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International audience; IntroductionTNFRSF1A is involved in a Mendelian autosomal dominant autoinflammatory disorder called TNFR-associatedperiodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affectingconserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequentR92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor tomultifactorial inflammatory disorders.ObjectivesThis study investigates TRAPS pathophysiology in a family exceptional by its size (13 members).MethodsTNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electro-static properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1expression was assessed by western blotting and ELISA in lysates and supernatants of HEK293T cells transfectedwith plasmids encoding wild-type and mutated TNFR1.ResultsA TNFRSF1A heterozygous missense mutation, R92W(c.361C>T) perfectly segregated with typical TRAPS mani-festations within the family (p

Methods We launched a non-interventional study with analysis of clinical, biological and pharmacokinetic information. Full-PK profiles of MPA were modelled using an iterative two-stage approach (1). The clinical status was defined by the SLEDAI, the SLE being considered active for a score ≥6. Relationships between MPA through concentrations (C0), AUC (Area Under Curve) or AUC/ dose values, and the disease’s activity were studied using logistic regression analysis.

International audience; IntroductionHereditary recurrent fevers (HRF) are autoinflammatory disorders whose etiology remains unknown in many cases.ObjectivesTo identify a new HRF geneMethodsComparative genomic hybridization (CGH, 385K array) was performed in the proband. TNFRSF11A was screenedby Sanger sequencing in other patients. TNFRS11A expression was quantified by fluorescence-activated cellsorter analysis (FACS). NF-k B activation was assessed using a luciferase assay in HEK293 cells transfected withplasmids encoding wild-type and mutated TNFRSF11A.ResultsArray-CGH analysis performed in a patient with multiple congenital anomalies and a recurrent fever syndromerevealed a de novo heterozygous chromosomal rearrangement encompassing a duplication of TNFRSF11A. Thistransmembrane receptor binds the TNFSF11 cytokine, activates NF-k B signaling, and regulates fever in rodents,consistent with a possible role in HRF. TNFRSF11A screening in other patients with genetically-unexplainedHRF revealed a heterozygous frameshift mutation in a patient and her affected mother. The mutated protein isexpressed at similar levels as the normal receptor on leukocytes. Most importantly, this mutation results in a gainof function on NF-k B signaling, since the mutated protein is more responsive to TNFSF11 stimulation than the wild-type receptor. Since TNFRSF11A (also known as RANK) was previously known for its key role in osteoclastogenesis, the medical history of our patients was reassessed and revealed minor symptoms also found in patients with TNFRSF11A-associated bone disorders.ConclusionThe implication of TNFRSF11A in HRF reveals a key role of this receptor in autoinflammation and opens up newfields of research at the crossroads between bone metabolism and innate immunity.

RASopathies (Noonan syndrome (NS) and Noonan-related syndromes) are neurodevelopmental syndromes resulting from germline mutations in genes that participate in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway (PTPN11, SOS1, RAF, KRAS or NRAS and SHOC2). Some monogenic conditions are associated with the development of systemic lupus erythematosus (SLE), and a few reports described the association of SLE, with NS.

International audience; IntroductionDefinitions and classifications of autoinflammatory diseases have been multiple. Their succession highlightsthe advances in our understanding of the innate immune system, especially the role of interleukin 1b and theinflammasome. However, these definitions and classifications face a number of structure and content issues.ObjectivesTo propose a novel definition of autoinflammatory diseases and to challenge the global classification of inflammatory diseases.MethodsWe appeal to the desirable characteristics of classification systems (exhaustiveness, disjointness, naturalness, usefulness) and to a critical analysis of the notion of continuum.ResultsWe propose a clinically-oriented definition: “autoinflammatory diseases are diseases with clinical signs of inflam-mation, associated with elevated acute phase reactants and due to a dysfunction in the innate immune system,genetically determined or triggered by an endogenous factor”. It is hard to find natural properties able to underlie a useful classification of autoinflammatory diseases, and inflammatory diseases as a whole, into disjoint and exhaustive categories. The notion of continuum is therefore appealing. However, a single continuum from purely autoinflammatory to purely autoimmune diseases oversimplifies, and even distorts, reality. How to locate, for instance, the disease caused by a deletion in PLCG2 (the gene encoding phospholipase Cg2) that associatesautoinflammatory symptoms to both common variable immunodeficiency and autoimmune features? Herewe have an overactivation of both the innate and the adaptive immune system, associated with a deficiency ofthe adaptive immune system. More than one dimension is needed to properly represent the immunological dysfunctions underlying inflammatory diseases. Furthermore, a classification of inflammatorydiseases should also make sense of the clinical, pathological and biological phenotypes.ConclusionTo be adequate and useful, a definition of autoinflammatory diseases and a classification of inflammatory diseases must take the multiple facets of reality into account, including clinical features. This can be done within a continuum only if it is multidimensional.