Off balance: T-cells in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides

Abstract

There is substantial evidence that T-cells are off balance in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Genetic risk factors may influence shaping of the TCR repertoire and regulatory control of T-cells in predisposed individuals. T-cells are found in inflammatory lesions. Vigorous Th1-type responses are seen in Wegener's granulomatosis and microscopic angiitis, whereas a Th2-type response predominates in Churg-Strauss syndrome. Oligoclonality and shortened telomers indicate antigen-driven clonal expansion and replicative senescence of T-cells in ANCA-associated vasculitides. Potent CD28(-) Th1-type cells displaying an effector-memory/late differentiated, senescent phenotype are expanded in peripheral blood and are found in granulomatous lesions in Wegener's granulomatosis. Differences in proliferative peripheral blood T-cell responses to the autoantigens proteinase 3 (PR3)- and myeloperoxidase (MPO) have not consistently been detected between patients with ANCA-associated vasculitides and healthy controls in vitro. To recognize an autoantigen, break tolerance, and maintain autoimmune disease T- and B-cells require particular triggers and lymphoid structures. There is preliminary evidence of lymphoid-like structures and possible maturation of autoreactive PR3-ANCA-specific B-cells in granulomatous lesions in Wegener's granulomatosis. Alteration of the T-cell response and anomalous autoantigen-presentation in lymphoid-structures could facilitate development of autoimmune disease in ANCA-associated vasculitides.

Fig. 1

(a) Necrotizing granulomatous inflammation in WG. (b) Fibrinoid necrotizing small vessel vasculitis with inflammatory cell infiltration in and around the vessel wall in WG. (c) Capillaritis with eosinophil granulocytes in CSS.

Fig. 2

Principal illustration of the T-cell interaction with other cells in ANCA-associated vasculitis: alteration of the T-cell response with expansion of late-differentiation phenotype cells, vigorous cytokine responses, and aberrant costimulation might facilitate autoantigen recognition mediated by antigen-presenting cells (APC), and finally maturation of autoantigen-specific B-cells. PR3 and MPO may be released from polymorphnuclear cells (PMN).