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Aberrant activation of the innate immune system leads to systemic and organ specific inflammation in the absence of pathogens or autoimmunity. This system is genetically encoded and mutations stimulating those pathways or impacting cellular homeostasis cause auto-inflammatory diseases (AIDs). Monogenic and complex (for which other genetic factors and the environment play a role) AIDs share phenotypic features and physiopathologic mechanisms. Only about 15-40% of patients suspected of monogenic AIDs will receive a specific molecular diagnosis. The Australian Autoinflammatory Diseases RegistrY (AADRY) gathers undiagnosed patients and provides whole exome sequencing to patients and families in search of new mechanisms explaining their diseases. In this thesis, we functionally validate the polymorphism E148Q in pyrin showing its functional effect in vitro. In patients with familial Mediterranean fever (FMF), it potentiates pathogenic mutations in cis and therefore could have a role in disease presentation and severity. I also assess a new mutation in CDC42 found in a family with members presenting an AID over three generation. A phenotypic and mechanistic hypothesis based approach shows that this variant promotes the pyrin inflammasome. Finally, I investigated somatic mosaicism which could explain around 15-20% of undiagnosed AID cases. I developed a cost effective ultra deep amplicon sequencing of the third exon of NLRP3, a part of the gene in which somatic mosaicism is particularly well described. These three projects intend to broaden our knowledge about the mechanism of autoinflammation.

SCOPUS: le.j, FLWIN, info:eu-repo/semantics/published

"Spondyloarthritis" consists of a group of several diseases sharing clinical, radiological and genetic similarities. Ankylosing spondylitis is the main representative of this group and is characterized by a predominant axial involvement. The presence of radiographic sacroiliitis is essential for the diagnosis of ankylosing spondylitis according to the modified New York criteria. Because the occurence of radiographic sacroiliitis takes 8 to 11 years, the diagnosis of spondyloarthritis is often delayed. Magnetic resonance imaging can depict sacroiliac joint inflammation before the appearance of radiographic damage thereby defining the concept of "non-radiographic axial spondylo-arthritis". This entity was defined by the axial spondyloarthritis classification criteria published by the Assessment of SpondyloArthritis international Society (ASAS). Some factors, such as elevated levels of C-reactive protein at baseline, have been identified as predictors of radiographic sacroiliitis progression, leading to a definite diagnosis of ankylosing spondylitis. These two entities show similar clinical expression (clinical features and activity levels), suggesting continuity between the two diseases. Non-radiographic forms most often affect women and patients with recent symptoms, and are therefore considered as a pre-radiographic status. If the use of magnetic resonance imaging is necessary for the identification of non-radiographic axial spondyloarthritis according to the ASAS criteria, the presumptive diagnosis is mainly based on complaints of inflammatory back pain. The presence of other typical clinical features, such as HLA B27 positivity and/or radiographic sacroiliitis increases the diagnostic probability and indicates the need for referral to a specialist., SCOPUS: ar.j, info:eu-repo/semantics/published