IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates

Abstract

IgD has remained a mysterious Ig class and a bane to immunology students since its discovery >40 years ago. Its spotty occurrence in mammals and birds and the discovery of an isotype with similarities to IgD in bony fish are perplexing. We have identified IgD heavy (H) chain (␦) from the amphibian Xenopus tropicalis during examination of the IgH locus. The Xenopus ␦ gene is in the same position, immediately 3 of the IgM gene, as in mammals, and it is expressed only in the spleen at low levels, primarily as a transmembrane receptor by surface IgM ؉ cells. Our data suggest that frog IgD is expressed on mature B cells, like in mouse͞human. Unexpectedly, Xenopus IgD is orthologous to IgW, an Ig isotype found only in cartilaginous fish and lungfish, demonstrating that IgD͞W, like IgM, was present in the ancestor of all living jawed vertebrates. In striking contrast to IgM, IgD͞W is evolutionarily labile, showing many duplications͞deletions of domains, the presence of multiple splice forms, existence as predominantly a secretory or transmembrane form, or loss of the entire gene in a species-specific manner. Our study suggests that IgD͞W has played varied roles in different vertebrate taxa since the inception of the adaptive immune system, and it may have been preserved as a flexible locus over evolutionary time to complement steadfast IgM.evolution ͉ immune system S ince the pioneering work of comparative immunologists in the 1960s, IgM has been the Ig isotype believed to be primordial and most stable in vertebrate evolution (1). Despite differences in the degree of polymerization of the secretory form in different vertebrate groups (1, 2) and a major splice variant of the transmembrane (TM) form in teleost fish (3), IgM is renowned for its molecular, biochemical, and functional stability. Present in all living jawed vertebrates, IgM is the first isotype to be expressed both in ontogeny and during humoral adaptive immune responses and is found as the major TM receptor on the surface of both conventional and ''innate'' B cells (4).By contrast, IgD has remained an enigmatic isotype since its discovery long ago (5). Like IgM, IgD is expressed as a TM receptor on B cells of mouse and human, generated as a result of alternative splicing of pre-mRNA containing the transcribed variable (V) region and the IgM and IgD heavy (H) chain constant (C) regions ( and ␦, respectively). Because of its spotty presence in mammals and absence in birds, IgD was assumed to be a recently evolved isotype (6). However, the discovery of an isotype in ray-finned bony fish with sequence similarity to IgD (7) and its presence in some mammals previously believed to lack IgD (8) have greatly modified our view of Ig isotype evolution and suggested it may have arisen much earlier.A similarly strange phylogenetic jump surrounds the isotype IgW, which was discovered first in skates (9, 10) and later in sharks (11,12). The secreted version of the IgW H chain ( ) is present in long and short forms in all elasmobranchs tested to date, and the TM form is al...

IgM, IgD and IgY and their expression pattern in the Chinese soft-shelled turtle Pelodiscus sinensis

“…The IgY in P. sinensis as well as in other vertebrates such as in amphibians (Amemiya et al, 1989;Warr et al, 1995) and avians (Zhao et al, 2000;Lundqvist et al, 2001), in which this Ig molecule is found, has also a conserved four constant domain structure. Phylogenetic analysis similarly indicated that the IgM and IgD in the Chinese soft-shelled turtle are well closely clustered with their counterparts reported in other reptiles, despite the variation in the number of constant domains in IgD in different classes of vertebrates and even in different species within same class of vertebrates (Wilson et al, 1997;Hordvik et al, 1999;Stenvik and Jorgensen, 2000;Hirono et al, 2003;Saha et al, 2004;Ohta and Flajnik, 2006;Deza and Espinel, 2008). The IgY, as indicated in the phylogenetic tree is closely related with those IgY found in avians; but its relationship with the GenBank deposited IgY sequence (GenBank accession no.…”

“…IgX has been considered to be an analogue of mammalian IgA because a large number of IgXpositive B cells were preferentially expressed in the gut epithelium (Mussmann et al, 1996). The Xenopous ␦ gene (IgD, possess eight Cdomains) locates in the same gene cluster, following immediately 3 end of the IgM gene, as in mammals (Ohta and Flajnik, 2006). IgF heavy chain with only two constant domains, is similar to amphibian IgY in sequence, but its gene contains a hinge exon making it the earliest example in evolution of an Ig isotype with a separately encoded genetic hinge (Zhao et al, 2006).…”

The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins

“…1A) are most homologous to the primordial IgW of sharks (14). Of the five human antibody classes, IgA, IgD, IgE, IgG, and IgM, IgW is most closely related to IgD, which, along with IgM, are the oldest Ig isotypes (14)(15)(16)(17). Except for low-resolution electron microscopic images (18), no structural data are available for any of the constant IgNAR domains.…”

Extensive diversification of IgH subclass-encoding genes and IgM subclass switching in crocodilians

“…7). As IgM and IgD(W) are now commonly accepted to be the most primordial IgH classes in evolution 17,21,22 , it is reasonable to conclude that all other IgH classes evolved from them through various molecular mechanisms such as gene duplication, conversion or recombination. These processes gave rise to IgNAR and IgZ(T) after the divergence of cartilaginous fish and bony fish, respectively [12][13][14] .…”

“…Differential diversification of the Ig classes or subclasses may have arisen from a long evolutionary period of environmental selection pressure, thus conferring survival advantages. IgM and IgD are thought to be the most primitive Ig classes 17,21 , as IgM has been identified in all species examined to date and IgD is found in most species except for birds and certain mammals 22 . Logically, other IgH (H: heavy-chain genes) classes should be evolutionarily derived from IgM and IgD, likely through various mechanisms such as gene duplication, gene conversion or recombination.…”