Novel Aspects in Immunodeficiencies

This thesis reports the results I obtained during my PhD course in †œHuman Reproduction, Development and Growth†� (XXII Cycle) from 2006 to 2009. The field of the clinical description, genetic characterization, and immunological investigation of novel PIDs, born in the 1950s, in the last twenty years of the 20th century has revealed a formidable numbers of scientific discoveries. 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. Although today we know the genetic and molecular basis of those principal mechanisms involved in the immune response, this field retains a great potential for growth. During the three years of my PhD program I have contributed in some measure to clarify some †œNovel aspects in Immunodeficiencies†�, through the combination of clinical, cellular, functional and molecular approaches. In particular, studying a group of atypical patients with X-SCID I contributed to demonstrate for the first time a previously unappreciated functional interaction between the GHR apparatus and the gc. Furthermore, this knowledge helped me to reveal a prior unidentified property of the common gc trasducing element. I could demonstrate, in fact, that this subunit is able to influence the cell-cycle progression, spontaneous or GH-induced, in a concentration dependent manner. Moreover, I spent my PhD also to better characterize at both molecular and clinical levels the human Nude/SCID phenotype. In this context, I could suggest for the first time a functional role of FOXN1 transcription factor in the development and differentiation of the central nervous system. In addition, among those PIDs whose causing genes are not selectively expressed in the hematopoietic compartment, I contributed to the study first of the effects of steroid treatment in patients affected with Ataxia telangiectasia, currently without an effective treatment, and after of the role of oxidative stress in its beneficial therapy. During my PhD I also paid a particular attention to T-cell ontogeny defects affecting both the positive and negative selection processes. In this field I had a unique opportunity to study T-cell development in humans in the absence of a functional thymus; this study led to the identification of some subsets of T-cell able to mature in extrathymic sites. In the context of the negative selection process, I studied the role of peripheral tolerance mechanisms in the high phenotypic intra-familiar variability existing in the APECED syndrome. Overall, all my studies were designed in order to clarify some unknown mechanisms underlying the functionality and the development of the immune system well as to study the basis of some regulatory networks governing the interactions existing between the immune and other systems.