Pathogenesis of ANCA-Associated Pulmonary Vasculitis

Abstract

Antineutrophil cytoplasmic antibodies (ANCAs) are autoantibodies specific for antigens located in the cytoplasmic granules of neutrophils and lysosomes of monocytes. ANCAs are associated with a spectrum of necrotizing vasculitis that includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. Pulmonary vasculitis and related extravascular inflammation and fibrosis are frequent components of ANCA vasculitis. In this review, we detail the factors that have been associated with the origin of the ANCA autoimmune response and summarize the most relevant clinical observations, in vitro evidence, and animal studies strongly indicating the pathogenic potential of ANCA. In addition, we describe the putative sequence of pathogenic mechanisms driven by ANCA-induced activation of neutrophils that result in small vessel necrotizing vasculitis and extravascular granulomatous necrotizing inflammation.

Fig. 1

ANCA vasculitis lung lesions (H&E stain). (A) Pulmonary hemorrhagic capillaritis showing numerous neutrophils within alveolar septal capillaries (arrow) and red blood cells in air spaces (H&E stain). (B) Intense segmental acute arteritis in lung with transmural inflammation (arrow). (C) Granulomatous inflammation with multinucleated giant cells (arrow) (H&E stain). ANCA, antineutrophil cytoplasmic antibody.

Fig. 2

Systemic vasculitis and granulomatous inflammation in Rag2^−/− mice 13 days after receiving anti-MPO splenocytes. (Reproduced from Xiao et al.) (A) Pulmonary hemorrhagic capillaritis showing numerous neutrophils within alveolar septal capillaries (arrow) and red blood cells in air spaces (H&E stain). (B) Intense acute arteritis in lung with transmural (arrow) and perivascular infiltration of predominantly neutrophils (Masson’s trichrome stain). (C) Granulomatous inflammation with multinucleated giant cells (arrow) (H&E stain). MPO, myeloperoxidase.

Fig. 3

Putative sequence of pathogenic events in ANCA-mediated vasculitis. (Reproduced from Jennette and Falk.) Circulating neutrophils are primed for activation by ANCA by inflammatory cytokines or C5a derived from complement activation (note that monocytes can be similarly primed and activated but are not illustrated). Primed neutrophils release ANCA antigens at the cell surface and into the microenvironment, where they interact with ANCA. Fc receptor engagement by ANCA bound to ANCA antigens as well as F(ab′)2 binding to ANCA antigens on neutrophil surfaces cause neutrophil activation. ANCA-activated neutrophils release factors that activate the alternative complement pathway, generating C5a. C5a and ANCA create an inflammatory amplification loop, with C5a attracting and priming more neutrophils for activation by ANCA, which causes, in turn, further activation of the alternative complement pathway and production of more C5a. ANCA-activated neutrophils marginate and penetrate vessel walls and undergo respiratory burst, degranulation, NETosis, apoptosis, and necrosis. Disruption of endothelium allows plasma to spill into vascular and perivascular tissue where activation of the coagulation cascade produces the fibrin strands of fibroid necrosis. The innate inflammatory response orchestrates the conversion of the initial acute neutrophil-rich inflammation into mononuclear leukocyte-rich inflammation and subsequent collagen deposition and fibrosis. ANCA, antineutrophil cytoplasmic antibody.

Fig. 4

Putative sequence of pathogenic events in ANCA-mediated necrotizing granulomatosis. (Reproduced from Jennette and Falk.) An inflammatory prodrome, such as an infectious or allergic inflammatory respiratory tract disease, positions increased numbers of primed neutrophils in extravascular interstitial tissue. ANCA immunoglobulin in the interstitial fluid would activate primed neutrophils and initiate an inflammatory amplification loop that wouldattract and activate more neutrophils, resulting in the formation of a necrotizing microabscess. This acute inflammation and necrosis would initiate an innate inflammatory response that would wall off the necrotic zone with granulomatous inflammation containing a predominance of monocytes and macrophages with admixed lymphocytes. ANCA, antineutrophil cytoplasmic antibody.