ImmunAID 2016 NETWORK

Auto-inflammatory Disorders (AID) is a group of inflammatory diseases involving chronic dysregulation of innate immunity, initially described in familial monogenic periodic syndromes but including nowadays numerous sporadic entities (either mono- or polygenic). The prevalence of sporadic AIDs is currently unknown, ranging from 0.5 to 5 / 100 000. By opposition to auto-immune diseases in which specific auto-antibodies enable accurate diagnosis, AID diagnosis remains challenging due to the diversity and lack of specificity of many symptoms, as well as the numerous differential diagnoses (e.g., infectious or neoplastic diseases). Although the pathogenic pathways may be different among AIDs, we hypothesized that there was a common pathogenic backbone to all AIDs with additional features specific of each sporadic AIDs. Up to now, the search for biomarkers has been conducted by research domains, e.g., genetics, serum proteins, cytokine production, without any comprehensive approach covering a wider AID spectrum. The overall aim of the project is thus to identify a generic AID signature and biomarkers enabling rapid and accurate diagnosis making of AIDs using a multi-omics approach. The project will focus on a limited number of sporadic AIDs: - Adult-onset Still disease (AoSD) and Systemic-onset Juvenile Inflammatory Arthritis (SoJIA); - Behçet disease and Takayasu arteritis; - Familial Mediterranean Fever (FMF)-like syndromes for which no familial aggregation is present and no specific gene mutation is present; - Syndrome Acne Palmoplantar pustulosis Hyperostosis Osteitis (SAPHO); - Neutrophilic dermatoses such as Schnitzler syndrome. The choice of these diseases has been made for 2 main reasons: Although clinical diagnosis is challenging at the patient level, those diseases are clinically well-defined entities in the context of clinical research. In addition, there are existing networks or international working groups involved in this field: F-CRIN-labelled IMIDIATE clinical network, RaDiCo-labelled ACOSTILL in France, JIR in Switzerland, European Vasculitis Network, National Reference Center for FMF or Autoinflammatory disorders. For the SC1-PM03-2017 Call, the research project will be organized into several work packages (WP) applying innovative technics to characterize the pathogenic pathways implicated in different steps of the inflammation process. Several modules have been identified so far: - Management of patient data and biological samples collection, including legal and regulatory aspects, to constitute the central dataset. - Genomics investigations from candidate-gene approach – based on the knowledge of hereditary monogenic AID – to whole exome sequencing for identification of new genes. - Transcriptomics and deep immunophenotyping using LUMINEX cytokine analyses and mass cytometry to understand specific cytokine profiles and their evolution during AID flares. - Quantification of soluble lipid mediators involved in inflammation start and resolution. - Inflammasome function analyses to understand the alteration leading to IL-1 hyperproduction. - Specific role of innate cells such as neutrophils, basophils and mast cells. - Biostatistics modeling integrating work package-derived data in order to develop robust and accurate diagnostic biomarkers. This global and comprehensive approach will enable: - The identification of biomarkers and combination of biomarkers in specific algorithms, specific of these diseases; - A deeper understanding of AID pathogenesis of several rare disorders in one single project. - A more accurate and reliable diagnosis of AIDs at the patient level which will optimize patient management by personalizing therapeutic management. - The confirmation or update of the AID classification proposed by Grateau et al., or - The identification of new AID-specific targets that could translate into new targeted therapies in the future.