A solution to the genetic and environmental puzzles of insulin-dependent diabetes mellitus.

Studies of the segregation of heterozygous immunoglobulin allotypes in families with several cases of insulin-dependent diabetes mellitus (IDDM) show that germline heavy-chain V (variable region) genes are not major genetic determinants for IDDM, but data for IDDM and Graves' disease together suggest involvement of kappa light-chain V genes. Absence of IDDM at birth, the semi-random age of onset, and the 50% discordance of identical twins suggest that somatic mutation of germline V genes is involved in the development of the pathogenetic anti-beta-cell clones. The effect of histocompatibility and other alloantigens on the prevalence of IDDM is readily accounted for by the effect of the "holes" they induce, by natural tolerance, in the immune response repertoire; these alterations apparently affect the chance of emergence of anti-beta-cell clones by the somatic mutations and network of interclonal deletions that constantly change the fringes of the repertoire. Histocompatibility antigens can also influence repertoire development by changing the specificity of conjoint presentation of foreign antigens by macrophages. Antigenic stimulation by particular environmental microorganisms is probably essential to the repertoire development necessary for the occurrence of IDDM. Additionally, beta-cell damage by local infection may play a part by facilitating autoantigen presentation to the immune system.