Aetiology and pathogenesis of ANCA associated vasculitis

• ANCA-Associated Vasculitis (AAV) are of unknown aetiology but generally considered to be autoimmune diseases due to the strong association with ANCA
  • evidence for an important genetic contribution to AAV has been growing, including a familial association
    • a genome-wide association study has confirmed that the pathogenesis of AAV has a genetic component, and that there are genetic distinctions between GPA (Wegeners) and MPA (microscopic polyangiitis) that are associated with ANCA specificity
      • PR3-ANCA was associated with HLA-DP, SERPINA1 (which encodes alpha1 antitrypsin, a serine proteinase inhibitor for which PR3 is one of several substrates) and PRTN3 (which encodes PR3), while MPO-ANCA was associated with HLA-DQ
      • ANCA are antibodies directed against neutrophil granule constituents
        • Two main patterns of staining are recognised using indirect immunofluorescence:
          • cytoplasmic (cANCA), a coarse granular staining of the cytoplasm, and perinuclear (pANCA), with staining chiefly around the nucleus, leaving the cytoplasm unstained
            • main target antigen for cANCA is serine PR3 located in azurophilic granules
          • main target for pANCA is MPO, an enzyme from azurophilic granules that catalyses peroxidation of chloride to hypochlorite
        • anti-PR3 antibodies are highly specific (>90%) for GPA
        • MPO antibodies are more typically found in MPA (microscopic polyangiitis) and EGPA (Churg-Strauss) but are much less specific
    • ANCA often correlate with disease activity, and there is increasing evidence to support their role in pathogenesis.

Reference:

1. Mahr A et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): evolutions in classification, etiopathogenesis, assessment and management. Curr Opin Rheumatol. 2014 Jan;26(1):16-23.