Fusco, Anna (2010) New characterization of congenital immunodeficiencies due to different functional alterations. [Tesi di dottorato] (Unpublished)

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In the last thirty years of the 20th century, a formidable numbers of scientific discoveries in the field of PIDs were made. Many scientific papers have been published on the molecular and cellular basis of the immune response and on the mechanisms involved in the correct ontogeny of immune system components. Today we know the genetic and molecular basis of the principal mechanisms involved in the immune response, thus it’s possible to classify immune diseases in different way, by different points of view. In this thesis, during the three years of my PhD program, I tried to group the congenital immunodeficiencies on the basis of the altered immune function and on the basis of the cell type where the mutated genes are expressed in order to perform a novel characterization of such diseases through the combination of clinical, cellular, functional and molecular approaches. In particular, my research work was focused on the study at both molecular and clinical levels of the Nude/SCID phenotype as the real human model of athymia in comparison with the DiGeorge syndrome which was erroneously considered for long time the human counterpart of the Nude murine model. Moreover, in this context, I also participated to better define the functional role of FOXN1 transcription factor in the development of the pleiotropic aspects of the Nude/SCID syndrome. From this study, FOXN1 emerged as a cofactor in the development and differentiation of some structures in the central nervous system. Of note, these immunodeficiencies are due to mutated genes expressed in non hematopoietic cells. In addition, I participated to the study of patients affected with Ataxia Telangiectasia (A-T) whose causing gene is not selectively expressed in the hematopoietic compartment and related to cerebellar functions. In this context I contributed to evaluate whether the beneficial effect of betamethasone therapy in (A-T) patients could be mediated by interference in ROS generation/neutralization process. Our research led to conclude that betamethasone response in A-T patients is inversely correlated to cerebellar atrophy and directly to antioxidative capacity. During my PhD course I also participate to the study of some immunodeficiencies due to alterations of genes expressed in hematopoietic cells giving a contribution to the description of the mechanism altered in the case of high serum level of IgE. The data obtained in this context revealed the alteration of IL-12R signaling in a group of patients with high levels of serum IgE but without Hyper IgE Syndrome. Overall, all my studies were designed in order to better understand the mechanisms involved in the pathogenesis of such immune diseases. The results of this thesis by adding novel information in this field could be useful both in the clinical practice and in the basic research of immune disorders by revealing unknown aspects of these diseases.

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