Personalized Immunomonitoring to Understand Juvenile Dermatomyositis - Summary JDM R01; PIs: Pascual, V. & Wilson, P. Juvenile Dermatomyositis (JDM) is the most common pediatric idiopathic inflammatory myopathy. It typically presents with a pathognomonic rash and/or proximal muscle weakness that interferes with activities of daily living and may severely impair the patient’s quality of life. JDM is a systemic autoimmune disease as, in addition to the skin and muscle, organs such as the lungs, heart, and intestines can be involved. Characteristic immune findings include the presence of autoantibodies, increased interferon (IFN) activity and infiltration of immune cells across involved tissues. In addition, JDM is considered a “vasculopathy”, as endothelial cell loss and/or dysfunction is a pathognomonic feature of the disease. The outlook for children affected by JDM has improved in the past fifty years, but significant gaps remain around disease pathogenesis. As a result, therapy continues to rely on non-specific immunosuppression. Furthermore, sensitive, specific and minimally invasive methods to diagnose, measure disease activity and predict JDM disease course are not available. As most systemic autoimmune diseases, JDM is clinically and molecularly heterogeneous. Thus, a variety of disease phenotypes are linked to the presence of myositis-specific (MSA) autoantibodies. Differences in transitional and memory B cell and helper T cell subpopulation frequencies have been reported, but the mechanisms leading to autoantibody development are not known. We recently identified expansions of CXCR5low/neg CD27+ memory B cells and Th2 cells in JDM patient’s blood in correlation with IFN-stimulated gene (ISG) signatures and with muscle weakness. We hypothesize that these cells contribute to JDM autoreactivity and represent a valuable biomarker of disease activity (DA). Single cell (SC) transcriptional profiling of JDM PBMCs has permitted us to confirm and extend these observations and to gain insights into innate and adaptive immune alterations that correlate with DA. Here, we will leverage our preliminary cross-sectional findings through longitudinal systems-level immune monitoring of patients and in-depth characterization of MSA responses, as well as spatial analyses of involved muscle. Importantly, this project will capitalize on a very well characterized longitudinal pediatric JDM cohort, resources developed over twenty years to study the human immune system, and an exclusive group of co-investigators with complementary expertise. In order to achieve these goals, we propose the following aims: a) to assess longitudinally and at the SC level, the PBMC and antigen-specific B/T cell compartments of JDM patients stratified according to i) organ involvement, ii) autoantibody specificities, and iii) response to therapy; b) to characterize MSA responses through SC cloning, expression and repertoire analyses and test their function and pathogenic potential; and c) to map the heterogeneity of muscle resident and infiltrating immune cells using state-of-the-art spatial transcriptomic and proteomic tools. Altogether, these studies will bring important clues to understand JDM pathogenesis and disease heterogeneity and will inform novel and personalized therapeutic approaches.
