Issue: 2003 > December > review

Pathophysiology of ANCA-associated vasculitides: are ANCA really pathogenic?

J.W. Cohen Tervaert, P. Heeringa


The strong relation between antineutrophil cytoplasmic
autoantibodies (ANCA) and primary vasculitic syndromes
suggests a pathophysiological role for ANCA.
Experimental evidence for the pathogenic potential of ANCA has been derived from <i>in vitro</i> studies that demonstrate that ANCA can activate tumour necrosis factor &alpha; primed neutrophils, monocytes and/or endothelial cells. The binding of ANCA to primed neutrophils results in activation of these cells by a process that is largely dependent on engagement of &beta;-2 integrins and on the interaction of the Fc portion of ANCA. An Fc-independent mechanism is,
however, also operative. In experimental animal models, it has been demonstrated that immunisation with myeloperoxidase (MPO) induces MPO-ANCA. The induction of ANCA, however, is not sufficient to induce vasculitis in rats since immune complexes first have to be deposited along the vessel wall before lesions develop. When MPO-deficient mice are, however, immunised with murine MPO, anti-MPO
immunoglobulins are purified and subsequently injected into mice that are not deficient for MPO, systemic vasculitis and glomerulonephritis is induced. These experiments suggest that ANCA indeed induces vasculitis. Risk factors for breaking self-tolerance to ANCA antigens are genetic factors, drugs, chemical substances and/or infectious agents.