Dysregulation of Type I interferon signalling in Juvenile Dermatomyositis: from pathophysiology to new biomarkers. – JDMINF2
Understanting the Juvenile Dermatomyositis pathophysiology
Juvenile dermatomyositis is a rare autoimmune disease of unknown origin characterized by sustained overproduction of type I interferons. We are interested in the mechanisms responsible for this overproduction of type I interferons and its impact on disease progression and severity.
Understanding the pathophysiology of juvenile dermatomyositis
Juvenile dermatomyositis (JDM) is a rare and severe pediatric autoimmune myopathy associated with significant morbidity and mortality. Some patients experience chronic or relapsing disease, resulting in muscle atrophy and persistent muscle weakness. The lack of progress in understanding JDM pathophysiology has limited the identification of reliable biomarkers and the development of new therapies for severe forms of the disease. While the central role of the type I interferon (IFN-I) pathway in tissue damage is acknowledged, the precise sequence of events, specific mechanisms, and cellular processes underlying this abnormal IFN-I production remain to be elucidated. The variability in JDM prognosis, ranging from a monophasic disease to a more chronic disease with relapses, highlights the need of understanding the causes of the disease. Idetntifying biomarkers of disease activity and response to treatment represents an unmet medical need. The main objectives of the project are: 1. Understanding the pathophysiology of JMD by testing the hypothesis that a viral infection is a triggering factor and characterizing the dysregulated inflammatory pathways (IFN-I production and responses) at the circulating and tissue levels. This will provide crucial information for the development of new targeted treatments. 2. Identifyng biomarkers of disease progression (severity and response to first-line treatment) at diagnosis. Early adjustment of treatment will help reducing morbidity and mortality in JDM.
The project adopts a comprehensive methodological approach, combining various advanced techniques to explore the pathophysiology of juvenile dermatomyositis (JDM) and identify biomarkers:
-For the study of circulating immune cells, the project uses standardized immunomonitoring tools, including TruCulture functional immune assays on whole blood, developed by the “Milieu Intérieur” consortium (patient samples are stimulated with TLR activators (ODN, Poly(I:C), R848) that induce IFN-I production). These tests allow for the in-depth characterization of type I interferon (IFN-I) signaling dysregulation via Luminex multi-analyte profiling for the quantification of 45 cytokines and NanoString hybridization chips for the transcriptomic analysis of 800 genes.
-To identify viral infectious triggers, the project aims to evaluate the presence of IgG and IgM antibodies to the most common viruses in DMJ patients using Luminex assays. In addition, the presence of viral transcripts can be investigated in muscle tissue using spatial transcriptomics data.
-Detailed characterization of muscle tissue is based on an optimized spatial transcriptomics protocol (10x Genomics Visium technology) applied to muscle biopsy sections from patients with DMJ. This technique allows for the analysis of pathological signatures with a resolution of 55 µm, measuring gene expression in areas of interest such as vasculopathy or damaged myofibers, and enabling unsupervised tissue segmentation. The parallel study of cell transcriptomics, performed on dissociated biopsies, helps define the specific transcriptomic signatures of each cell type in healthy and pathological muscles. Bioinformatic analyses are conducted to link transcriptomic signatures to tissue lesions characteristic of the disease.
In this research project, we adopted a translational approach to explore the IFN-I signaling mechanisms contributing to the pathophysiology of juvenile dermatomyositis (JDM). We recruited patients with JDM prospectively through a consortium of several European reference centers. This allowed us to analyze and correlate IFN-I signaling markers with the clinical activity of JDM. This analysis was further refined according to various clinical criteria, including the expression of specific autoantibodies, providing a better understanding of the intrinsic heterogeneity of JDM. We also evaluated the efficacy of JAK inhibitors, an innovative treatment that directly targets IFN-I signaling. This therapeutic strategy was effective, with 82% of patients with active disease going into remission after the introduction of this treatment. These results confirm the potential of IFN-I modulators in the management of JMD, particularly in patients who do not respond to conventional treatments.
In parallel with these therapeutic evaluations, we studied a group of patients with JMD recruited at the time of diagnosis. Our work revealed the deregulation of a nucleic acid detection pathway, accompanied by significantly increased seropositivity to certain viruses. In an independent follow-up study conducted on retrospective plasma samples collected between 2020 and 2024, we identified a predominant virus among 20 common childhood infections screened as the only virus with significantly increased seropositivity in patients with JMD compared to age-matched controls. In addition, we identified a major dysregulation of immune pathways stimulated by Poly:IC, a double-stranded RNA analog used to mimic RNA viral infections. Finally, spatial transcriptomics analysis of muscle tissue allowed us to associate specific molecular pathways with specific muscle fiber lesions. Furthermore, comparison of biopsies from the same patient, taken at the time of diagnosis and two years after disease remission, revealed normalization of the interferon signature, but persistent overexpression of transcripts associated with myofibrillar stress and muscle remodeling.
The results obtained improve our understanding of the pathophysiology of JMD, and have a direct implication for patient management. Our observations support the hypothesis that a viral infection could trigger the disease. We were able to associate specific molecular pathways with particular muscle fiber lesions. We have also demonstrated that abnormal signatures persist after remission, paving the way for understanding disease relapses in JMD.
A major advance in understanding the pathophysiology of JMD has been the identification of the pivotal role of the type I interferon (IFN-I) pathway in tissue pathology, distinguishing it clearly from other myopathies. IFN-I plays a well-defined role in innate antiviral immunity, and epidemiological studies have shown that JDM is regularly preceded by symptoms consistent with infections. Type I IFN is typically produced in response to the detection of nucleic acid by intracellular sensors. At this stage, it is not yet known whether a specific pathway is involved in all cases of JMD. Viral infections are common in children in the age group affected by JMD, so the occurrence of the disease in a small percentage of exposed children suggests the presence of intrinsic predisposing factors that trigger the pathological process.
We hypothesize that once the IFN-I pathway is induced by an infectious trigger, the mere increase of systemic IFN-I is insufficient itself to induce JDM, implying that a more refined biological processes underlie the disease. JDM may result from the combination of an exacerbated activation of IFN-I production, an enhanced sensitivity of patient’s cells to IFN-I, or a perturbation in controlling this response. The individual sensitivity of muscle resident cells to IFN-I related inflammation could be a key factor in determining disease progression. A better understanding of this aspect of the disease could pave the way for the development of novel targeted treatments.
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.
Project coordination
Cyril Gitiaux (Université Paris-Est Créteil)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
UPEC Université Paris-Est Créteil
IMAGINE INSTITUT DES MALADIES GÉNÉTIQUES (IHU)
Laboratoire Immunologie Translationnelle
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
Help of the ANR 538,559 euros
Beginning and duration of the scientific project:
October 2021
- 48 Months
