D'Assante, Roberta (2016) Congenital Immunodeficiencies: novel diagnostic and therapeutic approach. [Tesi di dottorato]

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The immune system is a complex integrated network of chemical and cellular mediators that developed during evolution to defend the body from any form of chemical, traumatic or infective insult to their integrity. A proper immune response relies on the innate immunity, that is responsible for a first line of defense against aggression and the aspecific recognition of a limited repertoire of antigens, and, later, on the adaptative immunity which includes chemical and cellular mediators responsible for a more powerful and specific defensive response from any form of antigen. Alterations of any part of the immune response results in failure of host defense and, in particular, of immunodeficiency, autoimmunity and cancer predisposition. Primary immunodeficiency disorders (PIDs) are rare inherited disorders characterized by poor or absent function in one or more components of the immune system, that result in chronic, recurrent and life-threatning infections if not promptly diagnosed and treated (2). Traditionally, PIDs are classified according to the component of the immune system that is primarily disrupted: innate or adaptive immunity. In the last 20 years, thanks to the progress in molecular technologies, a remarkable improvement of the knowledge in the field of PIDs, concerning both their pathogenetic mechanisms and clinical features, has been observed. Nowadays, about 300 forms of well-characterized PIDs have been identified underlying complex phenotypes which encompass a wide spectrum of clinical features ranging from recurrent bacterial infections to other unusual manifestations, such as autoimmune disorders, cancer susceptibility, allergy and auto inflammation (8, 142). However, a recent study reported that PIDs are underdiagnosed and, therefore, they are presumably more common than previously estimated. Thus far, the diagnosis of a specific PID has been based onthe demonstration of a functional immune defect and on the subsequent identification of candidate genes, which are selectively involved in the biochemical pathway implicated in that specific functional alteration. In this thesis, during the three years of my PhD program, I have contributed to elucidate “Congenital Immunodeficiencies: novel diagnostic and therapeutic approach”, through the clinical, cellular, functional and molecular study of some Immunological disorders. In particular, my research work has been focused on the study of the potential involvement of autophagy in the pathogenesis of Ataxia Telangiectasia, and the potential positive effect of glucocorticoids on the rescue of a proper cell clearance process in lymphocytes of the patients affected with this disease. Moreover, I contributed in the characterization of the potential oncogenic role of the common gamma chain (γc) in primary human hematopoietic malignant cell lines, by evaluating the molecular mechanisms by which this protein promotes tumor growth. In addition I contributed to better define the role of the epithelial cells in the immune system and of thymic stromal alterations responsible for immunological disorders. Eventually I participated to two studies focused on the application of Next Generation Sequencing technique for the diagnosis of immunodeficiencies. Overall, the results obtained during my PhD course could be useful both in the clinical practice and in the basic research of immunological diseases.

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