We recently have identified an antigen receptor in sharks called NAR (new or nurse shark antigen receptor) that is secreted by splenocytes but does not associate with Ig light (L) chains. The NAR variable (V) region undergoes high levels of somatic mutation and is equally divergent from both Ig and T cell receptors (TCR). Here we show by electron microscopy that NAR V regions, unlike those of conventional Ig and TCR, do not form dimers but rather are independent, f lexible domains. This unusual feature is analogous to bona fide camelid IgG in which modifications of Ig heavy chain V (V H ) sequences prevent dimer formation with L chains. NAR also displays a uniquely f lexible constant (C) region. Sequence analysis and modeling show that there are only two types of expressed NAR genes, each having different combinations of noncanonical cysteine (Cys) residues in the V domains that likely form disulfide bonds to stabilize the single antigen-recognition unit. In one NAR class, rearrangement events result in mature genes encoding an even number of Cys (two or four) in complementarity-determining region 3 (CDR3), which is analogous to Cys codon expression in an unusual human diversity (D) segment family. The NAR CDR3 Cys generally are encoded by preferred reading frames of rearranging D segments, providing a clear design for use of preferred reading frame in antigen receptor D regions. These unusual characteristics shared by NAR and unconventional mammalian Ig are most likely the result of convergent evolution at the molecular level.At the heart of the adaptive immune system are the antigen receptors, Ig and T cell receptor (TCR), that are generated in anticipation of recognition of pathogens (1). The typical antigen receptor is composed of two polypeptide chains [heavy (H) and light (L) for Igs and ␣ and ␤ or ␥ and ␦ for TCRs]. Each chain, in turn, is composed of a single, variable (V) domain at the N-terminal end followed by one to seven constant (C) domains. C domains define the effector functions characteristic of a given class of Ig whereas V domains each display a unique sequence and structure defining antigen specificity. Igs can be subdivided further into Fab and Fc fragments, responsible for antigen binding and for effector function, respectively. Ig and TCR V regions are encoded by a mosaic of genes ligated together somatically during lymphocyte ontogeny (2). Specifically, single V and J elements are joined together at the DNA level for Ig L chain or TCR ␣ and ␥ V regions. In Ig H chains and TCR ␤ and ␦ chains, one or, occasionally, two D elements are joined between the V and J segments. Together, the V, (D), and J elements encode framework (FR, responsible for protein folding and structure) and complementarity-determining regions (CDR, responsible for antigen interactions) within the V domains.The evolutionary origin of antigen receptors is unknown, but the first indication of their emergence phylogenetically is in cartilaginous fish (sharks, skates, and rays), where at least three types of Ig (3-9)...

Major histocompatibility complex (MHC) class I and class II molecules bind to and display peptidic antigens acquired from pathogens that are recognized by lymphocytes coordinating and executing adaptive immune responses. The two classes of MHC proteins have nearly identical tertiary structures and were derived from a common ancestor that probably existed not long before the emergence of the cartilaginous fish. Class I and class II genes are genetically linked in tetrapods but are not syntenic in teleost fish, a phylogenetic taxon derived from the oldest vertebrate ancestor examined to date. Cartilaginous fish (sharks, skates, and rays) are in the oldest taxon of extant jawed vertebrates; we have carried out segregation analyses in two families of nurse sharks and one family of the banded houndshark that revealed a close linkage of class II␣ and ␤ genes both with each other and with the classical class I (class Ia) gene. These results strongly suggest that the primordial duplication giving rise to classical class I and class II occurred in cis, and the close linkage between these two classes of genes has been maintained for at least 460 million years in representatives of most vertebrate taxa.