10 - Pathobiology of Vasculitis

Abstract

“Vasculitis” encompasses many diseases that share the feature of inflammatory destruction of blood vessels but otherwise show fundamental differences. Diseases that affect large arteries appear to be mediated by T cell infiltration, starting with extravasation from the vasa vasorum, followed by local activation of macrophages and chronic inflammation. Epidemiological studies, including genetics showing HLA associations, indicate that it is appropriate to consider the more common large-vessel vasculitides as diseases rather than as syndromes with multiple underlying causes, although target antigens are unknown. Diseases that affect venules, capillaries, and arterioles are mediated by neutrophils activated at the endothelium, leading to necrosis. These small-vessel vasculitides are, in turn, caused by either the deposition of immune complexes (antibodies bound to antigens) or by antineutrophil cytoplasmic antibodies (ANCAs), including complement activation in both cases. Immune complex vasculitis is a generic mechanism downstream of many underlying causes. ANCA vasculitis, despite its variability in clinical presentation, probably has a more limited set of underlying causes. Autoantibodies to proteinase-3 (PR3) or myeloperoxidase (MPO) show high specificity in clinical use and can activate neutrophils in vitro. Anti-MPO antibodies can cause the characteristic pathology of pauci-immune glomerulonephritis in mice. It is unclear whether vasculitides affecting small arteries always begin with a necrotizing, neutrophilic phase or can sometimes begin with a mononuclear infiltrate. In all the vasculitides, the outcome depends on the extent of vascular injury, the nature of the blood supply to the organs involved, and the capacity of those organs to heal.