The association between antibodies to neutrophil cytoplasm (ANCA) and systemic vasculitis has transformed our understanding of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). ANCA undoubtedly play a major role in their pathogenesis. There are different forms of ANCA, but only two of direct clinical relevance: cytoplasmic c-ANCA (usually directed against proteinase 3, PR3), and perinuclear p-ANCA (usually directed against myeloperoxidase, MPO). P-ANCA can also be directed against other antigens including bactericidal/permeability-increasing protein, lactoferrin, human neutrophil elastase, cathepsin G and azurocidin, but their clinical significance is not clear.
Transfer of MPO ANCA in humans (maternal-foetal route) and animal models (necrotizing pauci-immune glomerulonephritis after passive transfer of purified antibody or splenocytes from MPO-deficient mice immunized with murine MPO) has resulted in features of MPA. By contrast, the pathogenicity of anti-PR3 antibodies is less well-established. There is a significant genetic predisposition to disease in patients with AAV. Patients with PR3-ANCA have a strong association with HLA-DP and genes encoding alpha-1-antitrypsin and proteinase 3; by contrast, patients with MPO-ANCA have an association with HLA-DQ. Other factors that could interact with ANCA include: loss of B cell and T cell tolerance; direct involvement by neutrophils and their mediators in vascular injury and damage, degranulation and cytokine production; environmental exposure to silica or certain strains of Staphylococcus aureus, coupled with a lack of effective T cell regulation to prevent inflammation. Neutrophils spontaneously release of neutrophil extracellular traps (NETS), which directly cause endothelial cell damage and complement activation. NETS retain proteinase 3 and myeloperoxidase, helping to break immune tolerance and inducing antibody formation. The alternative complement pathway plays a crucial role in the pathogenesis of AAV. Activated neutrophils produce C5a, which in addition to recruitment, primes additional neutrophils for further activation by ANCA. C3a, C5a, soluble C5b-9 are elevated in active disease and plasma levels of complement factor H, a regulator of the alternative complement pathway is significantly lower in patients with active AAV.
Central to the pathogenesis of AAV is a dysregulated immune response to ANCA and aberrant expression of their target autoantigens, MPO and PR3. Environmental exposure to silica may inactivates α1-antitrypsin, whilst activating monocytes and macrophages releasing cytokines such as interleukin-1 and TNF-α, oxygen radicals and lysosomal enzymes (such as PR3 and MPO). Other environmental interactions include CpG-ODN, a short synthetic DNA containing unmethylated CpG and several drugs, especially propylthiouracil and levamisole-adulterated cocaine. Some of these associations could provide a better insight into the development of ANCA associated disease.
ANCA play a central role in the pathogenesis of systemic vasculitis, supported by a dysregulated immune system, with significant interactions with micro-organisms, environmental toxins and drugs, all of which can contribute to the development and severity of disease.
Disclosure of Interest R. Luqmani Grant/research support from: Arthritis Research UK, GSK, MRC, UCSF/OIF, Canadian Institutes of Health Research, The Vasculitis Foundation, Consultant for: GSK, Medpace, MedImmune, Roche