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• W2000851475 abstract "Innate immunity is mediated by a variety of different, non-rearranging receptors and soluble molecules that recognize and facilitate the elimination of a wide range of pathogens [1.Medzhitov R. Janeway Jr., C.A. Decoding the patterns of self and nonself by the innate immune system.Science. 2002; 296: 298-300Crossref PubMed Scopus (1665) Google Scholar]. Immunoglobulin (Ig)-type variable (V) region-containing chitin-binding proteins (VCBPs) found in the protochordate amphioxus, which diverged from the vertebrate lineage before the emergence of adaptive immunity, show structural characteristics of innate immune receptors [2.Cannon J.P. Haire R.N. Litman G.W. Identification of diversified immunoglobulin-like variable region-containing genes in a protochordate.Nat. Immunol. 2002; 3: 1200-1207Crossref PubMed Scopus (166) Google Scholar]. Here we describe a very high degree of regionalized hypervariability in one family of VCBPs at the level of the individual germline, producing a unique repertoire of proteins in every animal so far analyzed. In species with large populations, such as amphioxus, extensive polymorphisms may compensate for the absence of somatic modification in the maintenance of immune receptor diversity. The diversified VCBPs in the amphioxus Branchiostoma floridae, a cephalochordate, are soluble proteins consisting of two Ig-type V regions joined to a carboxy-terminal chitin-binding domain [2.Cannon J.P. Haire R.N. Litman G.W. Identification of diversified immunoglobulin-like variable region-containing genes in a protochordate.Nat. Immunol. 2002; 3: 1200-1207Crossref PubMed Scopus (166) Google Scholar]. Although their ligands are unknown, VCBPs are likely candidates for innate immune receptors and represent the only example of an innate receptor in which the functional unit is a hyperdiversified Ig-type V region. VCBPs are distributed in at least five families and are expressed specifically and abundantly in the gut. Regionalized peptide sequence hypervariability was noted in the V regions of pooled amphioxus VCBP2 cDNAs [2.Cannon J.P. Haire R.N. Litman G.W. Identification of diversified immunoglobulin-like variable region-containing genes in a protochordate.Nat. Immunol. 2002; 3: 1200-1207Crossref PubMed Scopus (166) Google Scholar]. The hypervariable region is centered ∼18 residues amino-terminal to the first intradomain cysteine and does not correspond to any of the known complementarity-determining regions of the rearranging antigen-binding receptors found in jawed vertebrates. However, the basis for the hypervariation is not clear. The hypervariable region of the amino-terminal V region of VCBP2 has been characterized in genomic DNA from individual animals collected in the same local geographical area. The germline of every animal encodes a unique VCBP2 receptor repertoire. In a parallel investigation, a 17-fold representative bacterial artificial chromosome library (CHORI-302) constructed from a single reference animal was screened and six VCBP2 family genes were identified, consistent with previous Southern blot analyses [2.Cannon J.P. Haire R.N. Litman G.W. Identification of diversified immunoglobulin-like variable region-containing genes in a protochordate.Nat. Immunol. 2002; 3: 1200-1207Crossref PubMed Scopus (166) Google Scholar]. In sum, a total of 43 different peptides are encoded across the amplified region of VCBP2 by only 13 different animals. The most pronounced differences occur across a segment of ∼12–15 residues within a 23–30 residue-encoding amplicon (Figure 1). In the majority of cases, any two animals share no more than two specific VCBP2 hypervariable sequences; however, four pairs of animals share three specific hypervariable sequences. Amplicons encoding more conserved regions of the amino-terminal V region of VCBP2 and defensin, an unrelated innate immunity gene, lack extensive polymorphic differences. Non-systematic studies carried out with additional animals revealed further VCBP2 diversity, implying a still larger gene pool. The localized differences in both length and peptide sequence in the hypervariable region of soluble VCBP2 molecules resemble the junctional variation seen in antigen-binding receptors after combinatorial rearrangement; however, comparisons of cDNA sequences to germline genes amplified from 2 of the 13 specimens indicate that the hyperdiversity in VCBP2 is not derived somatically. High levels of polymorphism have been described previously for other Ig gene superfamily transmembrane molecules. However, in the killer cell Ig-like receptors (KIRs), variation tends to occur throughout the molecule, and in the major histocompatibility complex (MHC) class I and II molecules, variation in the peptide-binding domains is pronounced but is not generally associated with length polymorphism [3.Trowsdale J. Parham P. Mini-review: defense strategies and immunity-related genes.Eur. J. Immunol. 2004; 34: 7-17Crossref PubMed Scopus (148) Google Scholar, 4.Uhrberg M. Valiante N.M. Shum B.P. Shilling H.G. Lienert-Weidenbach K. Corliss B. Tyan D. Lanier L.L. Parham P. Human diversity in killer cell inhibitory receptor genes.Immunity. 1997; 7: 753-763Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar]. Innate immunity provides an immediate response to pathogenic invasion, a significant and shifting challenge within the marine microbial environment [5.Fuhrman J. Marine viruses and their biogeochemical and ecological effects.Nature. 1999; 399: 541-548Crossref PubMed Scopus (1623) Google Scholar] and a likely factor in the survival of the filter-feeding amphioxus. But recognition of molecular patterns on pathogens can be compromised by immune evasion. The ability of amphioxus, which comprises 70% of the total biomass in some ecosystems [6.Bloom S.A. Simon J.L. Hunter V.D. Animal-sediment relations and community analysis of a Florida estuary.Mar. Biol. 1972; 13: 43-56Google Scholar], to maintain a very high degree of receptor diversity by genetic hypervariation within its large population could provide an effective alternative to somatic diversity, a later acquisition of the vertebrate lineage. Increasing evidence points to innate immune receptor diversification as a means of maintaining resistance to pathogens. Maintenance of extensive variation in non-adaptive immune molecules among individuals, well characterized in the leucine-rich repeat plant R genes [7.Bergelson J. Kreitman M. Stahl E.A. Tian D. Evolutionary dynamics of plant R-genes.Science. 2001; 292: 2281-2285Crossref PubMed Scopus (400) Google Scholar] in which variation is regionalized, and in several Drosophila genes [8.Lazzaro B.P. Sceurman B.K. Clark A.G. Genetic basis of natural variation in D. melanogaster antibacterial immunity.Science. 2004; 303: 1873-1876Crossref PubMed Scopus (189) Google Scholar], can serve as an effective protective mechanism in the absence of adaptive immunity [9.Hamilton W.D. Axelrod R. Tanese R. Sexual reproduction as an adaptation to resist parasites (A review).Proc. Natl. Acad. Sci. USA. 1990; 87: 3566-3573Crossref PubMed Scopus (937) Google Scholar]. In this light, various strategies for diversifying innate receptors may have evolved independently in invertebrates, protochordates and jawless vertebrates before the acquisition of receptor gene rearrangement. Although the particular mechanism that gives rise to the observed genetic polymorphism in VCBP2 genes is unknown, hyperdiversification of the Ig superfamily and other receptors in chordates, either at the germline or somatic level, could have provided an advantageous bridge between innate and adaptive immune function until mechanisms emerged in the vertebrates that could generate and select for diversity of antigen-binding receptors. Supplemental data are available at http://www.current-biology.com/cgi/content/full/14/12/R465/DC1/ Thanks to R. Litman, K. Krumeich, B. Pryor, C. Amemiya, and T. Ota. Supported by NIH grant AI23338. Download .pdf (.04 MB) Help with pdf files Supplemental Data" @default.
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• W2000851475 title "Individual protochordates have unique immune-type receptor repertoires" @default.
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