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Régulation immunitaire, angiogenèse et homéostasie tissulaire au cours des vascularites des gros vaisseaux

Abstract : Large vessel vasculitis (LVV) mainly include Takayasu arteritis (TA) and giant cell arteritis (GCA), which are characterized by arterial inflammatory lesions, associated with adventitial neo-angiogenesis and fibrotic lesions. They predominantly involve aorta and its major branches. These diseases are related to unbalanced Th1 and Th17 immune responses. The mechanisms regulating lymphocyte differentiation, endothelial response and tissue homeostasis in arterial inflammatory diseases are not sufficiently known. First, we have studied the role of IL-33, which is a cytokine secreted by endothelial cells in response to tissue necrosis and is involved in the regulation of immune response. We demonstrated the immunomodulatory impact of IL-33 and mast cells in LVV. IL-33 had a direct immunomodulatory impact by increasing Th2 and regulatory T cells in PBMC. IL-33 and MC further enhanced Th2 and regulatory responses by inducing a 6.1 fold increased proportion of Tregs through increased indoleamine 2 3-dioxygenase (IDO) and IL-2 secretion. IL-33 and mast cells also had a paradoxical impact in LVV, by promoting angiogenesis, endothelial activation and vascular permeability. IL-33 and mast cells, through Th2 and regulatory responses and angiogenesis, were associated with tissue repair and arterial fibrosis. Although IL-33 did not appear to directly lead to arterial fibroblast activation and proliferation, mast cells activated by LVV serum induced increased production of type 1 collagen and fibronectin by arterial fibroblasts. In the second part of our work, we have demonstrated distinct differentiation profiles of CD4 + T cells in TA and GCA. We demonstrated an increase in circulating T follicular helper lymphocytes (cTfh), defined as CXCR5+ CD4+ T cells, in TA. The increase of cTfh was associated with an increase in circulating B lymphocytes and the presence of tertiary lymphoid organs in TA aorta. CXCR5+ CD4+ T cells of TA patients helped B cells to differentiate into memory cells, to proliferate and to secrete type G immunoglobulins. Our data provide evidence of the key coordinated role of Tfh and B cells in tertiary lymphoid structures in TA and suggest an antigenic trigger.
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Submitted on : Saturday, October 13, 2018 - 1:02:33 AM
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Anne-Claire Desbois. Régulation immunitaire, angiogenèse et homéostasie tissulaire au cours des vascularites des gros vaisseaux. Physiologie [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066268⟩. ⟨tel-01894892⟩



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