Dysregulation of Type I interferon signalling in Juvenile Dermatomyositis: from pathophysiology to new biomarkers. – JDMINF2

Juvenile dermatomyositis (JDM) is a rare and severe idiopathic inflammatory myopathy that begins in childhood. JDM is associated with significant morbidity and mortality and although recent immunomodulating therapies have improved outcome, 40-60% of patients present with relapsing or chronic disease leading to persistent muscle weakness and disability. The disease is characterized by a sustained overproduction of type I interferons (IFN-I) however, the exact pathophysiology remains largely unknown and the role of IFN-I in JDM onset and progression still need to be deciphered. The lack of improved understanding of this disease has hampered both the identification of sensitive and reliable biomarkers and the development of novel therapies for children with severe recalcitrant disease. We hypothesize that JDM results from an initial environmental trigger such as infection leading to exacerbated IFN-I production combined with an enhanced sensitivity to interferon signalling of immune and/or non-immune cells. In our project we aim: 1) to fully understand the pathophysiology of JDM by testing the hypothesis of a viral infection triggering the disease and by characterizing the dysregulated inflammatory pathways (signaling and cellular specificity driving IFN-I production and responses) at the circulating and tissue levels. This will provide the basis for the identification of new targeted treatments. 2) To identify biomarkers of disease progression (severity, response to first line treatment) at disease onset by correlating a pathological signature in muscle tissues to disease progression history. This should allow adjustment of the immunosuppressive treatment at an early stage of the disease, and thus contribute to decrease the morbidity and mortality of JDM. For this project, we will rely on an established large biocollection of plasma and muscle biopsies from JDM patients and an active national network of recruiting clinicians. Blood samples at disease onset will be analysed using a combination of the highly standardized immunomonitoring protocols developed by the Milieu Interieur consortium in parallel with complementary single cell mass cytometry analysis. Muscle biopsies will be studied using the first protocol of spatial RNAseq on human muscle tissue that we specifically optimised for this study. Our project will provide crucial information for the identification of newly targeted or repositioned treatments in JDM. It will also help to identify new biomarkers predictive of disease progression and response to first-line treatment that will be validated in future clinical trials. We also predict that our work will help the identification of novel molecular partners in IFN-I signaling regulation which could have a significant impact for fundamental and applied immunology. The information generated from muscle biopsy spatial RNAseq will provide a template to study muscle responses to inflammatory or ischemic injuries (including information on the transcriptomic response of each individual resident/infiltrating cells types and their interplay in pathological conditions). We expect this work to have a tremendous impact on the overall field of muscle biology, as it will pave the way for the comparison of compensatory mechanisms to a variety of pathological challenges in muscle.