title: Effector memory T‑cells in the pathogenesis of ANCA-associated vasculitides.
abstract: Patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) have an expansion of effector memory T‑cells in peripheral blood. The enlarged effector memory cell population contains distinct cell subsets, including T‑helper type 1 (Th1) CD4+T‑cells lacking co-stimulatory CD28 expression and Th17 cells in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and Th2 type and Th17 cells in eosinophilic granulomatosis with polyangiitis (EGPA). The cytokine response of autoreactive proteinase 3 (PR3)-specific effector memory T‑cells is skewed towards an increase of Th2 type, Th17, and Th22 cell fractions in GPA. Anomalous effector memory CD4+T‑cell co-stimulation is suggested by the aberrant expression of P‑selectin glycoprotein ligand-1, β‑2 integrin, chemokine receptors, natural-killer group 2 member D (NKG2D) and other activating receptors. The increased expression of these receptors is accompanied by T‑cell activation and migration to inflamed tissues. T‑cells are abundant and secrete proinflammatory cytokines in inflammatory lesions in AAV. The T‑cell mediated tissue damage correlates with renal outcome, whereas B‑cell infiltration does not. Activation of lesional CD4+NKG2D+effector memory T‑cells is independent of the antigen; moreover, CD4+NKG2D+effector memory T‑cells display NK-cell-like cytotoxicity towards microvascular endothelial cells in vitro. Thus, effector memory T‑cells play an important role in tissue damage and disease progression in AAV. Sequentially administered or combined with B‑cell depleting therapy, T‑cell-directed therapies, especially those directed against effector memory CD4+T‑cells, may further improve the outcome and help to achieve long-term remissions in AAV.
authors.affiliation: Department of Rheumatology, University of Lübeck & Vasculitis Center UKSH, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kerstein
authors.affiliation: Department of Rheumatology, University of Lübeck & Vasculitis Center UKSH, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Müller
authors.affiliation: Institute of Immunology, Christian-Albrechts University Kiel & Vasculitis Center UKSH, Kiel, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kabelitz
authors.affiliation: Department of Rheumatology, University of Lübeck & Vasculitis Center UKSH, Ratzeburger Allee 160, 23538, Lübeck, Germany. peter.lamprecht@uksh.de.
authors.forename: P
authors.initials: P
authors.lastname: Lamprecht
keywords: ANCA; Granulomatosis with polyangiitis; Inflammation; Microscopic polyangiitis; T-cells