Emergence of the immunoglobulin family: conservation in protein sequence and plasticity in gene organization

The immune response of jawed vertebrates is an inducible, highly specific defense mechanism that is characterized by an enormous diversity in recognition capacity. This allows responses to potential pathogens that have never been previously encountered in the evolution of the species. The molecules that carry out the specific recognition of antigen are glycoproteins termed immunoglobulins (Igs) or T-cell receptors (TCRs) that occur as heterodimers consisting of pairs of light and heavy chains (Igs) or a/|3 or 7/8 TCR chains (Kabat et al, 1991). These molecules are homologous members of the same family that express variable (V) and constant (C) domains, with the V/V pairs containing the combining site for antigen and the C domains involved in dimerization and effector function. The genes specifying each chain comprise individual multigene families which, in mammals, contain large arrays of variable segments (50-300), 1-10 diversity segments (heavy chains, TCR 3 chains), a set of joining (J) segments, (a few for Igs, but as many as a 100 for TCR a chains), and a few constant domains (1 for K light chains, approximately 10 for the heavy chain translocon). Individual sequence diversity and commitment of a B or T cell to differentiation into an antigen-specific immunocyte (B or T cell) results from the recombination of a V, D, and J element to form a complete variable region for surface expression with an appropriate constant region. Since Igs and TCRs exist as heterodimers, further amplification of recognition capacity is contributed by the selection of the partner chain; for example, if there are 5000 possible complete VH (VDJ) segments and 1500 possible complete VK (VJ) segments, there are 7,500,000 possible VH/VK combining sites that can be formed. This calculation illustrates the magnitude of individual combining sites that can be generated, but is an underestimate because other mechanisms including somatic mutation and junction diversification within the D and J segments contribute additional possibilities. We will summarize recent evidence to illustrate that the fundamental genetic mechanism allowing the combinatorial diversification of antibody occurs in all jawed vertebrates, and is clearly present in representatives of the most primitive of living gnathastomes, the sharks. Early in the course of biochemical studies of Igs, Hill and his associates (Hill et al, 1966) made the seminal discovery that V and C domains of light and heavy chains were homologous to one another and proposed a scheme for the evolution of Igs based upon their derivation from a domain size precursor of approximately 110 residues. Attempts to gain an understanding of the 'big picture' of the evolution of Igs required the application of recombinant DNA technology. We will review recent data showing that clearly defined homologs of light chains (Schluter et al, 1989; Shamblott and Litman, 1989a; Greenberg et al, 1993; Raster al, 1994; Hohman etal, 1995), heavy chains (Kokubu et al, 1988a,b; Vazquez et al, 1992; Shen et al, 1996), and TCRs (Rast and Litman, 1994) are present in the most primitive of jawed vertebrates. In addition, sharks contain an additional class of Ig having many of the properties expected of the primordial Ig (Bernstein et al, 1996b) as proposed by Hill et al. (Hill et al, 1966). Overall, the data obtained on the evolution of Igs, and their close relatives the TCRs, supports the concept that approximately 450 millions years ago (coincident with the origins of ancestral vertebrates) a 'big bang' (Marchalonis and Schluter, 1990a) of gene duplication occurred which, coupled with the addition of DNA processing enzymes facilitating recombination (Greenhalgh et al, 1993; Bernstein et al, 1994, 1996a), generated the combinatorial immune response typical of vertebrates.