New insights that link microbes with the generation of antineutrophil cytoplasmic autoantibodies: the theory of autoantigen complementarity.

PURPOSE OF REVIEW

Reviewed are recent discoveries that provide insights into novel mechanisms involved in the aetiology and pathology of anti-neutrophil cytoplasmic autoantibodies (ANCA) disease.

RECENT FINDINGS

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).

SUMMARY

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.