Anti-neutrophil cytoplasm antibodies, ANCAs

Background

Antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against antigens found in the cytoplasmic granules of neutrophils and monocytes.  There are two main kinds of ANCA: pANCA and cANCA. The c-ANCA antigen is maily (over 90%) proteinase 3 (PR3), other antigens exist for c-ANCA (atypical). p-ANCA antigens include myeloperoxidase (MPO) and bacterial permeability increasing factor Bactericidal/permeability-increasing protein (BPI). ANCA testing is usually performed to help to diagnose and monitor inflammatory activity in Wegener granulomatosis, microscopic polyangiitis and its renal-limited variant (pauci-immune crescentic glomerulonephritis), and Churg-Strauss syndrome. Testing for pANCA can also help diagnose certain types of inflammatory bowel disease (IBD).

Pathogenesis

ANCA are not only a measureable blood marker in patients with ANCA-associated vasculitis but they are harmful autoantibodies that are directly involved in small blood vessel damage. MPO and PR3 specific ANCA can activate neutrophils and monocytes through their Fc and Fab'2 receptors, which can be enhanced by cytokines that cause neutrophils to display MPO and PR3 on their surface. The activated neutrophils can then adhere to endothelial cells, resulting in damage to the endothelium via the induction of necrosis and apoptosis. Furthermore, neutrophils release chemoattractive signaling molecules that recruit more neutrophils to the endothelium, acting as a positive feedback loop. Animal models have shown that MPO antibodies can induce necrotizing crescentic glomerulonephritis and systemic small vessel vasculitis. ANCAs induce excess activation of neutrophils, resulting in the production of neutrophil extracellular traps (NETs), which cause damage to small blood vessels. In addition, ANCA reactive B-cells can be found in circulation in patients with AAV, an alternative hypothesis has been proposed assigning a direct pathogenic role of these cells, whereby activated neutrophils and ANCA-reactive B-cells engage in intercellular cross-talk, which leads not only to neutrophil degranulation and inflammation but also to the proliferation and differentiation of ANCA-reactive B-cells (2).

Fig. 1 Diagram showing ANCA-induced 'activation' of neutrophils causing inflammation of the blood vessel wall

Therapy

Systemic vasculitis with ANCA [ANCA-associated vasculitides (AAV)] is a subgroup of life-threatening inflammatory disorders affecting small- to medium-sized vessels. Immunosuppressants and glucocorticoids represent the current therapeutic mainstay, but with a 25% present with severe adverse events, and standard therapy does not sustain remission. It has turned ANCA-associated vasculitis (AAV) into chronic, relapsing disorders. Therefore, an unmet need for safer and more effective therapies has prompted interest in biological agents.

A reasonable strategy to suppress the autoimmune cellular response might be the blockage of costimulating molecules that intervene in the antigen presenting cell-dependent T cell activation which is thought to be the initial step in Wegener granulomatosis granuloma formation. At the vasculitic pole of the spectrum, monoclonal antibodies and fusion proteins aimed at inhibiting ANCA, suppressing neutrophil priming and endothelial activation, and interfering in the neutrophil-endothelium adhesion cascade or neutrophil degranulation might also prove fundamental in healing vasculitic damage.

• Intravenous immunoglobulin may be effective by interfering with ANCAs binding to their antigens (due to anti-idiotype antibodies) and by inhibiting ANCAs-mediated neutrophil activation. The primary end point was the number of patients with decreased Birmingham Vasculitis Activity Score (BVAS) of at least 50% at 3 months. However, there were no significant differences in either the score beyond 3 months or the exposure to immunosuppressants following intravenous immunoglobulin (3).
• Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody. In AAV, the depletion of B cells, the immediate precursors of plasma cells, might halt the replacement of true ANCA-producing cells (ie, CD20 negative plasma cells) leading to the disappearance of pathogenic antibodies and the resolution of vasculitic lesions (3).
• It has been reported that the addition of infliximab led to an 88% remission rate in AAV patients with persistent activity despite immunosuppressive therapy and can ease glucocorticoid tapering (4).