Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update

Abstract

Vasculitides associated with serum positivity for anti-neutrophil 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.

Figure 1

Histological hallmarks of ANCA-associated vasculitis. A: A lung biopsy specimen shows severe alveolar capillaritis with alveolar hemorrhage. Observe the thickened interalveolar septum with infiltrates of mononuclear cells and some neutrophils (H&E stain; original magnification ×60). B: Renal biopsy specimen showing necrotizing and crescentic glomerulonephritis in a patient with MPA. Note the crescentic formation and glomerular capillary necrosis (H&E; original magnification, ×400).

Figure 2

ANCA-associated vasculitis pathogenic model. A: Granulomatous inflammation in WG. a: Lung DCs are exposed to an undefined antigen (perhaps PR3). b: Antigen-loaded DCs travel to peripheral lymph nodes and present the antigen to naïve CD4⁺ T lymphocytes. DCs produce interleukin-18 (IL-18), among other cytokines, and skew T cells to a Th1 phenotype. c: Activated Th1 effector memory T cells (TEMs) return to the lungs, where the antigen persists. TEMs secrete large amounts of interferon-γ (IFN-γ) and TNF-α, which induce macrophage recruitment and maturation and eventually lead to granulomata formation and tissue destruction. Chronic T-cell activation might promote neogenesis of lymphoid-like tissue, where affinity maturation of autoreactive B cells and plasma cells takes place (the latter secreting PR3-ANCA, which will reach the bloodstream causing vasculitis). (PAR)-2, protease-activated receptor. B: ANCA-induced necrotizing vasculitis in WG, MPA, and CSS. a: TNF-α induces “priming” of neutrophils and endothelial cells. b: Cytokine priming allows PR3 and MPO to travel from azurophilic granules to the neutrophil surface and interact with ANCAs. In addition, TNF-α induces enhanced expression of adhesion molecules by endothelial cells. c: Simultaneous interaction of ANCA with their antigen and Fc-γ receptor prompts several effector functions including firm adhesion (and not rolling) of neutrophils to the cytokine-primed endothelium. d: Once adhered, ANCAs induce neutrophil respiratory burst and degranulation which, ultimately, cause vasculitic damage. ANCAs also promote neutrophil secretion of proinflammatory cytokines and activating complement factors, leading to the recruitment of more inflammatory cells and amplifying and perpetuating the process. ICAM-1, intercellular adhesion molecule-1.