Living organisms with innate immunity only (invertebrates)^{ref1, ref2, ref3} : It is present in an individual from birth, i.e., does not require prior contact with an infectious agent in order to become active. Neither offender discrimination nor challenge memory occur (i.e. : response to a following challenge with the same offender is the same as to the first challenge). No clonal expansion of reacting cells occurs : further generally it does not require sensor/response mechanism. Innate immunity is present in phylogeny at least since speciation of Caenorhabditis elegans.

• physiologic antisepsis / autoantisepsis : the combination of methods by which the body excludes germs

• Caenorhabditis elegans innate immune responses : nsy-1 MAPKKK => sek-1 MAPKK => p38^MAPK ortholog pmk-1^ref. Although they lack the Toll and Imd pathways by which Drosophila respond to bacterial and funmgal infections, can produce antimicrobial peptides in response to infection. Microarrays experiments shown that only 2 genes (nlp-29 and cnc-2) are strongly induced after infection with the fungus Drechmeria coniospora and the Gram-negative bacterium Serratia marcescens. An additional 4 genes are induced after infection with D.coniospora. A representative member of the peptide family, neuropeptide-like protein-31 (nlp-31), was synthesized and found to have antifungal activity in vitro. Expression of nlp-31 in the hypodermis and in the vulval region (where the fungal spores adhere) increases after D.coniospora infection. Worms have a single Toll-like receptor gene, tol-1, which does not control antifungal defence, and an additional gene that encodes another TIR-domain-containing protein, called tir-1. Of the 5 possible isoforms, tir-1a is a homologue of the vertebrate TIR-domain containing adaptor protein sterile a and armadillo motif protein (SARM), the function of which is unknown. When tir-1 is inactivated by RNAi, the worms are more susceptible to infection, and production of the antimicrobial peptides is reduced. Because tol-1 has no role in regulating peptide expression, it seems that tir-1 is not coupled to an upstream TIR-domain-containing receptor, and the authors suggest that this might also be the case for SARM. 8 proteins, as well as tir-1, intereact with tir-1 : the small GTPase Rab1 and the f-subunuit of ATP synthase are required for expression of antimicrobial peptides^ref.
• Euprymna scolopes : the circulatory system has only a single blood-cell type, the haemocyte, that can participate in host defence against microorganisms. These haemocytes come into close contact with the highly vascularized crypt epithelium of the light organ (see the figure in which Vibrio fischeri cells (green) are shown adhering to a single squid haemocyte (red)) and are often observed migrating into the crypt spaces and interacting with the bacterial symbiont, V. fischeri.^{ref1, ref2, ref3}


Web resources :
• V. fischeri genome
• E. scolopes EST database
• the purple sea urchin, Strongylocentrotus purpuratus, is a member of the phylum Echinodermata, which is basal to the phylum Chordata within the deuterostome lineage of the animal kingdom. This relationship makes the analysis of the sea urchin immune system relevant to understanding the evolution of the deuterostome immune system leading to the Vertebrata. Subtractive suppression hybridization was employed to generate cDNA probes for screening high-density arrayed, conventional cDNA libraries to identify genes that were upregulated in coelomocytes responding to lipopolysaccharide. Results from 1,247 expressed sequence tags (ESTs) were used to infer that coelomocytes upregulated genes involved in RNA splicing, protein processing and targeting, secretion, endosomal activities, cell signaling, and alterations to the cytoskeletal architecture including interactions with the extracellular matrix. Of particular note was a set of transcripts represented by 60% of the ESTs analyzed, which encoded a previously uncharacterized family of closely related proteins, provisionally designated as 185/333. These transcripts exhibited a significant level of variation in their nucleotide sequence and evidence of putative alternative splicing that could yield up to 15 translatable elements. On the basis of the striking increase in gene expression in response to lipopolysaccharide and the unexpected level of diversity of the 185/333 messages, we propose that this set of transcripts encodes a family of putative immune response proteins that may represent a major component of an immunological response to bacterial challenge^ref.

Living organisms with adaptive immunity (phylum Chordata > ...

• subphylum Urochordata; Ascidiacea; Stolidobranchia; Botryllidae; Botryllus : Histocompatibility—the ability of an organism to distinguish its own cells and tissue from those of another—is a universal phenomenon in the Metazoa. In vertebrates, histocompatibility is a function of the immune system controlled by a highly polymorphic major histocompatibility complex (MHC), which encodes proteins that target foreign molecules for immune cell recognition. The association of the MHC and immune function suggests an evolutionary relationship between metazoan histocompatibility and the origins of vertebrate immunity. However, the MHC of vertebrates is the only functionally characterized histocompatibility system; the mechanisms underlying this process in non-vertebrates are unknown. A primitive chordate, the ascidian Botryllus schlosseri, also undergoes a histocompatibility reaction controlled by a highly polymorphic locus. A candidate gene encoding an IgSF member has been isolated and, by itself, predicts the outcome of histocompatibility reactions. This is the first non-vertebrate histocompatibility gene described, and may provide insights into the evolution of vertebrate adaptive immunity^ref
• subphylum Craniata > Vertebrata (vertebrates)) : the main features of the adaptive immune system are :
• clonal selection and expansion of cells expressing clonally distributed Ag-specific receptors that arise from random recombination of gene segments and from untemplated nucleotide additions between such segments (generation of diversity (GOD))
• challenge memory : responses to previously encountered Ags are more fast and vigorous on subsequent exposures. Please note the ability to "remember" a previous response at the cellular level is quite unusual in biology (neurons have short-term potencing, but, as the word itself tells us, it is far shorter !) : it allows us to survive without recurring debilitating diseases.
However, the adaptive immune response has 2 main limitations :
• randomly generated antigen receptors are unable to determine the source and the biological context of the antigen for which they are specific.
• a clonal distribution of antigen receptors requires that specific clones expand and differentiate into effector cells before they can contribute to host defence. As a result, primary adaptive immune responses are delayed, typically for 4-7 days, a latency period longer than the one of aspecific immune system.
The evolution of adaptive immunity appears to have been made possible by the invasion of a putative immunoglobulin-like gene by a retrotransposon encoding a gene able to catalyze gene rearrangement (corresponding to nowadays RAGs, still able to catalyze a transposition event), and thus generate diversitiy. While the invasive ends of the retrotransposon remained into the right place near the Ig-like gene, the retrotransposon-encoded enzyme jumped to another chromosome. In order to have a system where you just express one type of receptor per cell, you've got to have millions of lymphocytes to make it worthwhile : for a small animal, it wouldn't make any sense to have this type of adaptive immune system. Any animal that lives for a long time, or is complex, is going to try to come up with an adaptive immune system.
Different evolutionary strategies were used to generate highly variable lymphocyte receptors (VLRs) since Vertebrata through rearrangement  :
• agnathans [jawless fish : ...
• in-part phylum Chordata > subphylum Craniata > Hyperotreti(family Myxinidae (hagfishes))
• in-part phylum Chordata > subphylum Craniata > Vertebrata > Hyperoartia (cyclostomes)] : the sea lamprey Petromyzon marinus shows some of the characteristics of an adaptive immune system, such as accelerated rejection of second skin grafts and antigen-specific agglutinin, but orthologues of the immunoglobulin, TCR and MHC genes have not been found^ref. Activated lymphocytes from sea lamprey larvae injected with a cocktail of antigen molecules produced 13 times more copies of a genetic sequence that generates a new type of VLR versus non-activated lymphocytes. The most common sequences contains variable numbers of highly diverse leucine rich repeat (LRR) motifs. Each VLR has 8 different features:
• a signal peptide
• an amino-terminal LRR
• a variable number of diverse LRRs
• a connecting peptide
• a carboxy-terminal LRR
• a conserved carboxyl terminus
• an invariant glycosylphosphatidylinositol anchor
• a hydrophobic tail
Individual lymphocytes express VLRs in a monoallellic manner. Genomic analysis reveals a single germline gene that comprised only 4 exons and that can not encode the diverse full-length VLRs. A series of variable diverse LRR sequences adjacent to the partial VLR gene are inserted into the partial VLR gene to generate mature VLR genes^ref. This is not yet convergent evolution but merely a continuation of the usage of a very ancient motif that is conserved in invertebrates, plants, and man (see TLRs).


Somatic diversification of the VLR gene occurs through a multistep assembly of LRR modules randomly selected from a large bank of flanking cassettes. The predicted concave surface of the VLR is lined with hypervariable positively selected residues, and computational analysis suggests a repertoire of about 10¹⁴ unique receptors. Lamprey immunized with anthrax spores responded with the production of soluble antigen-specific VLRs. These findings reveal that two strikingly different modes of antigen recognition through rearranged lymphocyte receptors have evolved in the jawless and jawed vertebrates^ref.
It is anticipated that the mechanism will be present in hagfish (Myxinidae) as well, and it will still be present going forward into ...
• gnathostomes (jawed vertebrates : superclass Gnathostomata) : together with lymphoid tissue (a particular kind of connective tissue), their appeared abruptly at some point in the divergence of the class Chondrichthyes (cartilaginous fishes) from Hyperoartia (cyclostomes), where it is completely absent, around 400 millions years ago (see here).

Members of the subclass Elasmobranchii (elasmobranchs) are the oldest organisms with Ig-like genes (e.g. Raja eglanteria (clearnose skate)^{ref1, ref2}). Elasmobranchs have 3 isotypes of Ig :
• IgM
• IgNAR : heavy-chain, homodimeric immunoglobulins with each monomer consisting of 1 variable (V) domain and 5 constant (C) domains. The variable domains recognize antigen with only a single Ig domain, akin to camelid VHH domains. The 1.45 Å resolution crystal structure of the Type I IgNAR variable domain in complex with hen egg-white lysozyme (HEL) reveals a minimal antigen binding domain that contains only 2 of the 3 conventional CDRs, but still binds HEL with nanomolar affinity via a binding interface comparable in size to conventional antibodies^ref.
• IgW
IgD have been found in channel catfish Ictalurus punctatus, Atlantic salmon Salmo salar, Atlantic cod Gadus morhua, primates and rodents.
TcR genes were identified in the different lineages of Gnathostoma. In the fish, TcRb genes were first described in the rainbow trout (Oncorhyncus mykiss) and in the horned shark (Heterodontus francisci). TcR genes a, b, g, and d were finally identified in the skate (Raja eglanteria), a Chondrychthian, suggesting that all Gnathostoma should express both ab and gd TcR. Complete TcRb sequences are now availbale for several species of teleosts: in Atlantic salmon (Salmo salar), channel catfish (Ictalurus punctatus), Atlantic cod (Gadus morhua), damsefish (Stegastes partitus), and Japanese flounder (Paralichthys olivaceus). In rainbow trout, 4 different Vb families were described. In all these species, the sequence of b-chains showed typical V and C1 domains with key residues conserved, suggesting that the general 3D structure of this protein was conserved from fish to mammals. Phylogenetic studies showed that TcRb sequences are conserved in mammals, but no close similarity was observed between fish and mammalian Vb sequences. In teleosts, T cell-dependent responses were suggested by the presence of TcR genes, and by the structure of the MHC locus and by the polymorphism of class I and class II mmolecules. However, a functional T cell response has been directly proved in only a limited number of species.
In all gnathostomes there appear to be 2 main embryonic locations derived from the early mesoderm, both intra- and extraembryonic, which contribute to primitive and definitive hematopoiesis based upon their differential expression of SCL, Gata-1, Gata-2 and c-myb.
• in Teleostomi > Euteleostomi >
• in Actinopterygii > Actinopteri > Neopterygii > Teleostei (teleost fishes), a unique intraembryonic dorsal location for HSCs termed the intermediate cell mass (ICM) of Oellacher appears to be responsible for primitive or definitive hematopoiesis depending upon the species being investigated. Vertebrate HSCs are derived from vental mesoderm, which is postulated to migrate to both extra- and intraembryonic positions during gastrula and neurula stages. Extraembryonic migration has previously been documented, but the origin and migration of intraembryonic hematopoietic cells have not been visualized. The zebrafish and most other teleosts do not form yolk sac blood islands during early embryogenesis, but instead hematopoiesis occurs solely in ICM. cDNAs encoding zebrafish homologs of the hematopoietic transcription factors GATA-1 and GATA-2 have been isolated and used as markers to determine that the ICM is formed from mesodermal cells in a posterior-lateral position on the yolk syncytial layer of the gastrula yolk sac. Surprisingly, cells of the IM then migrate anteriorly through most of the body length prior to the onset of active circulation and exit onto the yolk sac. These findings support a hypothesis in which the hematopoietic program of vertebrates is established by variations in homologous migration pathways of extra- and intraembryonic progenitors^ref.
• in Sarcopterygii > Tetrapoda > Amphibia > Batrachia > Anura > Mesobatrachia > Pipoidea > Pipidae > Xenopodinae > Xenopus, elegant grafting studies in combination with specific molecular markers has led to a better definition of the roles that ventral blood islands and dorsal lateral plate play in amphibian hematopoiesis, that of primitive and definitive lymphopoiesis. After the early embryonic contribution to hematopoiesis, specialized tissues must assume the role of providing the proper microenvironment for T and B-lymphocyte development from progenitor stem cells.
• 8 full-length V_H genes were isolated and characterized by shotgun sequencing of a cosmid clone containing part of the V_H genomic region of the Japanese pufferfish, Fugu rubripes. They have higher homology to trout genes, but show the same structural features as V_H found in other vertebrates. 2 V_H subgroups have been identified whose members are interspersed. The frequency of synonymous and nonsynonymous substitution for V_H comparisons between family members was found to be higher in the complementarity-determining regions than in the framework regions. Finally, there are four other genes interspersed with the V_H genes, one of which is the first full-length retrotransposon element characterized in vertebrates^ref.
In all gnathostomes, the thymus is the major site for T-cell maturation as evidenced by strong expression of developmental markers such as Ikaros, Rag and TdT plus expression of T-cell specific markers such as TcRb and lck. In this respect, several zebrafish mutants have provided new insights on the development of the thymopoietic environment. On the other hand, the sites for B-cell lymphopoiesis are less clear among the lower vertebrates. In elasmobranchs, the spleen, Leydig's organ and the spiral valve may all contribute to B-cell development, although pre-B cells have yet to be fully addressed in fish. In teleosts, the kidney is undeniably the major source of B-cell development based upon functional, cellular and molecular indices. Amphibians appear to use several different sites (spleen, bone marrow and/or kidney) depending upon the species in question^ref.

As the adaptive immune system is the most recently appeared system in human body according to modern phylogeny (please note it is the last also in human ontogeny, satisfying Haeckel's biogenetic law), many features haven't had time enough to be selected for or against, yet : as nowadays natural selective forces have a far lower impact on survival of our species, it is expected that some defects will remain in this system and we will remain error-prone regarding immune-related disorders. Further it should be expected that complexity of adaptive immune system, although less fashinating, overwhelms that of nervous system.
• avians
• the avian equivalent of the mammalian bone marrow is the bursa of Fabricius, a thymus-like lymphoid gland in birds that is an outgrowth of the cloaca and the site of B cell maturation : it is composed of ~ 10⁴ lymphoid follicles that can be easily isolated, each one colonized by a small number of prebursal stem cells
• the follicle of Stannius is a lymphoid unit in chicks, resembling the thymus and developing from nodules formed by proliferation of points of the epithelium of the bursa of Fabricius
• the colorful beaks on the males of 2 bird species (zebra finches (Taeniopygia guttata) and blackbirds (Turdus merula)) gives honest information about individual immune systems. When females choose bright beaks, they select healthy males. In the animal kingdom, males often sport the species' more flamboyant features, from peacock's tails to rooster's combs. Carotenoids are the red and yellow pigments that color the beaks of the males of certain species of birds including blackbirds and zebra finches. Birds can not synthesize carotenoids and must obtain them through the diet. Carotenoids stimulate the production of antibodies and absorb some of the damaging free radicals that arise during the immune response. The colored surface of the bill may rapidly signal a change in carotenoid allocation because it is continually renewed with carotenoids. This kind of information is not available from feather color, because pigments in sex-signaling plumage are only allocated to feathers once or twice a year during molt events. Carotenoid-based signals may have evolved because they are honest signals of individual quality. Bmp-4 expression in eggs from 6 species of Galapagos finches (genus Geospiza: the sharp-beaked finch (G. difficilis), which has a small, symmetrical beak; the small, medium, and large ground finches (G. fuliginosa, G. fortis, and G. magnirostris), with their broad, deep beaks for crushing seeds; and cactus and large cactus finches (G. scandens and G. conirostris)) which use their long, narrows beaks for sipping nectar correlates with beak shape : Bmp2 and Bmp7 correlate with beak size development rapidly and in response to environmental pressures

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