Category: Autoimmune rheumatologic diseases
Autoimmune-prone NOD mice represent an invaluable model of type 1 diabetes (T1D). Inducible T cell co-stimulator (ICOS) is involved in induction of helper T cell responses, T-dependent antibody responses and germinal center reaction. Our objective was to investigate the consequences of ICOS invalidation on the autoimmune manifestations in NOD mice and study myositis pathogenesis.
Neither Icos-/- nor Icosl-/- NOD mice developed T1D. In contrast, myositis spontaneously occurred by 28 wks in both lines with decreased grip strength, impaired cadence and death around 40 wks. Pathological muscle analysis revealed necrotic myofibers and important inflammatory infiltrates (CD4+ T cells, macrophages). Muscle lesions yielded T2 hypersignals in MRI that correlated with histopathology and regressed under steroid therapy. CD4+ T cells were Th1 biased. Myositis developed in CD8- but not CD4-deficient mice. Disease was adoptively transferred to NOD.scid recipients by Icosl-/- CD4+ T cells. Activating IL-2/anti-IL-2 complexes exacerbated myopathy. Oxydative stress was present in muscle, as attested by transcriptomic and proteomic analyses, histo-enzymology, reactive oxygen species production and evaluation of mitochondrial function. Abnormalities in mitochondria were found by electron microscopy. Anti-oxydant therapy ameliorated disease. Similar oxidative stress was found in biopsies from patients with dermatomyositis.
Catalina Abad– PhD, Normandie Univ, UNIROUEN, INSERM, U1234, IRIB, Rouen, France
Alain Meyer– MD, PhD, 2Strasbourg University Hospital, Reference center for rare autoimmune diseases, Department of rheumatology, Strasbourg, France
Laurent Drouot– PhD, Normandie Univ, UNIROUEN, INSERM, U1234, IRIB, Rouen, France
Gwladys Bourdenet– PharmD, PhD, Normandie Univ, UNIROUEN, INSERM, U1234, IRIB, Rouen, France
Christian Boitard– MD, PhD, INSERM, U1016, Paris, France
Olivier Boyer– Faculty of Medicine _ University of Rouen Normandy