Natural antibodies and innate-like B cells

Abstract

The range of mechanisms available for the molecular diversification of human and murine antibody genes can mold a limited set of germline elements into a total potential repertoire of distinct antigen receptors that approximates Avogadro’s number (i.e., ~10), and as a consequence it is generally believed that as long as it is accessible in the aqueous environment, an Ig-based receptor can be made for any possible ligand. With the further superimposition of somatic hypermutation, a receptor, which initially has functional properties as attractive as those of a “sow’s ear”, can subsequently be refined into something akin to a “silk purse”. While such broad engineering capabilities are especially attractive to those with the perspectives of the structural chemist, immunologists have instead found that lymphocytes with only a relative parsimony of BCR types are expressed in vivo. Moreover, the immune systems of different individuals commonly include clonal sets of lymphocytes expressing antigen receptors that are encoded by gene rearrangements that are nearly identical, or even identical, complete with the same somatically generated gene splices (see Chapters 1 and 2). Such findings, which in part reflect inherent molecular biases that yield the recurrent somatic production of conserved canonical receptors, yield the repertoire of natural antibodies made by B cells that initially arise and expand without specific immunization. The limited diversity of natural antibodies has also led to the designation of their B cell clonal sources as innate-like B cells, because their BCR repertoires harness only a small proportion of the full combinatorial power of the lymphocyte antigen receptor system (see Chapter 3). However, in only a few cases have specific candidate self ligands involved in the antigenic selection of these clonal sets been identified, or even implicated (Chapters 3 and 4). The best available evidence suggests that these putative ligands include non-protein antigens like the carbohydrates that are post-translational modifications on some cell surface molecules. In another case, they have been linked to neo-antigens, like phosphoryl choline and maledialdehyde, which can be generated by the oxida-