergic reactions vary according to the site of
mast-cell activation.
Williams, C.M., and Galli, S.J.: The diverse potential effector and immunoreg-
ulatory roles of mast cells in allergic disease. J. Allergy Clin. Immunol. 2000, deShazo, R.D., and Kemp, S.F.: Allergic reactions to drugs and biologic
105:847–859. agents. JAMA 1997, 278:1895–1906.
Dombrowicz, D., Flamand, V., Brigman, K.K., Koller, B.H., and Kinet, J.P.:
13-8 Eosinophils are normally under tight control to prevent inappropriate Abolition of anaphylaxis by targeted disruption of the high affinity
toxic responses. immunoglobulin E receptor a chain gene. Cell 1993, 75:969–976.
Bisset, L.R., and Schmid-Grendelmeier, P.: Chemokines and their receptors in Fernandez, M., Warbrick, E.V., Blanca, M., and Coleman, J.W.: Activation and
the pathogenesis of allergic asthma: progress and perspective. Curr. Opin. hapten inhibition of mast cells sensitized with monoclonal IgE anti-penicillin
Pulm. Med. 2005, 11:35–42. antibodies: evidence for two-site recognition of the penicillin derived determi-
nant. Eur. J. Immunol. 1995, 25:2486–2491.
Dombrowicz, D., and Capron, M.: Eosinophils, allergy and parasites. Curr.
Opin. Immunol. 2001, 13:716–720. Finkelman, F.D., Rothenberg, M.E., Brandt, E.B., Morris, S.C., and Strait, R.T.:
Molecular mechanisms of anaphylaxis: lessons from studies with murine
Lukacs, N.W.: Role of chemokines in the pathogenesis of asthma. Nat. Rev.
models. J. Allergy Clin. Immunol. 2005, 115:449-457; quiz 458.
Immunol. 2001, 1:108–116.
Kemp, S.F., Lockey, R.F., Wolf, B.L., and Lieberman, P.: Anaphylaxis. A review
Mattes, J., and Foster, P.S.: Regulation of eosinophil migration and Th2 cell
of 266 cases. Arch. Intern. Med. 1995, 155:1749–1754.
function by IL-5 and eotaxin. Curr. Drug Targets Inflamm. Allergy. 2003, 2:169–174.
Oettgen, H.C., Martin, T.R., Wynshaw Boris, A., Deng, C., Drazen, J.M., and
Robinson, D.S., Kay, A.B., and Wardlaw, A.J.: Eosinophils. Clin. Allergy Immunol.
Leder, P.: Active anaphylaxis in IgE-deficient mice. Nature 1994, 370:367–370.
2002, 16:43–75.
Padovan, E.: T-cell response in penicillin allergy. Clin. Exp. Allergy 1998, 28
Suppl 4:33–36.
13-9 Eosinophils and basophils cause inflammation and tissue damage in
allergic reactions. Reisman, R.E.: Insect stings. N. Engl. J. Med. 1994, 331:523–527.
Dvorak, A.M.: Cell biology of the basophil. Int. Rev. Cytol. 1998, 180:87–236. Schwartz, L.B.: Effector cells of anaphylaxis: mast cells and basophils.
Novartis Found Symp. 2004, 257:65–74; discussion 74–69, 98–100, 276–185.
Kay, A.B., Phipps, S., and Robinson, D.S.: A role for eosinophils in airway
remodelling in asthma. Trends Immunol. 2004, 25:477–482. Weltzien, H.U., and Padovan, E.: Molecular features of penicillin allergy.
J. Invest. Dermatol. 1998, 110:203–206.
MacGlashan, D., Jr., Gauvreau, G., and Schroeder, J.T.: Basophils in airway
disease. Curr. Allergy Asthma Rep. 2002, 2:126–132.
13-12 Allergen inhalation is associated with the development of rhinitis
Odemuyiwa, S.O., Ghahary, A., Li, Y., Puttagunta, L., Lee, J.E., Musat-Marcu, S., and asthma.
and Moqbel, R.: Cutting edge: human eosinophils regulate T cell subset selec-
tion through indoleamine 2,3-dioxygenase. J. Immunol. 2004, 173:5909–5913. Bousquet, J., Jeffery, P.K., Busse, W.W., Johnson, M., and Vignola, A.M.:
Asthma. From bronchoconstriction to airways inflammation and remodeling.
Plager, D.A., Stuart, S., and Gleich, G.J.: Human eosinophil granule major
Am. J. Respir. Crit. Care Med. 2000, 161:1720–1745.
basic protein and its novel homolog. Allergy 1998, 53:33–40.
Boxall, C., Holgate, S.T., and Davies, D.E.: The contribution of transforming
Thomas, L.L.: Basophil and eosinophil interactions in health and disease.
growth factor-bb and epidermal growth factor signalling to airway remodelling in
Chem. Immunol. 1995, 61:186–207.
chronic asthma. Eur. Respir. J. 2006, 27:208–229.
Busse, W.W., and Lemanske, R.F., Jr.: Asthma. N. Engl. J. Med. 2001, 344:350–362.
13-10 Allergic reactions can be divided into immediate and late-phase
responses. Dakhama, A., Park, J.W., Taube, C., Joetham, A., Balhorn, A., Miyahara, N.,
Takeda, K., and Gelfand, E.W.: The enhancement or prevention of airway hyper-
Bentley, A.M., Kay, A.B., and Durham, S.R.: Human late asthmatic reactions. responsiveness during reinfection with respiratory syncytial virus is critically
Clin. Exp. Allergy 1997, 27 Suppl 1:71–86. dependent on the age at first infection and IL-13 production. J. Immunol. 2005,
175:1876–1883.
Liu, M.C., Hubbard, W.C., Proud, D., Stealey, B.A., Galli, S.J., Kagey Sobotka, A.,
Bleecker, E.R., and Lichtenstein, L.M.: Immediate and late inflammatory responses Day, J.H., Ellis, A.K., Rafeiro, E., Ratz, J.D., and Briscoe, M.P.: Experimental
to ragweed antigen challenge of the peripheral airways in allergic asthmatics. models for the evaluation of treatment of allergic rhinitis. Ann. Allergy Asthma
Cellular, mediator, and permeability changes. Am. Rev. Respir. Dis. 1991, 144:51–58. Immunol. 2006, 96:263–277; quiz 277–268, 315.

Finotto, S., Neurath, M.F., Glickman, J.N., Qin, S., Lehr, H.A., Green, F.H., Lee, L.A., and Burks, A.W.: Food allergies: prevalence, molecular characteri-
Ackerman, K., Haley, K., Galle, P.R., Szabo, S.J., et al.: Development of sponta- zation, and treatment/prevention strategies. Annu. Rev. Nutr. 2006, 26:539–565.
neous airway changes consistent with human asthma in mice lacking T-bet.
Science 2002, 295:336–338.
13-15 Celiac disease is a model of antigen-specific immunopathology.
Grunig, G., Warnock, M., Wakil, A.E., Venkayya, R., Brombacher, F., Rennick, D.M.,
Sheppard, D., Mohrs, M., Donaldson, D.D., Locksley, R.M., et al.: Requirement for Ciccocioppo, R., Di Sabatino, A., and Corazza, G.R.: The immune recognition
IL-13 independently of IL-4 in experimental asthma. Science 1998, 282:2261–2263. of gluten in celiac disease. Clin. Exp. Immunol. 2005, 140:408–416.
Haselden, B.M., Kay, A.B., and Larche, M.: Immunoglobulin E-independent Koning, F.: Celiac disease: caught between a rock and a hard place.
major histocompatibility complex-restricted T cell peptide epitope-induced late Gastroenterology 2005, 129:1294–1301.
asthmatic reactions. J. Exp. Med. 1999, 189:1885–1894.
Shan, L., Molberg, O., Parrot, I., Hausch, F., Filiz, F., Gray, G.M., Sollid, L.M., and
Kuperman, D.A., Huang, X., Koth, L.L., Chang, G.H., Dolganov, G.M., Zhu, Z., Khosla, C.: Structural basis for gluten intolerance in celiac sprue. Science 2002,
Elias, J.A., Sheppard, D., and Erle, D.J.: Direct effects of interleukin-13 on epithe- 297:2275–2279.
lial cells cause airway hyperreactivity and mucus overproduction in asthma.
Sollid, L.M.: Celiac disease: dissecting a complex inflammatory disorder.
Nat. Med. 2002, 8:885–889.
Nat. Rev. Immunol. 2002, 2:647–655.
Lee, N.A., Gelfand, E.W., and Lee, J.J.: Pulmonary T cells and eosinophils:
coconspirators or independent triggers of allergic respiratory pathology?
13-16 Allergy can be treated by inhibiting either IgE production or the
J. Allergy Clin. Immunol. 2001, 107:945–957.
effector pathways activated by the cross-linking of cell-surface IgE.
Louahed, J., Toda, M., Jen, J., Hamid, Q., Renauld, J.C., Levitt, R.C., and
Nicolaides, N.C.: Interleukin-9 upregulates mucus expression in the airways. Am. Adkinson, N.F., Jr., Eggleston, P.A., Eney, D., Goldstein, E.O., Schuberth, K.C.,
J. Respir. Cell Mol. Biol. 2000, 22:649–656. Bacon, J.R., Hamilton, R.G., Weiss, M.E., Arshad, H., Meinert, C.L., et al.: A con-
trolled trial of immunotherapy for asthma in allergic children. N. Engl. J. Med.
Platts-Mills, T.A.: The role of allergens in allergic airway disease. J. Allergy 1997, 336:324–331.
Clin. Immunol. 1998, 101:S364–S366.
Ali, F.R., Kay, A.B., and Larche, M.: The potential of peptide immunotherapy in
Szabo, S.J., Sullivan, B.M., Stemmann, C., Satoskar, A.R., Sleckman, B.P., and allergy and asthma. Curr. Allergy Asthma Rep. 2002, 2:151–158.
Glimcher, L.H.: Distinct effects of T-bet in TH1 lineage commitment and IFN-gg
production in CD4 and CD8 T cells. Science 2002, 295:338–342. Bertrand, C., and Geppetti, P.: Tachykinin and kinin receptor antagonists:
therapeutic perspectives in allergic airway disease. Trends Pharmacol. Sci. 1996,
Wills-Karp, M.: Interleukin-13 in asthma pathogenesis. Immunol. Rev. 2004, 17:255–259.
202:175–190.
Bryan, S.A., O’Connor, B.J., Matti, S., Leckie, M.J., Kanabar, V., Khan, J.,
Zureik, M., Neukirch, C., Leynaert, B., Liard, R., Bousquet, J., and Neukirch, F.: Warrington, S.J., Renzetti, L., Rames, A., Bock, J.A., et al.: Effects of recombinant
Sensitisation to airborne moulds and severity of asthma: cross sectional study human interleukin-12 on eosinophils, airway hyper-responsiveness, and the
from European Community respiratory health survey. BMJ 2002, 325:411–414. late asthmatic response. Lancet 2000, 356:2149–2153.
Creticos, P.S., Reed, C.E., Norman, P.S., Khoury, J., Adkinson, N.F., Jr., Buncher,
13-13 Skin allergy is manifested as urticaria or chronic eczema. C.R., Busse, W.W., Bush, R.K., Gadde, J., Li, J.T., et al.: Ragweed immunotherapy
in adult asthma. N. Engl. J. Med. 1996, 334:501–506.
Grattan, C.E.: Autoimmune urticaria. Immunol. Allergy Clin. North Am. 2004,
24:163–181. D’Amato, G.: Role of anti-IgE monoclonal antibody (omalizumab) in the treat-
ment of bronchial asthma and allergic respiratory diseases. Eur. J. Pharmacol.
Howell, M.D., Gallo, R.L., Boguniewicz, M., Jones, J.F., Wong, C., Streib, J.E., and 2006, 533:302–307.
Leung, D.Y.: Cytokine milieu of atopic dermatitis skin subverts the innate
immune response to vaccinia virus. Immunity 2006, 24:341–348. Kline, J.N.: Effects of CpG DNA on Th1/Th2 balance in asthma. Curr. Top.
Microbiol. Immunol. 2000, 247:211–225.
Simpson, E.L., and Hanifin, J.M.: Atopic dermatitis. Med. Clin. North Am. 2006,
90:149–167. Leckie, M.J., ten Brinke, A., Khan, J., Diamant, Z., O’Connor, B.J., Walls, C.M.,
Mathur, A.K., Cowley, H.C., Chung, K.F., Djukanovic, R., et al.: Effects of an inter-
Tsutsui, H., Yoshimoto, T., Hayashi, N., Mizutani, H., and Nakanishi, K.: Induction leukin-5 blocking monoclonal antibody on eosinophils, airway hyper-respon-
of allergic inflammation by interleukin-18 in experimental animal models. siveness, and the late asthmatic response. Lancet 2000, 356:2144–2148.
Immunol. Rev. 2004, 202:115–138.
Oldfield, W.L., Larche, M., and Kay, A.B.: Effect of T-cell peptides derived from
Verhagen, J., Akdis, M., Traidl-Hoffmann, C., Schmid-Grendelmeier, P., Hijnen, D., Fel d 1 on allergic reactions and cytokine production in patients sensitive to
Knol, E.F., Behrendt, H., Blaser, K., and Akdis, C.A.: Absence of T-regulatory cell cats: a randomised controlled trial. Lancet 2002, 360:47–53.
expression and function in atopic dermatitis skin. J. Allergy Clin. Immunol. 2006,
117:176–183. Peters-Golden, M., and Henderson, W.R., Jr.: The role of leukotrienes in aller-
gic rhinitis. Ann. Allergy Asthma Immunol. 2005, 94:609–618; quiz 618-620, 669.
13-14 Allergy to foods causes systemic reactions as well as symptoms Roberts, G., C. Hurley, V. Turcanu, and Lack, G.: Grass pollen immunotherapy
limited to the gut. as an effective therapy for childhood seasonal allergic asthma. J. Allergy Clin.
Immunol. 2006, 117:263-268.
Astwood, J.D., Leach, J.N., and Fuchs, R.L.: Stability of food allergens to
Sabroe, I., Peck, M.J., Van Keulen, B.J., Jorritsma, A., Simmons, G., Clapham,
digestion in vitro. Nat. Biotechnol. 1996, 14:1269–1273.
P.R., Williams, T.J., and Pease, J.E.: A small molecule antagonist of chemokine
Ewan, P.W.: Clinical study of peanut and nut allergy in 62 consecutive receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-
patients: new features and associations. BMJ 1996, 312:1074–1078. mediated HIV-1 entry. J. Biol. Chem. 2000, 275:25985–25992.

References 597
Verhagen, J., Taylor, A., Blaser, K., Akdis, M., and Akdis, C.A.: T regulatory cells tuberculin delayed-type hypersensitivity reaction. J. Exp. Med. 1996,
in allergen-specific immunotherapy. Int. Rev. Immunol. 2005, 24:533–548. 183:277–282.
Verhoef, A., Alexander, C., Kay, A.B., and Larche, M.: T cell epitope Kalish, R.S., Wood, J.A., and LaPorte, A.: Processing of urushiol (poison ivy)
immunotherapy induces a CD4+ T cell population with regulatory activity. 2005, hapten by both endogenous and exogenous pathways for presentation to T
PLoS Med. 2:e78. cells in vitro. J. Clin. Invest. 1994, 93:2039–2047.
Youn, C.J., Miller, M., Baek, K.J., Han, J.W., Nayar, J., Lee, S.Y., McElwain, K., Kimber, I., and Dearman, R.J.: Allergic contact dermatitis: the cellular effec-
McElwain, S., Raz, E., and Broide, D.H.: Immunostimulatory DNA reverses estab- tors. Contact Dermatitis 2002, 46:1–5.
lished allergen-induced airway remodeling. J Immunol. 2004, 173:7556–7564.
Larsen, C.G., Thomsen, M.K., Gesser, B., Thomsen, P.D., Deleuran, B.W.,
Zhu, D., Kepley, C.L., Zhang, K., Terada, T., Yamada, T., and Saxon, A.: A chimeric Nowak, J., Skodt, V., Thomsen, H.K., Deleuran, M., Thestrup Pedersen, K., et al.: The
human–cat fusion protein blocks cat-induced allergy. Nat. Med. 2005, 11:446–449. delayed-type hypersensitivity reaction is dependent on IL-8. Inhibition of a
tuberculin skin reaction by an anti-IL-8 monoclonal antibody. J. Immunol. 1995,
155:2151–2157.
13-17 Innocuous antigens can cause type II hypersensitivity reactions in
susceptible individuals by binding to the surfaces of circulating Mark, B.J., and Slavin, R.G.: Allergic contact dermatitis. Med. Clin. North Am.
blood cells. 2006, 90:169–185.
Arndt, P.A., and Garratty, G.: The changing spectrum of drug-induced immune Muller, G., Saloga, J., Germann, T., Schuler, G., Knop, J., and Enk, A.H.: IL-12 as
hemolytic anemia. Semin Hematol. 2005, 42:137–144. mediator and adjuvant for the induction of contact sensitivity in vivo. J.
Immunol. 1995, 155:4661–4668.
Greinacher, A., Potzsch, B., Amiral, J., Dummel, V., Eichner, A., and Mueller
Eckhardt, C.: Heparin-associated thrombocytopenia: isolation of the antibody Tsuji, R.F., Szczepanik, M., Kawikova, I., Paliwal, V., Campos, R.A., Itakura, A.,
and characterization of a multimolecular PF4–heparin complex as the major Akahira-Azuma, M., Baumgarth, N., Herzenberg, L.A., and Askenase, P.W.: B cell-
antigen. Thromb. Haemost. 1994, 71:247–251. dependent T cell responses: IgM antibodies are required to elicit contact
sensitivity. J. Exp. Med. 2002, 196:1277–1290.
Semple, J.W., and Freedman, J.: Autoimmune pathogenesis and autoimmune
hemolytic anemia. Semin. Hematol. 2005, 42:122–130. Vollmer, J., Weltzien, H.U., and Moulon, C.: TCR reactivity in human nickel
allergy indicates contacts with complementarity-determining region 3 but
excludes superantigen-like recognition. J. Immunol. 1999, 163:2723–2731.
13-18 Systemic disease caused by immune-complex formation can follow
the administration of large quantities of poorly catabolized antigens.
13-20 Mutation or genetic variation in the molecular regulators of
Bielory, L., Gascon, P., Lawley, T.J., Young, N.S., and Frank, M.M.: Human serum inflammation can cause hypersensitive inflammatory responses
sickness: a prospective analysis of 35 patients treated with equine anti-thymo- resulting in ‘autoinflammatory disease.’
cyte globulin for bone marrow failure. Medicine (Baltimore) 1988, 67:40–57.
Chae, J.J., Komarow, H.D., Cheng, J., Wood, G., Raben, N., Liu, P.P., and
Davies, K.A., Mathieson, P., Winearls, C.G., Rees, A.J., and Walport, M.J.: Serum Kastner, D.L.: Targeted disruption of pyrin, the FMF protein, causes heightened
sickness and acute renal failure after streptokinase therapy for myocardial sensitivity to endotoxin and a defect in macrophage apoptosis. Mol. Cell 2003,
infarction. Clin. Exp. Immunol. 1990, 80:83–88. 11:591–604.
Gamarra, R.M., McGraw, S.D. Drelichman, V.S., and Maas, L.C.: Serum Delpech, M., and Grateau, G.: Genetically determined recurrent fevers. Curr.
sickness-like reactions in patients receiving intravenous infliximab. J. Emerg. Opin. Immunol. 2001, 13:539–542.
Med. 2006, 30:41–44.
Drenth, J.P., and van der Meer, J.W.: Hereditary periodic fever. N. Engl. J. Med.
Lawley, T.J., Bielory, L., Gascon, P., Yancey, K.B., Young, N.S., and Frank, M.M.: A 2001, 345:1748–1757.
prospective clinical and immunologic analysis of patients with serum sickness.
N. Engl. J. Med. 1984, 311:1407–1413. Hoffman, H.M., Mueller, J.L., Broide, D.H., Wanderer, A.A., and Kolodner, R.D.:
Mutation of a new gene encoding a putative pyrin-like protein causes familial
Schifferli, J.A., Ng, Y.C., and Peters, D.K.: The role of complement and its cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet.
receptor in the elimination of immune complexes. N. Engl. J. Med. 1986, 2001, 29:301–305.
315:488–495.
Houten, S.M., Frenkel, J., Rijkers, G.T., Wanders, R.J., Kuis, W., and Waterham,
Schmidt, R.E., and Gessner, J.E.: Fc receptors and their interaction with com- H.R.: Temperature dependence of mutant mevalonate kinase activity as a path-
plement in autoimmunity. Immunol. Lett. 2005, 100:56-67. ogenic factor in hyper-IgD and periodic fever syndrome. Hum. Mol. Genet. 2002,
11:3115–3124.
Skokowa, J., Ali, S.R., Felda, O., Kumar, V., Konrad, S., Shushakova, N., Schmidt,
R.E., Piekorz, R.P., Nurnberg, B., Spicher, K., et al.: Macrophages induce the INFEVERS [http://fmf.igh.cnrs.fr/infevers].
inflammatory response in the pulmonary Arthus reaction through Ga ai2 activa-
tion that controls C5aR and Fc receptor cooperation. J. Immunol. 2005, Inohara, N., Ogura, Y., and Nunez, G.: Nods: a family of cytosolic proteins that
174:3041–3050. regulate the host response to pathogens. Curr. Opin. Microbiol. 2002, 5:76–80.
Theofilopoulos, A.N., and Dixon, F.J.: Immune complexes in human diseases: Kastner, D.L., O’Shea, J.J.: A fever gene comes in from the cold. Nat. Genet.
a review. Am. J. Pathol. 1980, 100:529–594. 2001, 29:241–242.
13-19 Delayed-type hypersensitivity reactions are mediated by TH1 cells McDermott, M.F., Aksentijevich, I., Galon, J., McDermott, E.M., Ogunkolade,
and CD8 cytotoxic T cells. B.W., Centola, M., Mansfield, E., Gadina, M., Karenko, L., Pettersson, T., et al.:
Germline mutations in the extracellular domains of the 55 kDa TNF receptor,
Bernhagen, J., Bacher, M., Calandra, T., Metz, C.N., Doty, S.B., Donnelly, T., and TNFR1, define a family of dominantly inherited autoinflammatory syndromes.
Bucala, R.: An essential role for macrophage migration inhibitory factor in the Cell 1999, 97:133–144.

Stehlik, C., and Reed, J.C.: The PYRIN connection: novel players in innate
immunity and inflammation. J Exp Med. 2004, 200:551–558.
Wise, C.A., Gillum, J.D., Seidman, C.E., Lindor, N.M., Veile, R., Bashiardes, S.,
and Lovett, M.: Mutations in CD2BP1 disrupt binding to PTP PEST and are
responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Mol.
Genet. 2002, 11:961–969.
13-21 Crohn’s disease is a common inflammatory bowel disease.
Beutler, B.: Autoimmunity and apoptosis: the Crohn’s connection. Immunity

2001, 15:5–14.
Bonen, D.K., Ogura, Y., Nicolae, D.L., Inohara, N., Saab, L., Tanabe, T., Chen, F.F.,
Foster, S.J., Duerr, R.H., Brant, S.R., et al..: Crohn’s disease-associated NOD2
variants share a signaling defect in response to lipopolysaccharide and pepti-
doglycan. Gastroenterology 2003, 124:140–146.
Hampe, J., Cuthbert, A., Croucher, P.J., Mirza, M.M., Mascheretti, S., Fisher, S.,
Frenzel, H., King, K., Hasselmeyer, A., Macpherson, A.J., et al.: Association
between insertion mutation in NOD2 gene and Crohn’s disease in German and
British populations. Lancet 2001, 357:1925–1928.
Hugot, J.P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.P., Belaiche, J.,
Almer, S., Tysk, C., O’Morain, C.A., Gassull, M., et al.: Association of NOD2 leucine-
rich repeat variants with susceptibility to Crohn’s disease. Nature 2001,
411:599–603.
Marks, D.J., Harbord, M.W., MacAllister, R., Rahman, F.Z., Young, J., Al-Lazikani,
B., Lees, W., Novelli, M., Bloom, S., and Segal, A.W.: Defective acute inflammation
in Crohn’s disease: a clinical investigation. Lancet 2006, 367:668-678.
Wang, X., Kuivaniemi, H., Bonavita, G., Mutkus, L., Mau, U., Blau, E., Inohara, N.,
Nunez, G., Tromp, G., and Williams, C.J.: CARD15 mutations in familial granulo-
matosis syndromes: a study of the original Blau syndrome kindred and other
families with large-vessel arteritis and cranial neuropathy. Arthritis Rheum. 2002,
46:3041–3045.

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555

Allergy and Hypersensitivity

The adaptive immune response is a critical component of host defense

© Garland Science 2008

Type I Type II Type III Type IV

Immune IgE IgG IgG TH 1 cells TH 2 cells CTL

Soluble Cell- or matrix- Cell-surface Soluble Soluble Soluble Cell-associated

Complement, IgE production,

Example of Allergic rhinitis, Some drug Chronic urticaria Chronic asthma,

The biological role of IgE is in protective immunity, especially in response to

© Garland Science 2008

Fig. 13.2 IgE-mediated reactions to

Acute urticaria Animal hair Local increase in

Seasonal Pollens (ragweed, Edema of nasal

Sensitization and the production of IgE.

© Garland Science 2008

Der p 1 is taken up by dendritic Der p 1-specific IgE binds to

dendritic cell mast cell antigen presentation degranulation

© Garland Science 2008

The tendency of proteases to induce IgE production is highlighted by indi-

13-3 Class switching to IgE in B lymphocytes is favored by

The immune response leading to IgE production is driven by two main

The fate of a naive CD4 T cell responding to a peptide presented by a den-

© Garland Science 2008

dendritic cells and naive T cells in the absence of inflammatory stimuli

13-4 Both genetic and environmental factors contribute to the

Studies have found that as many as 40% of people in the populations of

© Garland Science 2008

Asthma Atopic dermatitis Psoriasis Autoimmune diseases

© Garland Science 2008

surface proteins. In mice, Tim-3 protein is specifically expressed on TH1 cells

© Garland Science 2008

Fig. 13.8 Candidate susceptibility

Enhanced presentation of particular

Enhanced T-cell recognition of certain

ADAM33 Structural variants Variation in airway remodeling

2-Adrenergic receptor Structural variants Increased bronchial hyperreactivity*

5-Lipoxygenase Promoter variant Variation in leukotriene production†

Promoter and structural

© Garland Science 2008

© Garland Science 2008

IFN- production (relative level)

Percentage of original weight

IFN- production (relative level)

Percentage of original weight

© Garland Science 2008

Effector mechanisms in allergic reactions.

Allergic reactions are triggered when allergens cross-link preformed IgE

Fig. 13.11 Mast-cell activation has

Gastrointestinal tract Airways Blood vessels

Increased fluid secretion, Decreased diameter, Increased blood flow,

Congestion and blockage of Increased fluid in tissues

© Garland Science 2008

effector cells, notably TH2 lymphocytes, eosinophils, and basophils, which

13-6 Most IgE is cell-bound and engages effector mechanisms of the

Antibodies engage effector cells such as mast cells by binding to receptors

13-7 Mast cells reside in tissues and orchestrate allergic reactions.

© Garland Science 2008

mast cells by Kit, and pharmacological inactivation of the p110d isoform of PI

Fig. 13.12 Molecules released by mast

IL-4, IL-13 Stimulate and amplify TH2-cell response

IL-3, IL-5, GM-CSF Promote eosinophil production and activation

Promotes inflammation, stimulates cytokine

Chemokine Attracts monocytes, macrophages,

2-Adrenergic receptor Structural variants Increased bronchial hyperreactivity*