Current understanding of the pathogenesis of granulomatosis with polyangiitis (Wegener's)

Granulomatosis with polyangiitis (Wegener's) (GPA) is a multisystem disease of unknown etiology, characterized by granulomata of the respiratory tract and systemic necrotizing vasculitis. Antineutrophil cytoplasmic antibodies (ANCA) with specificity for proteinase 3 (PR3) are a defining feature of this disease. GPA usually starts as a granulomatous disease of the respiratory tract and, in the majority of patients, progresses to systemic disease with PR3-ANCA-associated vasculitis. Today, epidemiological evidence indicates that GPA develops as a result of complex gene-environment interactions. The nature of these risk factors and pathogenic mechanisms involved, however, are only just beginning to be understood. Clinical data and in vitro experimental results point to the pathogenic pathways involved in tissue lesion development, in which ANCA, cellular immunity, neutrophils extracellular traps, fibroblasts, vascular endothelial cells and inflammatory mediators play a major role. Today, the pathophysiological significance of PR3-ANCA is still unclear and the pathogenic pathways leading to granuloma formation are not explained. New data unexpectedly suggest that the destruction of nasal cartilage in GPA is mainly mediated by fibroblasts that can be blocked by corticosteroids.