The Role of Proteinase 3 and Neutrophils in ANCA-Associated Systemic Vasculitis

Abstract

Systemic vasculitides are a group of disorders characterized by vascular inflammation, leading to vessel occlusion and consequent necrosis or ischemia. Depending on site and extent of inflammation, vasculitis has a varied presentation and prognosis. The classification of systemic vasculitides is based on the dominant vessel involved. They are also classified as idiopathic, primary and secondary to connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosis), infections (infective endocarditis) and drugs (Firestein GS, 2008; Watts R, 1995). AASV (ANCA-Associated Systemic Vasculitis) is the most common primary small-vessel vasculitis that occurs in adults, and recent data indicates that the incidence has shown an up-swing. As per recent reports, the annual incidence of AASV varies from 12.4 to 19.8 per million. In two recent studies by our group, we found an incidence for AASV of 20.9/million, with a point prevalence of 268/million inhabitants in southern Sweden (Knight, 2006; Mohammad, 2007; Mohammad, 2009). ANCA (anti neutrophil cytoplasmic antibodies)-associated Vasculitis is a term that refers to a group of disorders marked by multi-organ system involvement, small vessel vasculitis and the presence of ANCA. These include Wegener’s granulomatosis (WG), Churg-Strauss syndrome (CSS) and Microscopic polyangiitis (MPA). The two most important ANCA antigens are PR3 and MPO. The vast majority of anti-PR3 antibodies yield a c-ANCA (cytoplasmic) pattern on IIF, while most antiMPO antibodies produce a p-ANCA (perinuclear) pattern, with some exceptions (Segelmark, 1994). As per an international consensus document from 1999, anti-MPO and anti-PR3 antibodies are referred to as MPOANCA and PR3-ANCA. AASV is characterized histologically by leukocytoclasis, infiltration and accumulation of apoptotic and necrotic neutrophils in tissues, and fibrinoid necrosis of the vessel walls. The histological lesions in AASV are also termed pauci-immune, as only a few or no immunoglobulins/ complement components are detected in the vasculitic lesions. AASV is associated with significant morbidity and mortality (median survival of five months, in the absence of treatment), with almost all patients requiring long term and aggressive immunosuppressive treatment (Booth, 2003). The etiology of AASV remains largely unknown. Genetic predisposition (PIZ allele of ┙1AT, CTLA-4, PTPN22, HLA DR1-DQw1) and environmental factors including exposure to silica and asbestos, drugs (anti-thyroid medications), and various infections (bacterial endocarditis, hepatitis C virus) have been demonstrated to either predispose to, or correlate with ANCA and development of vasculitis (Beaudreuil, 2005; Choi, 2000; Elzouki, 1994;