LAMPs and NETs in the Pathogenesis of ANCA Vasculitis

Abstract

Strong evidence from in vitro studies, animal models, and clinical observations suggests that anti-neutrophil cytoplasmic antibodies (ANCA) play a critical role in the vascular damage of ANCA-associated vasculitis (AAV).1 Understanding the key pathogenic mechanisms of AAV may provide a safer and more rational therapeutic approach. Although the pathogenic role of ANCA in AAV has been studied extensively, it is still not clear why ANCAs appear. Two recent papers in Nature Medicine 2,3 provide a previously undescribed molecular explanation of the origin, development, and perpetuation of injury in AAV that may have important clinical implications. In the first article, Kain et al. 2 reported that infection by fimbriated bacteria triggers cross-reactive autoimmunity to a previously characterized ANCA antigen, lysosomal membrane protein 2 (LAMP-2), resulting in the production of autoantibodies that activate neutrophils and damage human microvascular endothelium in vitro and cause pauci-immune focal necrotizing glomerulonephritis (FNGN) in rats.2 In the second article, Kessenbrock et al. 3 demonstrated that the formation of neutrophil extracellular traps (NETs), which are involved in neutrophil cell death during infection, trigger vasculitis, and perpetuate the autoimmune response against neutrophil components in patients with AAV. It has long been suspected that infection plays a role in the development of ANCAs. They were discovered in 1982 while Davies et al. 4 were studying antinuclear antibodies in serum from patients with FNGN, many of whom were infected with the Ross River virus. Several ANCA autoantigens are leukocyte proteins implicated in host defense against infectious diseases.5,6 Wegener's granulomatosis may be an atypical cell-mediated immune response to an exogenous or endogenous antigen in the respiratory tract that results in granuloma formation and the development of humoral autoimmunity to proteinase 3 (PR3).6 One theory of PR3-directed autoimmunity involves the complementary peptide of PR3, which is …