PhD defence Benjamin Wilde

Keywords: ANCA, Vasculitis, T-cells, B-cells

"The kidney and the adaptive immune system in ANCA vasculitis: attack vs. regulation"

ANCA-associated vasculitis (AAV) is a necrotizing –depending on the type of vasculitis also granulomatous- small-vessel vasculitis of autoimmune origin. This small-vessel vasculitis is characterized by the presence of autoantibodies directed against neutrophil-derived antigens. Antineutrophil- cytoplasmic-antibodies (ANCA) usually have specificity for either proteinase-3 (PR3) or myeloperoxidase (MPO). Treatment options are not specific and the side effects of the treatment pose an additional risk to the patient suffering from ANCA-vasculitis. Thus, for the development of targeted treatment strategies, the disease mechanisms need to be unraveled further. It was the aim of this thesis to investigate the role of the adaptive immune system in the pathogenesis of ANCA-vasculitis. For this purpose, the regulatory mechanisms controlling effector T-cells were studied (“regulation”). Regulation was mediated locally within the kidney itself by specialized immune cells, so called dendritic cells. The co-inhibitor programmed-Death 1 (PD1) was functionally disturbed in T-cells from patients with AAV. Likewise, regulatory B-cells (Breg) controlling T-cells were altered in patients. Next to the regulatory mechanisms, effector mechanisms (“attack”) were investigated. The specific pro-inflammatory T-cell subset Th17 cells was expanded in patients but responsive to BTLA-mediated co-inhibition. In an animal model of AAV, neutralization of the effector cytokine IL-17A derived from Th17 cells was therapeutically not efficacious. In summary, profound alterations of immune regulatory and effector mechanisms are evident in patients with AAV. These alterations may serve as novel targets for future therapies.

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