Pathogenesis of ANCA-Associated Vasculitis: New Possibilities for Intervention

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) comprise granulomatosis with polyangiitis (GPA), primarily associated with antibodies to proteinase 3 (PR3-ANCA); microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA), both principally associated with antibodies to myeloperoxidase (MPO-ANCA). Genetic and environmental factors are involved in their etiopathogenesis, with a possible role for silica exposure in AAVs and Staphylococcus aureus infection in GPA. The distinct associations of PR3-ANCA and MPO-ANCA with different HLA class II antigens, which are stronger than those with the associated diseases, suggest a pathogenic role for those ANCAs and indicate that GPA and MPA are different diseases. Both in vitro and in vivo experimental data have shown that MPO-ANCA can induce necrotizing small-vessel vasculitis and glomerulonephritis. The additional role of the alternative pathway of complement activation has been demonstrated in human and experimental pathology. Also, T cells seem to be involved in lesion development, particularly in the kidney. Granuloma formation, as seen in PR3-ANCA-associated GPA, is not well explained by the presence of autoantibodies in experimental models. Here, T cells seem crucial. Recently obtained insights into the pathogenesis of AAVs have led to more targeted treatment of these life-threatening diseases.