Autoimmune rheumatologic diseases
Myositides are characterized by muscle weakness, leading to bedridden state and possibly death. Pathophysiological studies and therapeutic advances have been hampered by the lack of appropriate mouse models. We report the first model of spontaneous autoimmune myositis not requiring active immunization.
Disease clinical evolution in both Icos-/- and Icosl-/- NOD mice was attested by significantly decreased muscle grip strength and locomotor disability (impaired cadence and print area). Pathological analysis revealed the presence of necrotic myofibers and important inflammatory infiltrates (CD4+ T cells, macrophages). Muscle lesions were objectifiable using small animal MRI, 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 conferred to NOD.scid recipients by Icosl-/- CD4+ T cell adoptive transfer. Promoting in vivo activated CD4+ effector T cells, administration of IL-2/anti-IL2 complexes exacerbated myopathy. Serum proteomic analysis revealed five potential autoantibody targets, among two were over-expressed in diseased muscle. Searching for corresponding auto-antibodies in patients, we developed a ALBIA (Luminex™ immunoassay) using human ortholog proteins. One of them revealed positivity in a minority of individuals from a ~700 patients cohort.