Principles of autoimmune disease: pathogenesis, genetics and specific immunotherapy.

The immunity system has the daunting task of producing lymphocyte clones able to react with any pathogenic microbe, new or old, to defend against infectious disease. It cannot do this without occasionally producing a forbidden clone, Burnet's apt name for the pathogenic lymphocyte clones that cause the autoimmune diseases by accidentally reacting with a host antigen instead of an antigen on an invading microbe. Unfortunately, Burnet's insight has been lost by immunologists, for four decades. V genes code for the specificity of receptors for antigen on B and T lymphocytes. They change by the DNA sequence copying errors (somatic mutations) that create new clones during the lymphocyte cell divisions that occur in an immune response to microbial infection. These mutations are necessary for achievement of the higher affinity, between a lymphocyte clone and the microbe, that enables recovery from infectious disease. H genes code for histocompatibility antigens, major, minor and HY. These are peptides, which, unlike V gene products, are invariant throughout life. H genes dictate the immune repertoire by constantly deleting any nascent lymphocyte clone reactive with them. This protects, with imperfect success, against autoimmune disease arising from the V gene changes that produce forbidden clones. Microbial triggers cause an autoimmune disease by initiating a cascade of clonal development that produces a forbidden clone by unlucky somatic mutations in lymphocyte V genes, exemplified by group A streptococci triggering rheumatic fever and measles triggering encephalomyelitis. Specific immunotherapy will come from finding and targeting forbidden clones.