Autoantigen complementarity: A new theory implicating complementary proteins as initiators of autoimmune disease
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7155, USA.Journal of Molecular Medicine (Impact Factor: 5.11). 02/2005; 83(1):12-25. DOI: 10.1007/s00109-004-0615-3
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.
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ABSTRACT: Antineutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are closely associated with the idiopathic systemic necrotizing vasculitides, in particular Wegener's granulomatosis, microscopic polyangiitis and its renal limited manifestation, and Churg Strauss Syndrome. Many in vitro studies show that those ANCA have phlogistic potential, particularly at the interface of neutrophils and endothelial cells. A limited number of studies in experimental animals support their pathogenetic role. However, ANCA alone are not sufficient, as based on clinical and experimental data, and other, probably exogenous factors, seem necessary for disease induction and (re)activation. Among those silica and particularly, the carriage of Staphylococcus aureus have been proposed. Besides, various genetic factors are involved in disease susceptibility. The ANCA-associated vasculitides are systemic autoimmune diseases in which the interplay of autoimmunity with environmental and genetic factors determines their clinical expression.Autoimmunity Reviews 03/2002; 1(1-2):61-6. · 7.93 Impact Factor
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ABSTRACT: Reviewed are recent discoveries that provide insights into novel mechanisms involved in the aetiology and pathology of anti-neutrophil cytoplasmic autoantibodies (ANCA) disease. Gene expression profiles of circulating leukocytes from anti-neutrophil cytoplasmic autoantibody immunogenesis patients revealed high levels of proteinase 3 (PR3) and myeloperoxidase (MPO) mRNA. Combined with reports of increased expression of these proteins, it appears that increased antigen availability is a pathologic component of anti-neutrophil cytoplasmic autoantibody immunogenesis disease, which might be equally as important as the presence of anti-MPO or anti-PR3 autoantibodies. Genetic predisposition to develop anti-neutrophil cytoplasmic autoantibody immunogenesis disease may include a polymorphism in the promoter region of the PR3 gene. Signalling pathways affected by anti-neutrophil cytoplasmic autoantibody immunogenesis binding to neutrophils involve the p21 pathway. Lastly, a topic discussed at length in this review is the seminal observation that PR3-ANCA patients harbour antibodies reactive with a protein produced from PR3-antisense RNA, whose amino acid sequence has homologies with proteins from many microbes and viruses. Delineated in the Theory of Autoantigen Complementarity, it is proposed that the initiator of an autoimmune response is not the autoantigen, but instead is a protein that is 'antisense' or complementary to the autoantigen (e.g. from bacteria or PR3). The progress in research efforts in the past year, including the identification of complementary proteins as a potential cause of anti-neutrophil cytoplasmic autoantibody immunogenesis, should highly impact future approaches therapeutic intervention.Current Opinion in Nephrology and Hypertension 06/2005; 14(3):217-22. DOI:10.1097/01.mnh.0000165886.93427.b1 · 3.86 Impact Factor
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ABSTRACT: It has been suggested that complementary proteins are involved in autoimmunity through a network involving idiotype-anti-idiotype reactions termed 'autoantigen complementarity'. We propose that complementary proteins, which occur naturally or result from cellular dysfunction, might be more common than recognized currently. This implies that the role of complementary proteins in autoimmunity merits increasing investigation. The concept of complementary proteins is reviewed here and, also, new ideas are presented that underscore the role of open-reading frames in frame -1 of recognized genes in the production of complementary proteins (frame -1 is the reverse complement sequence of a gene that uses the antisense of the codons of frame +1). Furthermore, a novel role for palindromic sequences in autoimmunity and a new model explaining how abzymes and autoantigen complementarity might be related are proposed.Trends in Immunology 08/2005; 26(7):367-72. DOI:10.1016/j.it.2005.05.001 · 10.40 Impact Factor
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