Immunoglobulin Genes in Autoimmunity

Abstract

The contribution of V germline genes and somatic mutation as well as the mechanism governing expression of the various V family genes in response to self-antigens are still unknown. Thus, we are still far from understanding the contribution and role of the B cell repertoire in human autoimmunity. Much of our current data on autoantibody gene repertoire are derived from laboratory generated hybridomas or animal model of autoimmune diseases. These may not reflect the human situation. In contrast, very few human autoantibodies with defined specificities have been structurally and genetically analyzed. In the future, meaningful data, perhaps from direct cloning and sequencing of autoantibodies derived from patients with autoimmune diseases, will be necessary to resolve issues in autoantibody repertoire usage. In this article, the prominent features of the human Ig repertoire, the usage of germline genes in autoantibodies, identifications of somatic mutations among autoantibodies and current data supporting either restricted or nonrestricted Ig gene usage and idiotypic expression among autoantibodies in several well-studied autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis are discussed.

The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs

“…17,18 In B cells, V H (variable), D H (diversity), and J H (joining) of the heavy chain (H-chain) and V L and J L gene segments of the light chain (L-chain) rearrange to produce an individual, extremely variable immunoglobulin repertoire, 19 which further undergoes affinity maturation by somatic hypermutation, 20 most prevalent in the complementarity determining regions (CDR)1 to 3, of which CDR3 is the major antigen binding site. [21][22][23] The analysis of the functional impact of the immunoglobulin V H gene polymorphisms for pathogenicity has been facilitated by techniques allowing the generation of monoclonal antibodies, such as phage display, 24 hybridoma technology, 25 and EpsteinBarr virus (EBV) transformation of B cells, 26 enabling establishment of the link between the antibody genotype and phenotype.…”