The Role of Somatic Mutation of Immunoglobulin Genes in Autoimmunity

Abstract

The humoral arm of the immune system consists of cells producing immu­ noglobulin molecules capable of recognizing the myriad of foreign or nonself molecules to which an individual is exposed during his or her lifetime. How does the immune system produce enough unique immu­ noglobulin molecules to recognize the vast number of antigens it may encounter without at the same time producing harmful antibodies directed toward self antigens? The first part of this puzzle has been solved by molecular genetic technology, and several mechanisms responsible for generating the diversity of immunoglobulin molecules have been identified.· The relationship of autoantibodies to antibodies directed to foreign anti­ gens is not yet understood, however, and studies of the molecular genetic basis for autoantibody production are just now beginning. In this chapter we examine the evidence that autoantibodies are derived from genes that encode protective antibodies rather than from genes uniquely committed to autoantibody production. We discuss two possible mechanisms for their production: (a) that they are encoded by germline immunoglobulin genes or (b) that they represent a somatic diversification of those genes. The diversity of the antibody repertoire is generated by several mech­ anisms. Immunoglobulin heavy-chain and light-chain genes are composed of different gene segments, VDJC and VJC respectively, that undergo