Three theories which explain the occurrence and inheritance of the autoimmune diseases.

ABSTRACT

The immunity system uses random processes. In B lymphocytes these are antigen-driven somatic gene mutations which tighten antibody affinity for invading microbes to enable recovery from and prevention of infectious diseases. In T lymphocytes, randomized gene segment combinations continually provide new clones, needed to counter continually-changing microbial parasites. Because these B and T cell processes are random, they entail risk of producing forbidden (self-antigen-reactive) clones, a minority of which cause autoimmune diseases, as envisaged by Burnet in his forbidden clone theory. A corollary of the forbidden clone theory is the V gene theory, postulating that the specificities of the germline variable (V) genes coding for antigen receptors influence the risks of autoimmune diseases. The H gene theory, postulates that the main defense against autoimmune disease is mediated by the permanent, unbreakable tolerances imposed on the clonal repertoire by the histocompatibility (H) antigens, major, minor and H-Y. Recent work shows that the last two act as peptides which modify MHC antigens by occupying their Bjorkman grooves. The absolute absence of autoimmunity to histocompatibility, ABO and H-Y antigens shows that nascent clones with high affinity for these white cell antigens are continually eliminated. Application of molecular biological techniques has shown that H antigen tolerance impositions profoundly alter the clonal repertoire and hence the risks of development of the forbidden clones which cause the autoimmune diseases. Precise basic theory is crucially important for effective application of molecular biology and microbiology to the eminently achievable therapeutic and prophylactic conquest of the ubiquitous autoimmune diseases.