Pathophysiology
Clinical meaning
Granulomatosis with polyangiitis (GPA) is an ANCA-associated vasculitis (AAV) characterized by necrotizing granulomatous inflammation of small-to-medium vessels. The pathogenic mechanism centers on anti-neutrophil cytoplasmic antibodies targeting proteinase-3 (PR3-ANCA/c-ANCA). In genetically susceptible individuals, environmental triggers (silica, infections โ particularly S. aureus nasal carriage) promote loss of immune tolerance to PR3. PR3 is expressed on the surface of TNF-ฮฑ-primed neutrophils; when c-ANCA binds membrane-expressed PR3, it activates neutrophils through Fc receptor engagement and direct signaling, causing neutrophil degranulation, superoxide generation, and neutrophil extracellular trap (NET) formation. NETs expose more PR3 antigens, perpetuating the autoimmune cycle. Activated neutrophils adhere to endothelium via ฮฒ2-integrins and damage vessel walls, producing the characteristic necrotizing vasculitis. Granuloma formation involves Th1/Th17-mediated delayed hypersensitivity with organized collections of epithelioid macrophages, multinucleated giant cells, and surrounding lymphocytes. At the NP level, understanding these mechanisms informs treatment selection: rituximab depletes B cells producing PR3-ANCA, cyclophosphamide broadly suppresses lymphocyte proliferation, and complement C5a receptor blockade (avacopan) targets the terminal complement pathway activated by ANCA-stimulated neutrophils.