20. novembril kell 14.00 kaitseb Rudolf Bichele Biomedikumis (Ravila 19) auditooriumis 1006 filosoofiadoktori kraadi (PhD (arstiteadus)) taotlemiseks esitatud väitekirja „TNF superfamily and AIRE at the crossroads of thymic differentiation and host protection against Candida albicans infection“ („TNF perekond ja AIRE tüümuse diferentseerumise ja Candida albicans-vastase kaitse ristteedel“).
Senior Research Fellow Martti Laan, PhD, University of Tartu, Faculty of Medicine,Institute of Biomedicine and Translational Medicine
Professor Pärt Peterson, PhD, University of Tartu, Faculty of Medicine,Institute of Biomedicine and Translational Medicine
Senior Research Fellow Kai Kisand, dr. med., University of Tartu, Faculty of Medicine,Institute of Biomedicine and Translational Medicine
Professor Graham Anderson (PhD), Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
One of the key mechanisms of preventing autoimmunity is the coordinated development of T-cells in the thymus, where developing lymphocytes are taught to differentiate between self and non-self. This process is largely under the control of medullary thymic epithelial cells (mTECs), which present developing T-cells with a wide array of otherwise tissue specific antigens, a large number of which are under transcriptional control of Autoimmune Regulator (AIRE).
AIRE deficiency in humans leads to APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy), a disease characterized by candidiasis, autoimmune attacks against multiple endocrine organs and autoantibodies against multiple inflammatory cytokines. Since mTECs express AIRE and are thus capable of facilitating proper T-cell development only in a short maturation window, it is necessary to understand how these cells function, what are the underlying mechanisms regulating AIRE expression as well as the pathogenic potential of various aspects of APECED.
This thesis describes the key transcriptional networks associated with thymic epithelial cell functions necessary for the establishment of the thymic microenvironment and explores in detail the activation principles of AIRE in the thymic epithelium. It was determined that signalling through receptor activator of nuclear factor kappa-B (RANK) directly induces AIRE expression through the activation of the canonical NF-κB pathway and that AIRE plays an important role in coordinating the mTEC maturation process, which ends in the formation of Hassall’s corpuscles. The potential of autoantibodies against cytokines found in APECED patients to precipitate Candida infections were also assessed, where it was found that neutralizing autoantibodies against IL-22 could act as a susceptibility factor for candidiasis. All in all, this thesis expands our knowledge of the key mechanisms that regulate thymic processes central to the formation of immune tolerance.