The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis

Abstract

The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals.

Figure 1

Proposed mechanism of action for antibodies to LAMP-2 in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis [90]. (a) Antibodies develop to FimH, an antigen found on fimbriated bacteria such as E. coli, develop during an infection. (b) In genetically susceptible individuals, these antibodies cross react with LAMP2, a widely-expressed protein found on cell surfaces as well as in lysosomes. (c) The auto-antibodies bind to LAMP2 on the surface of neutrophils and endothelial cells causing apoptosis. (d) Antibodies to LAMP2 may also mediate adherence of neutrophils to endothelial cells via Fcγ receptors. (e) Subsequent neutrophil degranulation causes endothelial cell necrosis and thus vasculitis.