Giardino, Giuliana (2016) Novel strategies in the approach to primary immunodeficiencies to discover new pathogenic mechanisms and complex clinical phenotypes. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Novel strategies in the approach to primary immunodeficiencies to discover new pathogenic mechanisms and complex clinical phenotypes
Creators:
CreatorsEmail
Giardino, Giulianagiu.giardino@hotmail.it
Date: 30 March 2016
Number of Pages: 269
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Mediche Traslazionali
Scuola di dottorato: Medicina clinica e sperimentale
Dottorato: Riproduzione, sviluppo ed accrescimento dell'uomo
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Pignata, Claudiopignata@unina.it
Tutor:
nomeemail
Pignata, ClaudioUNSPECIFIED
Date: 30 March 2016
Number of Pages: 269
Uncontrolled Keywords: Primary Immunodeficiencies, Next Generation Sequencing, MYD88, STAT1 Gain of Function, Chronic mucocutaneous candidiasis, FOXN1, NEMO, Ectodermal dysplasia, B cell
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/38 - Pediatria generale e specialistica
Date Deposited: 13 Apr 2016 07:36
Last Modified: 28 Oct 2018 02:00
URI: http://www.fedoa.unina.it/id/eprint/10894
DOI: 10.6093/UNINA/FEDOA/10894

Abstract

Primary immunodeficiency disorders (PIDs) represent a heterogeneous group of 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. Traditionally, PIDs are classified according to the component of the immune system that is primarily disrupted: innate or adaptive immunity, the latter comprising antibody deficiencies and combined immunodeficiencies. 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 etiopathogenesis mechanisms and clinical features, has been observed. Nowadays about 300 forms of well-characterized PIDs have been identified underliyng complex phenotype which encompass a wide spectrum of clinical features ranging from recurrent bacterial infections to other unusual manifestations, such as autoimmune disorder, cancer susceptibility, allergy and autoinflammation. Advances in next generation DNA sequencing (NGS) allowed new gene identification of several forms of PIDs of unknown cause making genetic identification of immunodeficiency syndromes more efficient. Only in the last two years, 34 new gene defects have been identified. In this context, my PhD program has been focused to the study of some Immunological disorders, in order to identify “Novel strategies in the approach to primary immunodeficiencies to discover new pathogenic mechanisms and complex clinical phenotype”. Particularly, I followed a first project focused on the novel insight in the diagnosis and management of primary immunodeficiencies aimed at the characterization of novel aspect of the pathogenesis and treatment of already known immunodeficiency, diagnosed conventionally or through Next Generation Sequencing. In particular, I studied the role of Myd88 deficiency, identified through Targeted Next generation sequencing, in the pathogenesis of the immunological and clinical features observed in a patient who had an atypical presentation characterized by chronic Yersiniosis and granuolomatous lymphadenitis, in absence of pneumococcal infections. On this topic, I contributed to the description of the case and to the planning of the experiments aimed at demonstrating the defect of TLRs signaling and the rescue of the function after the tranfection of plamids containing WT Myd88 in the patient fibroblasts. I also followed another project aimed at defining the broad spectrum of clinical manifestations caused by STAT1 gain of function mutation and at defining the role of STAT1 gain of function mutation in the pathogenesis of the clinical manifestation caused by mutations in this gene other than chronic mucocutaneus candidiasis. Moreover, my research effort has been devoted to the definition of the role of T-independent B-cell immunity in susceptibility to infections from encapsulated bacteria in Hypoidrotic Ectodermal Dysplasia with immununodeficiency (HED-ID). I also participated to the description of skin and skin annexa abnormalities associated to PIDs, which represent alarm signs that should lead the clinician to consider a deeper immunological assessment. I gave a contribution to better define the functional role of FOXN1 transcription factor in the T-cell ontogeny. Eventually, I also studied rare genetic syndrome involving immune system paying a particular attention to SCID, hemophagocytic lymphoistiocitosis (HLH) and Di George Syndrome (DGS).

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