Pathogenesis of small vessel vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens: new insights from animal models

Abstract

Morbidity and mortality associated with current treatment strategies in ANCA associated small vessel vasculitis (AASV) are unacceptably high and more specific therapies will require more detailed knowledge of the pathogenesis of the disease. In-vitro experiments have provided invaluable insight into the molecular mechanisms of antibody action and their subcellular effects; however, they may not reflect the in-vivo situation that can only be assessed in animal models. Rodent models provide convincing evidence that myeloperoxidase (MPO) and antibodies to it can cause small vessel vasculitis but the development of rodent models of anti-proteinase 3 (PR3) antibody mediated injury is proving much more problematic. Insight into the molecular differences of the human and mouse antigens and antibodies to them as well as analysis of the molecular interaction with their binding partner(s) have highlighted potential resolutions to this discrepancy. The recent characterization of autoimmunity to lysosomal membrane glycoprotein-2 (LAMP-2) in AASV and the possible inductions of autoantibodies to it by molecular mimicry open an entirely new area for study. Recent advances in the development of animal models that more faithfully model the disease and the discovery of novel ANCA antigens such as LAMP-2 provide new opportunities to dissect the mechanisms involved in the pathogenesis of AASV.