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Prof. Dr. med. Thomas Daikeler

Department of Clinical Research

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Giant Cell Arteritis towards a molecular understanding of pathogenesis

Research Project  | 3 Project Members

Failure of the immune system to discriminate self from non-self can result in autoimmune disease. An integrative model suggests that the balance between auto-reactive T cells and so-called regulatory T cells (Tregs) dictates the likelihood to develop autoimmunity. We aim to test this hypothesis in patients with Giant cell arteritis (GCA), an autoimmune disease of the blood vessels. Both, IL-17 producing Th17 cells -that represent the prototype of auto-reactive effector T cells- and Tregs, have been linked to GCA pathogenesis. We will investigate, whether dysregulated Treg function contributes to disease pathogenesis, e.g. via insufficient suppression of auto-aggressive T-cells or by inducing a Th17 promoting cytokine milieu. Following antigenic stimulation, T effector cells expand clonally. T cell receptor (TCR) sequencing can be used to assess the clonal T cell repertoire. In chronic infections, certain cancers and autoimmune diseases, T cell clones have been identified that occur frequently and are shared between different patients affected with the same disease ('public T cell clones'). Little is known about the TCR repertoire in GCA. We hypothesize that clonally expanded T cells detect common vascular self-antigens in GCA, which should be reflected in a narrow TCR repertoire and the presence of public TCR. To test this hypothesis, we aim to define the TCR repertoire at the site of autoimmune inflammation in GCA, taking advantage of laser capture microdissection of infiltrating T cells, combined with an unbiased PCR approach. Using computational epitope prediction tools, the target antigen will then be further characterized. As a clinical application, identification of disease-specific TCR clonotypes in inflamed tissue would permit to track and characterize them in the peripheral blood, opening the possibility for highly specific biomarker-research.