Novel insights in the pathogenesis of congenital immunodeficiencies”

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. Recent evidence highlights that the skin participates in a host defenses either acting as a primary boundary for germs, as the principal site of environment–host interactions, or directly in the developmental process of the immune system. As a matter of fact, skin and skin annexa abnormalities, such as skin dryness, brittleness of hair, nail abnormalities and abnormal dentition, can be not infrequently associated with distinct forms of immunodeficiency and may be a warning sign of immunodeficiency, since both epidermal and thymic epithelium have ectodermal origin. Severe combined immunodeficiency diseases (SCIDs) represent a heterogeneous group of rare genetic syndromes responsible for severe dysfunctions of the immune system, which share similar clinical manifestations. SCID is the most severe form of inherited primary immunodeficiency (PID) and its prevalence is approximately 1:100,000 live births, with a higher prevalence in males (1). SCIDs are difficult to recognize clinically because so many different infectious scenarios can occur. Without a functional cellular and humoral immune system SCID patients are susceptible to recurrent infections such as severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive. In 5 addition, some patients develop skin rashes, usually caused by maternal T cells transplacental engraftment during fetal life or by a wide autoreaction due to the activation of autologous T cells against skin components (2, 3). Patients affected with particular forms of PID show an increased susceptibility to cancer. In particular, a high cancer susceptibility has been reported for a rare form of PID called Ataxia Telangiectasia (A-T) whose clinical hallmark is represented by the cerebellar neurodegeneration with the loss of Purkinje cells. Recently, in a few clinical trial sit has been documented that a shortterm treatment with glucocorticoids (GCs) is able to partially rescue either the A-T neurological phenotype and lymphocytes proliferation, even though the mechanism of action has not yet been defined (4-7). Conventionally, SCIDs have been so far classified, on the basis of the involvement of different cell lines in the pathogenesis of the disease and of the subsequent different clinical immunological phenotypes related to a specific genetic defect. T cell–deficient but normal B cell (T−B+) SCID and both T cell– and B cell–deficient (T−B−) SCID, in the presence or absence of NK cells (8). This classification helps in directing molecular studies toward a certain genetic alteration, since it is representative of the stage where the blockage occurs during the differentiation process. More recently, advances in next generation DNA sequencing allowed new gene identification through whole exome or whole genome sequencing (WES, WGS) of several forms of PIDs of unknown causes making the genetic identification of immunodeficiency syndromes more efficient (9). Only in the last two years, using this technology 34 new gene defects have been identified. Most of these immunodeficiencies are rare, even though some of them occur more frequently than what previously reported, as documented by several groups (10). Based on the principle of massively parallel sequencing, NGS technology provides an advanced tool to 6 dramatically increase the speed at which DNA can be sequenced at a lower cost as compared to the traditional Sanger sequencing approach. In this context my PhD program has been focused on the study of some immunological disorders, in order to identify new scenarios in pathogenesis, diagnosis and therapeutic approaches. This thesis reports the results obtained during my PhD course in “Clinical and Experimental Medicine” (XXXI Cycle, years 2015-2018). During these years my research has been focused on the study of the following lines of research: • positive effect of oral betamethasone administration on the in vitro lymphocytes functionality in patients affected with Ataxia-Telangiectasia, and the identification of the molecular checkpoint responsible for the partial functional rescue in lymphocytes of the patients affected with this disease. • characterization of a novel immunodeficiency whose hallmarks are represented by high IgM levels, impaired B-cell homeostasis and cancer susceptibility, • autoimmune manifestations and the pathogenetic mechanism underlying autoimmunity in a specific PID