Vigliano, Ilaria (2011) New insights and unsolved issues in congenital immunodeficiencies. [Tesi di dottorato] (Unpublished)

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Primary immunodeficiencies comprise more than 200 different disorders that affect the development and the functions of the immune system. Many scientific papers have been published on the molecular and cellular basis of the immune response and on the mechanisms involved in the correct development of immune system components. Although today we know the genetic and molecular basis of those principal mechanisms involved in the immune response, some aspect in this field remain unclear. In this thesis, during the three years of my PhD program, I have contributed to elucidate “New insights and unsolved issues in congenital immunodeficiencies”, through the combination of clinical, cellular, functional and molecular approaches. In particular, my research work is focused on the study role of c in cell cycle progression, strongly related to its cellular amount and GH-R signaling, defining the basis of the physiological interaction between endocrine and immune systems. I demonstrate, moreover, that this subunit is able to influence the cell cycle progression in a concentration dependent manner in lymploblastoid and neoplastic cell lines. Moreover, I participated to better define the functional role of FOXN1 transcription factor in the development of the T-cell ontogeny in the Nude/SCID syndrome. I also documented that FOXN1 is a possible cofactor in the development and differentiation of some structures in the central nervous system. Of note, this immunodeficiency is due to mutated gene expressed in non hematopoietic cells. In addition, I participated to the study of patients affected with A-T. In this context I contributed to evaluate the beneficial effect of betamethasone on therapy in these patients. Our data indicate that betamethasone is effective in A-T at a minimal dosage and that GILZ may be a useful biomarker of the clinical response. Finally, I also participate to give a contribution to the description of new mechanism in immunodeficiencies associated with unidentified molecular defects. Our data revealed that in a group of patients with high levels of serum IgE the IL-12R signaling was altered. Moreover, we documented the possibility of an autoreactive anti-lymphocyte antibody able to induce a SCID phenocopy. Overall, all my studies were designed in order to clarify unsolved issues and unknown mechanisms underlying the functionality of the immune system. These results could be useful both in the clinical practice and in the basic research of immunedeficiencies.

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