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. 2005 Nov;5(11):866-79.
doi: 10.1038/nri1712.

Reconstructing Immune Phylogeny: New Perspectives

Free PMC article

Reconstructing Immune Phylogeny: New Perspectives

Gary W Litman et al. Nat Rev Immunol. .
Free PMC article


Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.


Figure 1
Figure 1. Phylogenetic occurrence of various immune functions, genetic organizations and mechanisms of receptor variation in selected representative species
The selection of individual invertebrate, protochordate, jawless-vertebrate and jawed-vertebrate species is based on emphasizing certain effects and is not intended to be comprehensive. Innate immunity uses various mediators that are not necessarily shared among the main groups that are represented; conventional, recombination-activating gene (RAG)-mediated adaptive immunity is thought to be confined to the jawed vertebrates, and alternative forms of anticipatory immunity are found in species that are below this level of phylogenetic development. Dashed lines are used to emphasize certain general or parallel relationships. Fusibility (Fu) genes are unrelated to the genes encoding MHC class I and class II molecules, but they are an alternative histocompatibility locus. A Fu locus has also been identified in Hydractinia species (cnidarians; which are invertebrates), and there might be homologous forms of Fu gene products in other species. RAG1-like gene sequences are found in amphioxus, which are cephalochordates; RAG2 sequences have not yet been characterized. Differential RNA splicing creates diversity in insect Down’s syndrome cell-adhesion molecule (Dscam), which is associated with bacterial binding and phagocytic function. Hypermutation occurs in the genes encoding fibrinogen-related proteins (FREPs) in a mollusc. Various leucine-rich repeat (LRR)-encoding genes, which are distantly related to the genes encoding the variable lymphocyte receptors (VLRs) of lampreys and hagfish and the Toll-like receptors of vertebrates, can be identified in the amphioxus genome (indicated by light-green shading); however, their relatedness to the genes encoding VLRs and to other LRR-encoding genes has yet to be determined, and the possibility that there might be VLRs in jawed vertebrates awaits further investigation. Throughout the metazoans, a huge number of different receptors and effector molecules are used to effect innate immunity, and these typically vary between the major phylogenetic groups. The background shows a simplified phylogeny of many of the species that feature in current considerations of the evolution of innate and adaptive immunity. IgV, immunoglobulin variable region; TCR, T-cell receptor; VCBP, variable-region-containing chitin-binding protein.
Figure 2
Figure 2. Main differences in the organization of rearranging segmental elements in immunoglobulin heavy and light chains in selected jawed-vertebrate models
Each jawed vertebrate is indicated by its common name: horned shark, zebrafish, coelacanth, chicken and mouse. The selection of the horned shark, chicken and mouse emphasizes the co-evolution of the organization of genes and the main mechanisms of diversification. In the case of mice, only an Igκ light-chain locus is shown; the Igλ light-chain locus has a cluster-type organization. Neither the number nor the relative position that is shown for variable (white), diversity (red), joining (blue) and pseudogene (green; used in gene conversion) elements in heavy and light chains is absolute. For the heavy chain, only the most proximal exons encoding the constant region (black) are indicated, except in the case of zebrafish, for which the exons encoding an additional heavy-chain class (grey) are shown. Additional pseudogenes are present in the continuous variable-element-encoding region in mice and zebrafish and probably also in coelacanths. The organization of genes in the type II light chain in the zebrafish has been inferred by annotation of the zebrafish genome and is not complete as represented; note the presence of two constant regions in the cluster. Light-chain gene organization has not been reported in coelacanths. The relative contributions of various diversifying mechanisms have been approximated in circles: combinatorial rearrangement (blue), junctional diversity (orange); somatic hypermutation (red) and gene conversion (pink). The differences in circle area roughly approximate the relative differences in overall effect and are not quantitative. The relative time of divergence from the lineage that gave rise to mammals is indicated in million-year increments; a ~50-million-year error is assumed. This figure is produced from data taken from REFS 29,.
Figure 3
Figure 3. Three main framework domains are incorporated in various proteins, including those that mediate adaptive and innate immunity
The immunoglobulin-domain framework includes a superfamily of homologous types: variable (V), intermediate (I) and constant (C1 and C2). Single or multiple copies of one or more types of immunoglobulin domain are present in different receptors: for example, novel immune-type receptors (NITRs) can have V and I domains. Other proteins have more than one type of framework domain: for example, immunoglobulin V domains and a chitin-binding lectin domain in V-region-containing chitin-binding proteins (VCBPs). Fibrinogen-related proteins (FREPs) and Down’s syndrome cell-adhesion molecule (Dscam) also contain immunoglobulin and lectin domains. Proteins that have both lectin and leucine-rich repeat (LRR) domains are rare; only polycystic kidney disease 1 (PKD1) is known to have all three domains. Proteins that share a specific domain type might not be related by common ancestry, so only the domains themselves have a homologous past (as products of recruitment). LRR-containing proteins are a special case. The LRR framework is a small motif (~11 amino-acid residues) that is generally encoded in contiguous copies. The functional site can be a single motif or a combination of motifs. LRR motifs are so divergent that even though the 11-residue-motif structure is highly conserved, together with the resulting solenoid structure of the LRR-containing protein, it is not possible to predict whether any two LRR motifs evolved from a common ancestor or whether they arose through evolutionary convergence. BCR, B-cell receptor; CATERPILLER, caspase-recruitment domain, transcription enhancer, R (purine)-binding, pyrin, lots of LRRs family; ficolin, collagen- and fibrinogen-domain-containing lectin; galectin, galactoside-binding lectin; Kek, kekkon; KIR, killer-cell immunoglobulin-like receptor; LINGO1, LRR- and immunoglobulin-domain-containing, NOGO (neurite-outgrowth inhibitor)-receptor-interacting protein; LRIG1, LRR and immunoglobulin-like domains 1; MBL, mannose-binding lectin; RLK, receptor-like kinase; Robo, roundabout; R proteins, plant disease-resistance proteins; TCR, T-cell receptor; TLR, Toll-like receptor; VLR, variable lymphocyte receptor.

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