Anti-Neutrophil Cytoplasmic Antibody Pathogenesis in Small-Vessel Vasculitis

Abstract

Vasculitides associated with serum positivity for antineutrophil cytoplasmic antibodies (ANCAs) that affect small-to medium-sized vessels are commonly known as ANCA-associated vasculitis (AAV) and include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Evidence derived from both in vitro studies and recent animal models points to a pathogenic role of ANCAs in AAV. In 2002, the first in vivo breakthrough in the pathogenesis of ANCAs showed that mouse ANCAs against myeloperoxidase (MPO) led to intrinsic pauci-immune renal vasculitis in mice. In 2004, a report using both in vitro and in vivo studies proposed that proteinase 3 (PR3)-directed autoimmunity involved the complementary peptide of PR3 (cPR3), which is encoded by the antisense strand of the PR3 gene. The last breakthrough came in October 2008 with a previously undescribed molecular explanation for the origin and development of injury in pauci-immune renal vasculitis, with potential clinical implications. This report showed that infection by fimbriated bacteria may trigger cross-reactive autoimmunity to a previously characterized ANCA antigen, lysosomal membrane protein-2, which is contained in the same vesicles that harbor MPO and PR3. Infection by fimbriated bacteria resulted in the production of autoantibodies, which activated neutrophils and killed human microvascular endothelium in vitro and caused renal vasculitis in rats. Although the evidence for a pathogenic role of ANCAs, mainly MPO-ANCAs, is striking, various questions remain unanswered. Understanding the key pathogenic mechanisms of AAV may provide a safer, more rational therapeutic approach than the traditional (ie, corticosteroids and immunosuppressants) treatment strategy.

A case of PR3–ANCA-positive anti-GBM disease associated with intrarenal arteritis and thrombotic microangiopathy

“…Interstitium revealed hemosiderin deposits (Fig. 2f), which reflect old interstitial hemorrhage [2]. In contrast, interstitial granulomatous lesion, rare but characteristic lesion of ANCA positivity [23], was not detected.…”

“…Second, ''double positive'' disease has a higher risk of relapse than ''pure'' anti-GBM disease [1,8,11]. This is supposed to be associated with disease nature that anti-GBM disease as a generally non-relapsing disease [1], while ANCA-associated vasculitis carries significant risk of relapse [2]. Third, one-third of ''double positive'' disease shows intrarenal arteritis, which is a histological observation theoretically specific for ANCA in ''double positive'' disease [7].…”

“…Anti-glomerular basement membrane (anti-GBM) disease and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are two major causes of pulmonary-renal syndrome, which is characterized by rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage [1,2]. Anti-GBM disease is caused by autoantibody against glomerular and alveolar basement membrane, and is pathologically distinct from arteritis [1].…”

“…Anti-GBM disease is caused by autoantibody against glomerular and alveolar basement membrane, and is pathologically distinct from arteritis [1]. However, anti-GBM disease accompanied by arteritis was reported soon after the establishment of the concept of anti-GBM disease [2,3], and after the generalization of ANCA assay, a substantial proportion (21.2-45.8%) of anti-GBM disease has been found to be positive for ANCA (Table 1) [4][5][6][7][8][9][10][11]. Therefore, ANCA is supposed to be responsible for the arteritis accompanied anti-GBM disease, and ANCA-positive anti-GBM disease is termed ''double positive'' disease.…”

De novo myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis 31 years after living-donor kidney transplantation

“…ANCA reacts with myeloperoxidase (MPO) and proteinase 3 (PR3), and can be a specific disease marker [1]. MPO-ANCA-associated disease is common in Japan, whereas PR3-ANCA-associated disease is much more common in western countries [2].…”