Autoimmune diseases: Solution of the environmental, immunological and genetic components with principles for immunotherapy and transplantation.

Autoimmune diseases have environmental and genetic components. These are the microbial trigger, the immunity system component and the genetic component. Here we describe these components and how they interact. Known microbial triggers are Streptococcus pyogenes for rheumatic carditis, Proteus mirabilis for rheumatoid arthritis and Klebsiella pneumoniae for ankylosing spondylitis. The immunity system component has been clarified by realisation that no autoimmune disease is caused by loss of suppressor T cells. This leaves Burnet's forbidden clones, clearly seen in Graves' disease, as the immunological defect. With wide scope for clonal diversification by somatic gene mutations, to prevent frequent autoimmunity the immunity system is policed by the histocompatibility system. This dictates the immune response repertoire by deleting complementary clones (H Gene Theory). We show molecular evidence of how specific histocompatibility antigens can predispose to an autoimmune disease by influencing choice of the microbial antigen to which the immunity system reacts. Because of the unlucky random element in the somatic mutations involved in their development, forbidden clones are unlikely to reappear in new immune repertoires developing after immune ablation and autologous bone marrow cell reconstitution, as observed clinically. Isolation of autoantigens and their attachment to cytotoxic moieties could provide specific immunotherapy for autoimmune diseases. Kaplans's discovery that xenografts can be accepted without rejection after immune ablation followed by autologous and xenogeneic bone marrow inoculation, could enable widespread use of pig grafts for humans. Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.