Abstract
Monogenic systemic autoinflammatory diseases (SAIDs) are Mendelian pathologies caused by gene mutations involved in innate immunity. Autoinflammatory patients exhibit inflammatory flares, tissue damage, without production of autoantibodies. The first part of the thesis is a comparative study between Sanger sequencing and Next Generation Sequencing (NGS). The 297 patients were included prospectively and randomized into 2 arms: Sanger and NGS. We concluded that the NGS approach doubled the diagnostic yield (10.1%) compared to the Sanger (4.1%). We also showed that the 4 historical hereditary recurrent fevers were not the most frequent in our series. The second study reports the first duplication of the MEFV gene in a FMF patient. We have shown that this is a tandem duplication and have been able to sequence the breakpoint. The implication of this duplication in the onset of the disease is unclear and studies of expression would be necessary. The third part deals with the phenomenon of mosaicism in SAIDs (cryopyrin associated periodic syndrom (CAPS) in particular)), by a literature review, enriched by new cases identified in Montpellier. We did not show any impact of the mosaicism rate on clinical manifestations or age of onset of symptoms.The fourth study reports a series of cases of patients with type 2 adenosine deaminase deficiency, allowing us to expand the mutation spectrum. We also proposed a decision tree to fasten the genetic diagnosis. Finally, the fifth study is the identification of a new gene responsible for proteasome-associated autoinflammatory syndrome (PRAAS) in a consanguineous patient. We have shown the involvement of the PSMB10 gene in the pathophysiology of the patient, conducting in vitro and ex vivo studies. The in vitro results showed, in a transfected cell line, an alteration of the enzyme functions of the immunoproteasome, and defects of the normal cleavage of the protein, probably preventing the correct assembly of the immunoproteasome. The ex vivo cell studies of the patient also showed enzymatic abnormalities, as well as ubiquitinylated protein accumulation, indicating immunoproteasome dysfunction.