Professional Documents
Culture Documents
(2008) 1:133–144
DOI 10.1007/s12065-008-0010-z
RESEARCH PAPER
Received: 12 November 2007 / Revised: 12 March 2008 / Accepted: 13 March 2008 / Published online: 29 April 2008
Ó Springer-Verlag 2008
Abstract Four binary-encoded models describing some as to maximize their profit. Numerical experiments and
aspects of the phylogenetics evolution in an artificial conclusions are shown. These considerations present many
immune system have been proposed and analyzed. The first similarities to biological immune systems and also some
model has focused on the evolution of a paratope’s popu- inspirations to solve real-world problems, such as pattern
lation, considering a fixed group of epitopes, to simulate a recognition and knowledge discovery in databases.
hypermutation mechanism and observe how the system
would self-adjust to cover the epitopes. In the second Keywords Artificial immune systems
model, the evolution involves a group of antibodies adapt- Evolutionary computation
ing to a given antigenic molecules’ population. The third Artificial immune systems models
model simulated the coevolution between antibodies’ gen-
erating gene libraries and antigens. The objective was to
simulate somatic recombination mechanisms to obtain final 1 Introduction
libraries apt to produce antibodies to cover any possible
antigen that would appear in the pathogens’ population. In The immune system (IS) is able to protect us from a number
the fourth model, the coevolution involves a new population of pathogens. It also monitors the organism, searching and
of self-molecules whose function was to establish restric- destroying anomalous cells. To perform such tasks, the IS
tions in the evolution of libraries’ population. For all the must recognize a great variety of different compounds and
models implemented, evolutionary algorithms (EA) were distinguish, among them, those which can remain in the
used to form adaptive niching inspired in the coevolutionary organism and those that are to be eliminated. It is believed
shared niching strategy ideas taken from a monopolistic that the IS identifies about 1016 foreign molecules [18],
competition economic model where ‘‘businessmen’’ locate which means that it can identify any molecule [10].
themselves among geographically distributed ‘‘clients’’ so The IS pattern recognition task is performed through
surface receptor molecules of T and B cells. The identifi-
cation of antigens in both these types of lymphocytes
G. P. Figueredo (&) L. A. V. de Carvalho N. F. F. Ebecken
occurs differently. B cells recognize antigens through
Federal University of Rio de Janeiro - COPPE,
Rio de Janeiro, Brazil immune globulins from its cell surface. T cells recognize
e-mail: gpfigueredo@gmail.com only antigens presented by an antigen presenting cell
(APC). The creation of these receptors and their capability
L. A. V. de Carvalho
to cover all antigens have their origin in a very sophisti-
e-mail: meucorreioeletronico@gmail.com
cated genetic mechanism. During the receptor’s formation
N. F. F. Ebecken process, the variation is caused by the combinatorial
e-mail: nelson@ntt.ufrj.br associations among the receptors codifying genes and the
hypermutation mechanism.
H. J. C. Barbosa
LNCC, MCT, Petrópolis, Brazil The hypermutations occur in the lymph nodes’ germi-
e-mail: hcbm@lncc.br native centers. Thus, when an APC penetrates the lymph
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node and shows an antigen to a T cell, or when a B cell There are many possible combinations of the available
finds a pathogen and identifies it, that means the combi- gene segments, which gives the IS the capability of pro-
nation was well succeeded. After the recognizing pattern is ducing an enormous number of distinct antibodies.
established, the lymphocyte becomes activated, cloning These concepts will be the building blocks of the models
itself. Clones with high capacity of recognizing a certain presented in this work, which simulates the dynamics
antigen tend to proliferate. On the other hand, clones with between paratopes and epitopes, and between antigens and
low recognizing capacity disappear and are replaced by antibodies inside the organism along the evolution of a
others with higher efficiency [19, 27]. The analogy species. This work was inspired by the ideas found in [3, 4,
between the clonal selection and the Darwinian natural 8, 10, 14–16, 21–25, 28–30].
selection [5] is clearly seen here. Basically, in the above ideas which served as inspiration
After recognizing an antigen by a B cell receptor, fol- to the present work, the objective was ‘‘to develop models
lowed by a sequence of other events, a formation of plasma directed at understanding the pattern recognition process of
cells clones responsible for the secretion of the same two aspects of the IS, clonal selection and long term evo-
receptor in its soluble form takes place. This secreted lution of genes.’’ In the works cited above most of the
receptor is the antibody and its function is to catch and bind models work with binary strings evolved by genetic algo-
the antigen. This binding occurs between the paratope of rithms (GAs) [10, 14, 16, 23, 28]. Other approaches
the antibody and the antigen’s correspondent epitope. A involving artificial models and citations of many other
paratope that presents a strong bind within the epitope has a Artificial immune systems (AIS) models can be found in
greater capacity of neutralizing the antigen [6, 7]. [2, 9, 20, 26, 36]. No comparison among the models of the
An antibody is constituted by two equal heavy chains present article has been made with the ones previously
and two light chains, as it can be seen in Fig. 1. The shape cited, because the focus of each work was different.
of the molecule is similar to a Y. The base of the Y has Evolutionary Computation has been chosen to imple-
parts of heavy chains and the arms are constituted by both ment the models studied [33]. A coevolutionary genetic
chains. The antibody’s recognizing site is located at the end algorithm (CGA) was used to form adaptive niching based
of each arm, and is known as V region. The antibody is on the ideas of [8]. In that work, in contrast with fixed
antigen-specific, and to provide the organism with anti- shared schemes, a niching formation strategy named
bodies able to recognize all the antigens, the antibodies’ coevolutionary shared niching (CSN) was proposed to
codifying genes suffer somatic recombinations (Fig. 2). allow for the adaptation of the location and the radius of
The variable portion of the light chain requires two each niche . CSN was inspired by Tullock’s [35] economic
distinct DNA encoding segments. The V one encodes most model of monopolistic competition where ‘‘businessmen’’
of the variable region. The remaining is encoded by a J
segment. In a non-activated B cell, the V and C regions
encoding DNA sequences are spatially apart from each
other. When B lymphocytes become mature, the somatic
recombination joins genes from segments V, J and C. The
C segment encodes the light chain constant portion of the
antibody. This mechanism is illustrated in Fig. 2.
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2.1.4 Mutation
An important question for this model is how to determine typical run with a mutation rate of 85%. The inefficiency
the efficacy of the generated system after a number of limit was set to 10%.
generations, or, in other words, if it is capable to combat As it can be seen in the graph of Fig. 3, at the start of the
the given epitopes. evolution of the paratopes, there is no good performance of
During the paratope’s population evolution, there will the system in recognizing and neutralizing the epitopes.
be, at least, one minimum site of bind to all epitopes. That is why the curve starts indicating a small number of
Nevertheless, it is prudent to say that weak binds are not recognized epitopes (vertical axis). However, along the
able to produce efficient neutralizations, since they could evolution course (horizontal axis), the artificial hypermu-
break when in contact with other molecules or under slight tation mechanism enables paratopes to cover the epitopes
environmental variation. population.
Concerning this problem, a performance measure has Another graph, presented in Fig. 4, shows the
been established to determine the efficiency rate in fighting improvement of the fitness of the paratopes through the
aggressors. This parameter was named Inefficiency Limit, generations. In this experiment, the number of epoches was
and its value corresponds to the minimum percentage of an set to 200, chromosome size 65, paratopes population size
epitope that must be recognized by a paratope so that the is 10, and epitopes population size is 300, which is the
latter can be considered inactive. maximum value to be reached by the paratopes population
as shown in the graph of Fig. 4.
2.1.6 Evaluation The results observed showed a great similarity to real
ISs. Those who were able to adapt to new pathogens
The evaluation is obtained by observing individually the
paratope; it is a self-organized system in which what is
expected is the individual action of each paratope leading
to an efficient global defense system.
2.2 Experiments
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3.1.2 Evaluation
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Fig. 8 The evolution of the AIS in the first example In order to implement the system, each individual in this
first GA’s population represents a simplified library which
3.2.2 The second example contains only three binary encoded segment groups V, D
and J. Initially, the libraries have only one segment of each
The second example, shown in Fig. 9 introduces a greater group and their initialization is entirely randomly made.
number of antibodies and shows how this could improve One example of an individual is shown in Fig. 10. The
the performance of the AIS. The paratopes’ population size junction between one segment of each group forms the
was set to 100 and the epitopes’ to 200. genetic code for producing an antibody.
Decoding an individual here means to produce all of its
potential antibodies repertoire. This is done by making
4 The third model recombination between the individual library segments of
V, D and J kind, in this order, as shown in Fig. 11. During
The antibodies’V region task consists of recognizing the the evaluation, this repertoire is contrasted to a binary
antigens. This region is encoded by libraries of gene seg- chained antigens population.
ments. The V light chain requires three DNA segments from The libraries’ recombination operator used was a
the types called V, J and C. The heavy chain is encoded by crossover in which one of the segment groups V, D, or J, is
four segments, V, D, J and C. The somatic recombination randomly chosen and exchanged between the parents, as
between these segments is one of the main lymphocytes— shown in Fig. 12.
and therefore, antibodies—diversity generators.
The third model simulates the coevolution between an
artificial species’ lymphocytes’ encoding genes library and
an antigens’ population. This simulation was implemented
using CGAs. The objective was to obtain a gene library
which produces antibodies that would recognize any
possible mutation in the antigens’ genes. It was also a goal
Fig. 9 The evolution of the AIS in the second example Fig. 12 Crossover operator
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mutation. The probabilities of application assigned to the The Evolution of the Artificial Immune System
Recognized Antigens
genetic operators’ values have been adopted based in what 100
150
Recognized Antigens
50 5.1 Experiments
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individual as part of elitism. The other parameters assumed The Evolution of the IS Considering Self Molecules
200
the same values used in the previous model, 4 bits per gene
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of paratopes and epitopes, the evolution involved a group 4. Cormack DH (1991) HAM histology (in Portuguese), 9 edn.
of antibodies adapting to a given antigen molecules pop- Guanabara Koogan
5. Darwin C (1872) On the origin of species by means of natural
ulation. The results of this second experiment has also selection, or the preservation of favoured races in the struggle for
shown an improvement of the adaptation curve, as in the life, 6th edn. John Murray, London
first model. It has also brought a recognizing pattern 6. de Castro LN (2001) Immune engineering: development of
apparatus able to find equal blocks into a population of bit computational tools inspired by the artificial immune systems (in
Portuguese). Ph.D. thesis, DCA FEEC/UNICAMP, Campinas/SP,
strings. This algorithm could be adapted in order to be Brazil
applied to other complex recognition systems [13]. 7. de Castro LN, Timmis J (2002) Artificial immune systems: a new
The third model has focused on the coevolution between computational intelligence approach, vol 1, 1st edn. Springer,
an antibodies producing gene libraries population and a set New York
8. Farmer JD, Packard NH, Perelson AS (1986) The immune sys-
of antigens. The objective of this experiment was to simu- tem, adaptation, and machine learning. Physica 22D:187–204
late the somatic recombination mechanisms and observe 9. Flores LE, Aguilar EJ, Barbosa VC, de Carvalho LAV (2004) A
how the system would self-adjust to provide the ability of graph model for the evolution of specificity in humoral immunity.
identifying any foreign molecule. This covering capacity is J Theoret Biol 229(3):311–325
10. Forrest S, Smith RE, Javornik B, Perelson AS (1993) Using
the measure of how well the system could protect an arti- genetic algorithms to explore pattern recognition in the immune
ficial species along its evolution. Results of the experiments system. Evolu Comput 1(3):191–211
have shown that, at the beginning of the evolution, the 11. Goldberg D (1989) Genetic algorithms in search, optimization,
libraries available were not well adapted to the exposed and machine learning. Addison-Wesley, Reading
12. Goldberg DE, Wang L (1998) Adaptive niching via coevolu-
antigens. However, as the evolution proceeded, they tionary sharing. Genetic Algorithms and Evolution Strategy in
became much more adapted to the environment presented, Engineering and Computer Science, pp 21–38
being able to recognize any new mutated antigen that would 13. Golub ES (1992) Is the function of the immune system only to
appear in the population. protect? In: Theoretical and experimental insights into immu-
nology, vol 66 of H: cell biology. NATO ASI Series, pp 15–26
With the third model, the real ISs coverage stability was 14. Hightower R, Forrest S, Perelson AS (1995) The evolution of
reached. Therefore, an artificial system able to adapt and emergent organization in immune system gene libraries. In:
recognize any given binary segment has been created. Eshelman L (ed) Proceedings of the 6th international conference
Also, the necessity and ability of a fast changing genetic on genetic algorithms. Morgan Kaufmann, San Francisco, pp
344–350
mechanism to provide robustness to a biological species 15. Hillis W (1990) Co-evolving parasites improve simulated evo-
antibodies’ genotype has been shown. lution as an optimization procedure. Physica D 42:228–234
In addition to libraries and antigens, in the fourth model 16. Hofmeyr SA, Forrest S (2000) Architecture for an artificial
the evolution has involved a new group of bit strings. They immune system. Evol Comput 8(4):443–473
17. Holland JH (1975) Adaptation in natural and artificial systems.
represented molecules belonging to the organism and University of Michigan Press, Ann Arbor
against who the IS could not activate defense mechanisms. 18. Inman J (1978) The antibody combining region: speculations on
With this new restriction, the libraries evolution had to the hypothesis of general multiespecificity. Theoretical Immu-
proceed in order to maximize matching against antigens nology, pp 243–278
19. Janeway CA, Travers P, Walport M, Shlomchik M (2001)
and minimize it against self. To implement this idea, a Immunobiology: the immune system in health and disease, 5th
penalty scheme has been adopted to reduce the fitness of (brazilian) edn. Artes Médicas Porto Alegre
those self-reacting libraries. 20. Jerne NK (1974) Towards a network theory of the immune sys-
The results obtained have shown that the antigens’ tem. Ann Immunol (Inst. Pasteur) 125C(3):73–89
21. Kepler TB, Perelson AS (1993) Cyclic reentry of germinal center
population evolution proceeded towards imitating self- b cells and the efficiency of affinity maturation. Immunol Today
molecules’ bits sequences. As a result, antigens became 14 14:412–415
invisible to the antibodies defense mechanisms pointing to 22. Kepler TB, Perelson AS (1993) Somatic hypermutation in b cells:
the necessity of other means of protection. In real ISs, these an optimal control treatment. J Theoret Biol 164:37–64
23. Oprea M, Forrest S (1999) How the immune system generates
other means are constituted by T-cells. diversity: pathogen space coverage with random and evolved
antibody libraries. In: Banzhaf W, Daida J, Eiben AE, Garzon
MH, Honavar V, Jakiela M, Smith RE (eds) Proceedings of the
References genetic and evolutionary computation conference, vol 2. Morgan
Kaufmann, Orlando, pp 1651–1656
1. Abbas AK, Lichman AH, Pober JS (1998) Molecular and cellular 24. Oprea M, Kepler TB (1999) Genetic plasticity of v genes under
immunology (in Portuguese), 2nd edn. Revinter, Rio de Janeiro somatic hypermutation: statistical analyses using a new resam-
2. Aguilar E (2003) Um estudo sistêmico de um modelo de sistema pling-based methodology. Genome Res 9(12):1294–1304
imune com evolução da especificidade. Master’s thesis, COPPE/ 25. Oprea M, Perelson A (1997) Somatic mutation leads to efficient
UFRJ affinity maturation when centrocytes recycle back to centroblasts.
3. Cayzer S, Smith J, Marshall JAR, Kovacs T (2005) What have J Immunol 158:5155–5162
gene libraries done for artificial immune systems? In: Interna- 26. Perelson A (1989) Immune network theory. Immunol Rev 110:5–
tional conference on artificial immune systems 36
123
144 Evol. Intel. (2008) 1:133–144
27. Perelson AS, Weisbuch G (1997) Immunology for physicists. Rev from homology modeling. In: Hunter L, Klein T (eds) Biocom-
Mod Phys 69:1219 puting: proceedings of the 1996 Pacific symposium. World
28. Ron J. The evolution of secondary organization in immune sys- Scientific Publishing, Singapore
tem gene libraries 33. Stewart J (1992) The immune system in an evolutionary per-
29. Rosin C, Belew R (1995) Methods for competitive co-evolution: spective. In: Theoretical and experimental insights into
finding opponents worth beating. In: Eshelman L (ed) Proc of the immunology, vol 66 of H: cell biology. NATO ASI Series, pp
6th international conference on genetic algorithms and their 27–48
applications. Pittsburgh, PA 34. Tizard I (1985) Introduction to veterinary immunology (In
30. Rosin C, Belew R (1997) New methods for competitive coevo- Portuguese), 2nd edn
lution. Evol Comput 5(1):1–29 35. Tullock G (1967) Towards a mathematics of politics. The
31. Rumjanek VM (2001) Próprio e estranho: é essa a questão? Ci- University of Michigan Press, Ann Arbor
ência Hoje 29:40 36. Twycross J, Aickelin U (2007) Biological inspiration for artificial
32. Shimura J (1996) Somatic mutations in immunoglobulin v gene immune systems. In: Artificial immune systems
determine the structure and function of the protein—an evidence
123