Научная статья на тему 'Modern notion of immune formation during evolution'

Modern notion of immune formation during evolution Текст научной статьи по специальности «Биологические науки»

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Ключевые слова
INNATE IMMUNITY / ADAPTIVE IMMUNITIES / EVOLUTION

Аннотация научной статьи по биологическим наукам, автор научной работы — Maslyanko R.P., Padovsky A.I., Shekel V.F., Levkivska N.D., Matviishyn T.S.

An ideal immune system should provide each individual with rapid and efficient responses, a diverse repertoire of recognition and effector molecules and a certain flexibility to match the changing internal and external environment. It should be economic in cells and genes. Specific memory would be useful. It should not be autoreactive. These requirements, a mixture of innate and adaptive immunity features, are modulated in function of the dominant mode of selection for each species of metazoa during evolution (K or r). From sponges to man, a great diversity of receptors and effector mechanisms, some of them shared with plants, are articulated around conserved signalling cascades. Multiple attempts at combining innate and adaptive immunity somatic features can be observed as new somatic mechanisms provide individualized repertoires of receptors throughout metazoa, in agnathans, prochordates, echinoderms and mollusks. The adaptive immunity of vertebrates with lymphocytes and their specific receptors of the immunoglobulin superfamily, the major histocompatibility complex, developed from innate immunity evolutionary lines that can be traced back in earlier deuterostomes.

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Текст научной работы на тему «Modern notion of immune formation during evolution»

UDK 619:612.017

Maslyanko R.P., Padovsky A.I., Shekel V.F., Levkivska N.D., Matviishyn T.S. ©

Lviv National University of veterinary medicine and biotechnologies named after S.Z. Gzhytsky

MODERN NOTION OF IMMUNE FORMATION DURING EVOLUTION

An ideal immune system should provide each individual with rapid and efficient responses, a diverse repertoire of recognition and effector molecules and a certain flexibility to match the changing internal and external environment. It should be economic in cells and genes. Specific memory would be useful. It should not be autoreactive. These requirements, a mixture of innate and adaptive immunity features, are modulated in function of the dominant mode of selection for each species of metazoa during evolution (K or r). From sponges to man, a great diversity of receptors and effector mechanisms, some of them shared with plants, are articulated around conserved signalling cascades. Multiple attempts at combining innate and adaptive immunity somatic features can be observed as new somatic mechanisms provide individualized repertoires of receptors throughout metazoa, in agnathans, prochordates, echinoderms and mollusks. The adaptive immunity of vertebrates with lymphocytes and their specific receptors of the immunoglobulin superfamily, the major histocompatibility complex, developed from innate immunity evolutionary lines that can be traced back in earlier deuterostomes.

Key words: innate immunity, adaptive immunities, evolution.

Introduction

In May 2004, the following text (a slightly shorter version of it) was submitted to a high impact factor journal upon the request of the editor for 'a good evolutionary article in the style of 'a commentary on the immune system with 'a lot of speculation as to what happened first, then next, then next.

I had put time and efforts to produce what the journal wanted. In fact, I tried to put into it original ideas and speculations and to meander among new findings in an integrated manner. Our views about the evolution of the immune system are altered drastically due to new exciting discoveries that were published a week apart in the summer of 2004. My text must have been poor, and it irritated some of the referees. The editor rejected it. However, to my surprise, hundreds of students and several congress audiences, whom I addressed since May 2004, liked it a lot as a talk. In fact, I was never so praised for the compelling logic of any of my presentations than for those directly derived from this text. So, Ivan, you remember in 1967 in Frankfurt during the EMBO course organized by Niels Jerne where we met for the first time, when we had to vote for or against the uni-commitment of lymphocytes? So please, cast your vote on this commentary. I doubled the content of the paper, and

© Maslyanko R.P., Padovsky A.I., Shekel V.F., Levkivska N.D., Matviishyn T.S., 2014

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I doubled the number of references to make the presentation more comprehensive. You can always tear a few pages of your Festschrift if you do not like it.

How to define an ideal immune system for Metazoa?

The metazoans arose most probably in the sea, from colonial protists. Immediate threats to their individuality must have been multiple, whether of internal or external origin. To fight these multiple simultaneous challenges, early metazoans must have developed almost simultaneously, multiple, rapid and efficient immune pathways. What could be the characteristics of an ideal immune system? It should confer to each individual the best chance of survival under changing conditions of the environment. It should act fast and efficiently. It should have diversity and flexibility of its recognition and effector functions. It should be economical, i.e. it should not use either too many genes or too many cells. It should be specific and above all not be autoreactive in a dangerous way. Memory might be a welcome feature.

How were these characteristics met across the animal kingdom? According to a current consensus, the primitive immune systems might have worked in the following way: triggered by various receptors recruited on epithelia, a few signalling cascades, led to apoptosis, rejecting allografts, avoiding tumours, encapsulating parasites, killing or melanizing bacteria, viruses etc.

In function of the organization of each phylum's body plan, local responses representing the first line of defence could be complemented by a systemic response. This early set constituted the core of the many metazoan innate immune systems that were going to be preserved along evolution [1] and then, later in evolution, and apparently only in jawed vertebrates, a so-called adaptive component was added [2]. It consisted in a 'do-it-yourself kit', i.e. a set of gene segments to be assembled during the ontogeny of lymphocyte that somatically and randomly generates receptors. After selection it provides each individual with an unparalleled diversity of recognition capacity. The combination of its innate and adaptive arms gets the immune system as close to an ideal system as one can get. Still many innate immunologists, flabbergasted by the rapidity and efficiency of many innate immunity processes, often ask the question "Why did vertebrates develop an adaptive immune system?", and some researchers claim that innate could do it all [3].

I would approach the issue from the other end: given the apparent enormous advantage represented by the possibility to adapt to the environment during one's life (which is a characteristic of adaptive immune systems), I would ask "why did not more organisms develop an adaptive system?" Clearly, the characteristics of an ideal immune system call for a mixture of innate and adaptive mechanisms. Indeed, as one unravels more and more immune systems of pregnathostomes, one discovers that several phyla that were thought to depend exclusively on innate mechanisms make use of adaptive features in the immune system. Somatic diversification of immune repertoires and individualization of the responses can be observed in some invertebrates and jaw-less vertebrates. They are the results of mechanisms quite different from those of jawed vertebrates. The reasons for these differences may perhaps depend on the context in which the different immune systems developed. They may lie, among other things, in the relative value of individuals for the survival

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of a species. When this relative value is high (K selection, small progenies of species living long and reaching sexual maturity late in life), the species will 'prefer' to adapt to the environment somatically with maximum individual flexibility [4, 5]. When the relative value of the individual is small (r selection, large progenies of rather short lived individuals reproducing usually only once and relatively early), polymorphism and multiplicity of germline immunity genes in the population will be perhaps adequate (innate arm) and will avoid the complexity of resorting to selection of large repertoires. However, many species fall between these extremes and might combine innate and adaptive features in as many different balances.

Many reviews address the conservation of the signalling cascades involved in innate immunity (Toll and Toll-like initiated cascades leading to the activation of Nf-kappa B and related agents) [1, 6]. Therefore, this commentary will focus on the diversification (and its consequences) of recognition structures in different organisms. The many ways used for this diversification will often blur the limit between what we are used to calling innate and adaptive immunities.

First diversity then multiplicity Diversity

Many different categories of molecules (the basic diversity) coexist in the immune systems of modern Porifera, Cnidaria and Bilateria (for Ctenophora and Placozoa we lack information): when looking at the receptor side we encounter as main actors: leucine-rich repeats (LRR) of Toll and Toll-like and related receptors, immunoglobulin superfamily members (Igsf) (to which vertebrate T-cell receptors and antibodies belong), thio-ester bond-forming proteins (TEP) of the complement family, lectins, peptidoglycan-recognizing proteins and scavenger receptors, e.g. 'cysteine rich' (SRCR) [7]. LRR and leucine-zipper/coil-coil motifs are conserved from plants to mammals [1]. The list does not contain yet the molecular features of the receptors responsible for recognizing the polymorphic histocompatibility loci of various invertebrates [8].

When looking at the effector side, one encounters, e.g. defensins, a diversified family of molecules with strong structural analogy from plants to mammals [9]. A multitude of antimicrobial peptides has been generated in practically all phyla: proline-rich peptides, hydrophobic wedges such as cecropins, glycin-rich attacins and cyclic penta-meric pentraxins involved in antifungal resistance [10]. The multiplicity of molecules that might be involved in defense in a single species of invertebrate [11].

Therefore, from the beginning of their existence, Metazoa recruited a basic diversity of molecular categories able to interact with proteins, sugars or lipids. They were articulated to signalling cascades (PK, Rel-Nf-kappa B), sometimes shared with (i) fertilization control; (ii) development; (iii) metamorphosis and (iv) regeneration pathways and coupled to a diversified set of effector mechanisms [7, 12]. The question of which came first, the involvement in immunity or in the latter above-mentioned tasks, is currently the object of many speculations [13, 14]. Under any circumstances, the resulting pathways covered a large spectrum of threats and were able to provide broad specificities to innate responses [1].

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Multiplicity

Within these categories, pressure for diversification resulted in the creation of large families (multiplicity). This occurred by tandem duplication or polyploidizations during the history of chordates [15]. Differenr levels of multiplicity were reached independently in many organisms as suggested, for instance, by phylogenetic analysis of the Toll and Toll-like receptor (TLR) families [6]. As a result of this independence, today there can be more TEP genes in dipters and more lectins in Caenorhabditis elegans than in vertebrates [1].

Apparently, the pressure for diversification persisted, and the genome of metazoans could not accumulate duplicates in an unlimited manner. Innate and adaptive immune system exploited two economic solutions to increase the number of receptors.

More diversity: getting more than what is in the genome

The first evolutionary solution (not mutually exclusive of the second one) is to add polymorphism to polylocism. It has been used many times during evolution. Shrimps' penaedins, worm lysins, SRCR of echinoderms, vertebrare TLR, Ig, T-cell receptor (TCR), major histocompatibility complex (MHC), natural killer (NK) receptors and related molecules are examples of polymorphic receptors [4]. Changing with time, polymorphism provides populations with flexibility in function of the changing environment and alterations of the pathogens. However, when thinking back to our definition in the Introduction, it does not provide an ideal solution for individual protection.

The second solution is to make more final products than what an individual genome 'officially' provides. This is where the word 'combination' makes sense, not only in classical adaptive immunity. This feature opens the path for individualization of responses and to somatic diversification in several phyla, therefore to analogies and homologies between innate and adaptive immunity.

At the protein level, combinatorial assembly of polypeptide chains can vary binding specificities on the cell surface (e.g. TLR-2 and TLR-6 [16], IgH and IgL chains, TCR-a, TCR-P, TCR-y and TCR-5, MHC-aand MHC-P heterodimers and microbicidal peptides from the gut). Intracellularly, differential utilization and combination of adaptor TIR domains may also provide the specificity in the TLR signalling [16].

At the nucleic acid level there are several possibilities. First, alternative splicing of RNA, a widespread mechanism that increases the diversity of expressed products in general, is indeed used from plants to Bilateria. It diversifies regulators, effectors or receptors of the innate immune system like the (i) penaeidins of shrimps;

(ii) immunoglobulin superfamily (Igsf) members of protochordates and mollusks and

(iii) peptidoglycan-recognizing proteins of dipteran insects and most likely many other families. Considering another example, the family of LRR receptors, involved in immunity from plants to vertebrates including a new form of adaptive response in jaw-less vertebrates is prone to alternate splicing [17], generating many different isotypes. LRR sequences are found on the surface of Ciona leucocyte and share

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structural analogy with vertebrate LRR such as RP105 (TLR distinguished by the absence of a TIR domain. This makes them different from the classical TLR).

Alternate splicing is also used for variegating the expression of SCR in sea urchin giving them the possibility to express thousand of types from only 150 genes [18].

Finally, one can modify the DNA somatically. In plants, stress and pathogens induce somatic recombination that may affect resistance genes [19]. As it was demonstrated in sharks, somatic mutations of Ig are not necessarily linked to rearrangement [20]. Therefore, if properly selected, they could play a role in nonrearranging Igsf of invertebrates, as it perhaps occurs in mollusks. In Biomphalaria (mollusk gastropod) FREPS, a large family of fibrinogen-related proteins with two N-terminal Igsf variable-like (V) regions, is involved in antiparasite resistance. Point mutations and gene conversion events have been reported in the genes encoding those molecules [1, 21] in association with a huge individual variability. The mechanism of rearrangement in lampreys, existence of the system in other species, and potential role(s) in adaptive immunity are so far untouched areas, but this is a spectacular result in the annals of comparative immunology. This work suggests an independent acquisition of somatic diversity in a molecular defense module (LRR) involved in immunity in plants and in animals [22]. These results allow reinvestigating the claim for specificity and memory in allograft rejection in this subphylum [23]. It illustrates how much our opinion on this subphylum has oscillated during the past 40 years, between belief in presence or absence of adaptive immunity, presence of immunoglobulin of the IgM type or their absence when the alleged Ig [24] turned out to be C3! [25] Altogether, the original claims for some form of adaptive immunity might have been correct but not for the reason advanced by the authors who simplistically but understandably tried to veneer the cyclostomes with the features of the gnathostomes. They did not expect an analogous mechanism being used by the lymphocytes of these animals.

So, Igsf genes do not have the monopoly of somatic modifications. Then two prerequisites for an adaptive system seem to be fulfilled outside gnathostomes: somatic generation of diversity and uni-potentiality of the cells carrying the receptor! Whether this represents an independent innovation or something evolutionary linked to the adaptive system of vertebrates via the lymphocyte lineage will have to be elucidated [22].

In vertebrates, the well known RAG-1- and RAG-2-mediated somatic recombination and gene conversion are used by gnathostomes to generate their receptors, to which somatic mutation adds further diversity in B cells. In addition (i) RNA editing; (ii) switch and (iii) N diversity addition diversifies further receptor and effector populations. The families of enzymes involved in many of those mechanisms are present in many phyla outside gnathostomes but have not yet been found involved in their immunity [4, 26].

Altogether large numbers of 'innate' or 'adaptive' receptors and effectors are generated from the simplest metazoa onwards, which may not go without problems.

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Problems with increasing diversity. Building and selecting repertoires

In vertebrates, with multiple TLR recognizing different ligands, the differential expression on different leucocyte categories reduces the problem [27]. Thus, as soon as diversity is large it must be put under control and must be restricted in expression. As a result, division of the work and build-up of repertoires in one form or another has to occur.

The selection of repertoires, necessary to avoid autoimmunity, may reveal surprising similarities in an innate and in an adaptive situation. The adaptive B- and T-cell repertoires of vertebrates vary from one individual to the other but so do that of innate NK-cells' receptors, although for different reasons. The T and B repertoires are the product of a filtering that eliminates dangerous self-reactive clones each expressing a single specificity. In NK cells, from about 15 different killer inhibitory receptors' genes, just a random smaller subset is expressed in each cell. Even when a cell expresses an inhibitory receptor, for the sake of self-tolerance, clonal variability of the specificity is seen. This innate NK repertoire is less random than the somatically generated B and T repertoires, yet they are also somatically selected in function of the self environment, like the B- and T-cell repertoires [28]. Is there really a hiatus between the adaptive and innate system? Is there a gradual transition from one system to another? Can a system be a little bit adaptive? In practical terms, we call a system adaptive when the potential number of somatically generated receptors is orders of magnitudes above the number of innate receptors and allows recognizing any epitope encountered during the life span of the organism. This system assumes, however, a permanent risk of autoimmunity. The consequences of generating somatically large repertoires of recognition structures, i.e. regulation of autoimmunity, are understood only in the immune system of the vertebrates. In vertebrates, somatic selection is the permanent companion of the adaptive system: selection during the establishment of repertoires and then further selection during responses and generation of memory. This is why antigen receptor generation and class I and class II antigen presentation have been locked together in the gnathostomes in a coevolutionary unit. It is this emergence of multiple and interacting systems in adaptive immunity that we want to understand from an evolutionary viewpoint [4, 29]. This means, given the present status of our knowledge, restricting ourselves to the origin of the immune system of gnathostomes.

The origin of gnathostome's adaptive immune system and innate immunity

The apparently abrupt acquisition of complexity from early gnathostomes onwards is striking with (i) the involvement of RAG-1 and RAG-2; (ii) multiple kinds of antigen specific receptors; (iii) antigen processing involving class I and class II molecules; (iv) selection of repertoires in the thymus; (v) regulatory networks and (vi) connection with innate immunity. One cannot help trying to understand where do its elements (TCR and Ig, MHC and lymphoid organs) come from and how they were put together. Many elements have been perhaps recruited in the vertebrate immune system only late in evolution, some from innate immunity pathways and other from perhaps unrelated functional evolutionary lines with 'jumps' in commitment. This is why, after observing many analogies in the different phyla, we can focus on immune

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system homologies to trace the elements, even if the function of the ancestral molecule is not always associated with immunity. The combination of analogies and homologies is going to give us a comprehensive picture of the evolution of the immune systems.

What looks like the abrupt emergence of the vertebrate adaptive immune system may in fact be the coalescing of ancient independent evolutionary lines [30]. These three major hypothetic lines: (i) cell interaction molecules in the Igsf leading to the rearranging receptors' genes; (ii) an antibacterial innate immunity region gathering complement toll inflammatory components leading to the MHC and (iii) an overlapping line, that of haemocytes, leading to lymphocytes, involved originally in allorecognition and with NK cells as a modern offshoot.

All of these lines came from far back and were probably linked to innate immunity in one way or another. Whether earlier in evolution they might have been involved in other function remains to be debated. The genome duplications currently believed to have generated the genome of vertebrates were probably instrumental in providing the context and the material for the merging of these lines into the adaptive immune system [31].

Immunoglobulins and T-cell receptors

The RAGl and 2 complexes looked so far like the only new component responsible for the adaptive system of vertebrates because no related genes were found in invertebrates. However, the discovery of a RAG2-like product with homologs among metazoa and plants (called 'peas' and showing the same composition in 'kelch' domains as RAG2) and associated with the meiotic chromatin, may force us to revise the hypothesis of a RAG transfer by transposition in the immediate ancestors of gnathostomes [32]. What is in question is perhaps not the transposing-like feature of this enzymatic system but the way it was involved in immunity and its association with RAGl. Could have the lymphocyte RAG2 arisen by duplication of a 'peas'-like gene at the time of genome duplications? Maybe the introduction of RAG 1 of which homolog can now be found in Echinoderms [33] was the key step for the adaptive system.

For the substrate, genes encoding variable (V) domains [more precisely domains with the V fold which is present also in the so-called intermediary set of Gist I domains [34]} without rearrangements are found from sponges onwards [35]. Structurally, closer ancestors of the Gist antigen receptors must share with them more specific structural features such as the association of the V with a CI constant domain, characteristic of gnathostomes [36] as well as transmembrane and cytoplasmic segments. The precursors also may have belonged to families of nonre-arranging Igsf genes prone to diversification and involved in innate immunity: (i) NK receptor families; (ii) fish NITR and (iii) protochordate variable chitin-binding protein (VCBP) [26, 35] {reviewed by Loker et a.1. in [1, 26, 37]}, in which case a Cl domain would be recruited by exon shuffling. In relatively close ancestors of vertebrates (Fig. 1), the protochordates, a few V-Cl-like structures can be found among nectins (V-Cl-like-C2 TM Cy), a family of adhesion molecules involved often in the nervous system edification but also found on hematopoietic cells (CD112 and CD111).

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Prone to many interactions, Igsf members are involved in cell adhesion and in the differentiation of the nervous system. A vast number of molecules with putative receptor function can be encountered in this family. Therefore, several different members with potential receptor features could have been recruited several times and independently in immunity. Some authors place the emphasis on modified self-recognition as a factor of recruitment. As an example of such interaction, they mention the recognition events taking place when eliminating old red cells: RAGE recognizing advanced glycosylation cell products or the interaction CD47-SIRP [38, 39]. Other scientists favour a pressure by pathogens. Indeed, some members like molluscan FREP, mollusk defense molecule and Lepidopteran hemolin are implicated in innate immunity, but they are not well-conserved [4]. Another possibility of recruitment would be ancient antiviral immunity. Viruses, extremely abundant in the sea where primitive vertebrates developed, might have provided a strong evolutionary pressure [40].

Several vertebrates Igsf: junction adhesion molecules (JAM) and Coxsackie's virus receptor of the CTX family (V-C2 Tm cy) or poliovirus receptors of the nectin family (VC1-1 C2 Tm Cy) bind virus via Ig domains. These domains are nonrearranging V domains and were identified as such following primary sequence analysis and crystallization [41]. The binding of V-JAM to virus can trigger apoptosis [42], a form of local immunity that can certainly be considered as part of the evolutionary history of immunity [43]. In primitive metazoan, 'induced suicide' (the word apoptosis was not invented yet) with sacrifice of part of the colony is used in coral after all recognition [4]. From the host point of view it would be a good arm's race attitude to exploit a binding property and to return it against the aggressor by transforming the passive receptor into an active 78 TCR-like immunoreceptor.

In fact, another member of the Igsf putative receptor ancestor identified in Ciona was precisely a member of the CTX/JAM family, structurally less similar to an ideal ancestor (V-C2 whereas a VCl or Cl-like would be closer) but linked to the history of the virus receptor.

Strikingly, all human homologs of the above protochordate genes segregate on a single group of paralogs (chromosomes 3, 1, 11 and 21) where they cluster with CD80 and CD86, two receptors with VCl-like architecture involved at the interface between the innate and the adaptive system [16]. They also cluster with CD 166 (W CCC tm Cy) and CD47 (V-CTXl-pentaspanin), homologs of which were found in Ciona or Amphioxus, respectively, and with Igsf CRTAM of which a relatively good homo-log, Beat, exists in Drosophila. In addition, the gene for CD96 or Tactile, an Igsf protein with an external set of VC2C2 domains that may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response, is a homolog of Drosophila Amalgam and is found in the same linkage group on chromosome 3 q between CD47 and Nectin3. The duplication of this apparently ancient mini-complex could have contributed the V-Cl domains to antigen receptors and to the MHC-linked Tapasin as well as the Cl to class I and class II of the MHC as already speculated [36]. Other pathways have been proposed involving internal recognition event such as Cd47/SIRP [39] or RAGE/old red cell [38]. In both cases,

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the gene considered is again part of the same linkage group (except SIRP that are located on chromosome 20 in human). Two recently discovered lamprey Igsf members with pre-TCR and Pre-CD4 features as well as a hagfish lymphocyte specific molecule are perhaps related to this family as [44] shown by the relationship to CD 166 of one of the members and by the relatively close homology to CTX family members for the other [45].

MHC

Understanding the origin of MHC and antigen processing is vital for understanding the selection of the T-cell repertoire and therefore the development of the vertebrate adaptive system [31]. In the present context, we would like to know whether some of its elements are linked to innate immunity. In addition to genes of the class I and class II-presenting molecules, the MHC and its paralogs contain a third region with genes of the complement, TLR, TNF, AIF, HSP, C3, Bf and NK-activating receptor lineages [31], which point to an early or late link with innate immunity [46]. The conservation of some MHC syntenies of this class III region has been demonstrated in Drosophila, protochordates and vertebrates by Danchin et al. in [1]. For the class I processing machinery, relatives of TAP and proteasomes' genes exist in invertebrates but their relationships to immunity are not known. Among the genes that probably emerged as a result of the chromosomal duplications that formed the MHC paralogons are those coding for proteasome subunit Beta-type 9(PSMB9), low molecular mass polypeptide 2 LMP2, LMP7 and PSMB10, the interferon-y inducible proteaso-mal subunits that facilitate the production of class-I-binding peptides, NOTCH 1 required for thymic development of T cells, retinoid X receptor beta (RXRB), which upregulates expression of MHC class I gene and VAV essential for Tand B-cell development and activation. These observations indicate that the chromosomal duplications were instrumental not only for the emergence of the MHC region but also for the 'creation' of multiple genes essential to the function of the adaptive immune system. Macrophages that could represent the antigen-presenting cell lineage exist in all phyla of Bilateria.

The relatively recent class I and class II genes, absent before gnathostomes, have apparently been created by exon shuffling of genes coding for CI and peptide-binding domains. In function of what was said on Ig domains earlier in the 'Immunoglobulin and T-cell receptor section, it is not too difficult to imagine the origin of CI domains. However, the origin of the peptide-binding region (pbr) poses problem. Some authors proposed a link between the pbr and Ig domains especially that of CD8 [47]. Otherwise, heat shock proteins once and again have been proposed as 'donators' of the pbr [4, 48]. Their conservation, their peptide presentation capacity, an intellectually interesting possibility of interaction with TLR that remains to be unequivocally demonstrared [49], their linkage to vertebrates' MHC, make them interesting candidates even if their linkage to primitive histocompatibility systems is not conserved [50].

Lymphocytes and lymphoid organs

Sequestration of the somatic rearrangement within lymphocytes is essential for the stability of the genome. Lymphocytes restricted in antigen receptor expression

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are also essential for clonal selection. The evolutionary relationships between lymphocytes and innate immunity effector cells are poorly understood. The number of lymphoid transcription factors increases from echinoderms to gnathostomes, another argument for a role of the gene duplication in shaping the lymphocyte compartment [4]. In Botryllus, NK-like cells are apparently involved in allorecognition as suggested by the discovery of a typical innate immunity C-type lectin receptor resembling CD94, obtained from subtraction libraries between allograft-rejecting and normal Botryllus haemocyte populations [51]. This observation adds a possibility of homology to the numerous reports of NK cells' activities in invertebrate phyla [4]. In lamprey the discovery of lymphocytes expressing somatically diversified LRR fits with the earlier discovery of lymphoid transcription factors and some CD homologs in several agnathans [4]. They do not use Igsf like gnathostomes for their diversified repertoire. In Ciona, LRR too might be involved in immunity because some homologs, structurally similar to RP 105 (LRR without TIR domains), have been found expressed on haemocytes [52]. Because LRR are prone to diversification by alternate splicing in many vertebrates' families, there could be amplification in this family also in invertebrates.

The equipment of the lymphocyte surface is not enough for clonal selection. The lymphocytes have to be selected in the appropriate geographical environment of lymphoid organs. Nothing illustrates more adequately this point than to observe the parallel between the ever better exploitation of somatic mechanisms and the complexification of lymphoid organs from elasmobranches to mammals. Unfortunately, our understanding of the phylogeny of organs is poor. For lymph node, there are interesting hypothesis linking the genesis of these structures to the exploitation of primitive inflammatory reaction pathways adapted as differentiation pathways involving chemokines, TNF and lymphotoxin alpha [53]. The thymus is present from Chondrichtyans onwards but has not been found in agnathans, although the genetic program specifying the distribution of neural crest cells, essential for the edification of the thymus, is shared between agnathans and gnathostomes [29].

As a conclusion, at least two evolutionary lines leading to the elements of the vertebrate adaptive immune system have been detected, both of them anchored in innate immunity and materialized by the existence of paralogs in modern vertebrate genomes: These paralogs are the landmarks of the duplications that took place during the evolution of the pregnathostome phyla (the chromosomes 1, 3, 11, 21 and the 1, 6, 9, 19 group). It will be perhaps interesting to monitor the origin of lymphocytes 'lineage' in the same way. The genesis of NK cells lineage is a first track. It leads us to understanding the history ancient receptors of the lectin type [51]).

Whichever coalescence of evolutionary lines have occurred we see from the first vertebrates onwards a relatively stable coevolutionary unit that could not break apart without serious risk of dysfunction.

Instead of independent systems - one immune system with interconnected networks is selected as a whole

Does it mean that no more evolutionary innovations will occur inside the immune system of gnathostome vertebrates?

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Figure 1 provides an answer to this question. The only feature that underwent major changes during vertebrate evolution is the organization of the lymphoid organ resulting in a better exploitation of the somatic events generating lymphocyte diversity in warm-blooded vertebrates. Differences are there and adaptiveness is not optimal in all instances, but there is a dynamic balance between innate and adaptive arms of the immune system in every class of vertebrates.

As soon as a duality 'innate/adaptive' is present, interactions, relationships and mutual influences occur. In Drosophila, a single ligand activates a single receptor and triggers the production of antimicrobial peptides. In vertebrates, many TLR receptors with different binding specificities trigger the production of regulatory cytokines in addition to antimicrobial peptides.

Another example of modulation is to observe how some gene families welcomed the generation of adaptive immunity receptors (the LRR and Igsf) while many 'innate' members participate in networks connecting the two systems. The Igsf is an example of flexibility at the phylogenetic level almost without parallel. Not only different members have been generated in large number but the principle of binding can be different from one category to the other. The interstrand loops are used for variability in TCR and Ig. The charge strand F can be used for DNA binding, the A strand is highly polymorphic in VCBP of amphioxus where the role of the Ig domain has still to be elucidated.

The next example is the complement system present from Cnidaria onwards {Nonaka in [1]} and which participates in both innate and adaptive systems (alternative, lectin and classical pathways). It never employed somatic diversity, but instead, it diversified in the germ line. Lectins with multiple members have also found their niche in both systems whether recognizing MHC epitopes or sugars from pathogens. The innate components look as if they had 'adapted' in function of the newly introduced adaptive components. The adaptive pathways too can be modified under evolutionary pressure for rapid efficiency. For example, vertebrate natural antibodies, products derived from the adaptive system machinery are used in an innate manner, especially after passive transfer form the mother to the young. Better still, early in ontogeny some elasmobranches express Ig genes, the V region of which have been generated by germline rearrangements during the history of the species, mimicking innate receptors [4, 20]. Once more the strategy of survival in the different species of vertebrates may decide which type of balance is reached. The relative individual value of species of shortlived small fish or frogs producing large progenies is not the same as in mammals. These organisms do not show pronounced antibody affinity maturation. In such species innate immunity is relatively very efficient, with multiplication of teleost C3 components or the frog microbicidal peptides [10].

Is the adaptive system less vital because of a good innate system or did the innate strategies fill the gap because the adaptive system was suboptimal? (Fig. 1) The different balances are probably due to the different contexts of complexity of the metazoa and of the environmental conditions rarher than to the presence or absence of a crucial gene family.

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Spl^ert

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Thymus

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Figure 1. The evolution of the immune system within vertebrates. AMP, antimicrobial peptides; C3, third component of the complement; CD ly CD determinants of lymphocytes; GALT, gut-associated lymphoid tissue; LRR, leucine-tich repeat; MHC, major histocompatibility complex; Poor Ab antibody response with no or weak affinity maturation by opposition to good maturation (good matur.); Som. mut., somatic mutation; RAG recombination associated gene; TCR, T-cell receptor; TF Ly, transcription factor specifying lymphocyte development.

Conclusion

In the Introduction, the simultaneity and the diversity of the pressures that led to the development of immunity at the beginning of the existence of metazoa were stressed. As a result, independent pathways of immunity functioning on different principles of recognition developed, probably in parallel, each being pushed for diversification during adaptation to the changing environment. Some organisms trusted conservatively the genes devoted to their immune system; other added and allowed some randomness in their expression. In the comparative studies one has observed convergences, mimicry, duplications, dead ends, complementation or even perhaps competitions, with a trend towards individualization of responses to the point where the distinctions between adaptive and innate immunity are uncertain. The diversification of the immune molecules has made the necessary control of their expression a difficult task, demanding the involvement of many other gene families that were recruited alongside in the build up of the integrated immune Systems. The individual defense mechanisms do not work in isolation in any organism but instead

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are part of a coherent whole. In fact, there are many unknown genes expressed during immune responses of the simplest organisms outside vertebrates [54]. In addition to the now more fashionable protochordates and jaw-less vertebrates, it would be important to include the study of arthropods less derived than Drosophila such as the horseshoe crab. One should also include the Cnidaria whose genes' sequences are surprisingly close to those of deuterostomes and the genome of which could contain a reservoir of interesting information for the immunologist preoccupied with evolutionary issues [55]. In those organisms, examination of the genome and individual studies of the regulations and interactions of the different components of their immune systems may provide information as to how to handle the dysfunctions of what I foolishly dared to call in the introduction our ideal Homo sapient immune system.

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Рецензент - д.вет.н., професор Гуфрш Д.Ф.

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