Overview of the Pathogenesis of ANCA-Associated Vasculitis

Abstract

Background: Antineutrophil cytoplasmic autoantibodies (ANCA) are associated with a spectrum of necrotizing vasculitis including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited necrotizing and crescentic glomerulonephritis. Clinical observations and in vitro and in vivo experimental evidence strongly indicate that ANCA are pathogenic. Summary: The etiology and pathogenesis of ANCA-associated vasculitis (AAV) are multifactorial, with contributions from genetic factors, environmental exposures, infections, characteristics of the innate and adaptive immune system, and the intensity and duration of the injury. Acute vascular inflammation is induced when resting neutrophils that have ANCA autoantigens sequestered in cytoplasmic granules are exposed to priming factors - for example, cytokines induced by infection or phlogogenic factors released by complement activation - that cause the release of ANCA antigens on the surface of neutrophils and in the microenvironment around the neutrophils. ANCA bind to these ANCA antigens, which activates neutrophils by Fcγ receptor engagement and F(ab′)₂ binding at the neutrophil cell surface. ANCA-activated neutrophils release factors that activate the alternative complement pathway, which generates C5a, a chemoattractant for neutrophils; C5a also primes the arriving neutrophils for activation by ANCA. Activated neutrophils adhere to and penetrate vessel walls, and they release toxic oxygen radicals and destructive enzymes that cause apoptosis and necrosis of the neutrophils as well as of the adjacent vessel wall cells and matrix. Key Messages: Patients with active AAV have ongoing asynchronous onsets of countless acute lesions, with each lesion evolving through stereotypical phases within 1 or 2 weeks. Induction of remission results in termination of new waves of acute lesions and allows all lesions to progress to scarring or resolution.

Bowman’s capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells

“…The involvement of myeloid cells, such as neutrophils and macrophages, in experimental NTSN is also well established (6). Similar considerations apply to various forms of human GN, and especially those with crescentic, rapidly pro-gressing GN (RPGN), such as observed with antibody-mediated and immune complex (IC) GN, including postinfectious GN, lupus nephritis, and IgA nephropathy, as well as anti-glomerular basement membrane (anti-GBM) disease and anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (3)(4)(5)7). However, the role of CD8 + T cells in the generation and progression of GN remains controversial.…”

“…Thus, it is critical to elucidate whether and how immune cells can interact with podocytes and what the main immune effectors are. Several immune cell types have been described as playing an important role in the pathology of glomerular disease (3)(4)(5)(6)(7). Evidence for CD4 + T cell involvement has been provided in antibody-mediated GN and comes mostly from experimental nephrotoxic serum nephritis (NTSN).…”

Regulation of macrophage activation by proteins expressed on apoptotic neutrophils: Subversion towards autoimmunity by proteinase 3

“…This expression is curtailing the appropriate mechanism of clearance of apoptotic neutrophils by macrophages, hence failing to drive immune silencing, and rather promoting inflammatory responses . Notably, PR3 is the target of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of granulomatosis with polyangiitis (GPA) . GPA is a systemic autoimmune disease characterized by granulomatous inflammation and necrotizing vasculitis (reviewed in ).…”

“…80,81 Notably, PR3 is the target of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of granulomatosis with polyangiitis (GPA). 82 GPA is a systemic autoimmune disease characterized by granulomatous inflammation and necrotizing vasculitis (reviewed in 83 ). Cellular PR3 expression promotes the ANCA proinflammatory actions at the surface of neutrophils and leads to an increased ROS production by these neutrophils.…”

Commentary on the recent international multicentre study (EUVAS) on antineutrophil cytoplasmic antibodies

“…Antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitis (AAV) is a group of potentially life-threatening conditions that require early and accurate diagnosis, most often based on a combination of clinical and serological features 1. Most of the therapeutic modalities have immune-suppressing activity and can result in serious consequences, especially if applied to patients without AAV, such as those with infectious diseases, which may have clinical features that mimic AAV.…”