What is the relevance of ANCAs in Vasculitides?
ANCAs are present in 90% of patients with pauci-immune glomerulonephritis, seen in GPA, MPA, and kidney-limited disease. ANCAs are also present in about 40% of patients with EGPA.
They are typically absent in patients with PAN. Immunofluorescence is most sensitive to the detection of ANCAs and demonstrates distinct patterns, either a cytoplasmic pattern (C-ANCA) or perinuclear pattern (P-ANCA).
The antigen specificity of C-ANCA is usually directed to a neutrophil and monocyte protease -proteinase-3 (PR3), while P-ANCAs are usually directed to myeloperoxidase (MPO). While both MPO and PR3 may be seen in any of the described manifestations, MPO-ANCA (P-ANCA) is more common in patients with MPA, and PR3-ANCA (C-ANCA) is more common in GPA. Approximately 40% of patients with EGPA will manifest ANCAs, and may be directed to either MPO or PR3. Again, 10% of patients with pauci-immune glomerulonephritis do not demonstrate ANCAs despite kidney biopsy findings consistent with this diagnosis. MPO-ANCA and PR3-ANCA rarely coexist in a patient with idiopathic ANCA vasculitis (<5%). The coexistence of high-titer MPO- and PR3-ANCA has been reported in patients with drug-associated vasculitis, such as that associated with levamisole-adulterated cocaine.
Both in vitro and in vivo studies support a pathogenic role of ANCAs in vasculitis and glomerulonephritis. Neutrophils and monocytes primed by inflammation express ANCA antigens near or on cell surfaces. Interaction between these antigens and ANCAs activate neutrophils and monocytes, leading to degranulation at the vessel wall and resulting in endothelial cell damage. In vivo , the transfer of mouse anti-MPO IgG to MPO-competent mice results in NCGN and pulmonary vasculitis, which is similar to the human disease, thus demonstrating the ability of these antibodies to confer disease. This same mouse model has demonstrated a role for complement activation via the alternative pathway in the pathogenesis of MPO-ANCA glomerulonephritis.
Other antigens besides MPO and PR3 that interact with ANCAs have also been reported. ANCAs directed to elastase have been reported in drug-induced ANCA vasculitis. Antibodies directed to lysosomal membrane protein-2 have also been reported, although their association with small-vessel vasculitis is controversial. In patients with inflammatory bowel diseases, ANCAs have also been described directed to catalase, α-enolase, lactotransferrin, and bactericidal permeability-increasing protein.
