Autoimmune diseases affect approximately 1 in 21 persons in the United States. Treatment often requires long-term cytotoxic
therapy. How and why these deleterious diseases occur is unclear. A serendipitous finding in our laboratory using serum from patients with autoimmune
vasculitis led us to develop the theory of
autoantigen complementarity, a novel concept that may elucidate the etiological and pathogenetic mechanisms underlying
autoimmune disease in general. The theory proposes that the inciting immunogen that elicits a cascade of immunological events is not the
self-antigen (the
autoantigen) or its mimic but rather a
protein that is complementary in surface structure to the
autoantigen; that is, a
protein homologous or identical to the amino acid sequence of translated
antisense RNA from the noncoding strand of the
autoantigen gene. The cascade begins when this complementary
protein initiates the production of
antibodies that in turn elicit an anti-antibody or anti-idiotypic response. These
anti-idiotypic antibodies can now react with the
autoantigen. Strikingly, homology search of complementary
proteins yields microbial and
fungal proteins, thus indicating that invading micro-organisms can deliver the inciting immunogen. Curiously, approximately 50% of our patients transcribe the complementary
protein's antisense RNA. If it transpires that these aberrant RNAs are translated, the complementary
protein would be produced by the individual. Here we review published research investigating complementary
proteins, anti-idiotypic immune responses, and antisense transcripts, all of which support complementary
proteins as initiators of
autoimmune disease. In addition, we provide possible microbial and/or fungal organisms that may incite some of the most studied
autoimmune diseases. Lastly, we propose mechanisms by which cell-mediated autoimmunity can be triggered by
autoantigen complementarity. Based on our data and the contributions of the researchers described in this review, identification of
proteins complementary to
autoantigens is likely to be informative in most
autoimmune diseases. This vein of study is in the early phases; however, we expect "
autoantigen complementarity" is an underlying mechanism in many
autoimmune diseases.