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The Spontaneous Autoimmune Neuromyopathy in ICOSL−/− NOD Mice Is CD4+ T-Cell and Interferon-γ Dependent

Abstract : Abrogation of ICOS/ICOS ligand (ICOSL) costimulation prevents the onset of diabetes in the non-obese diabetic (NOD) mouse but, remarkably, yields to the development of a spontaneous autoimmune neuromyopathy. At the pathological level, ICOSL −/− NOD mice show stronger protection from insulitis than their ICOS −/− counterparts. Also, the ICOSL −/− NOD model carries a limited C57BL/6 region containing the Icosl nul mutation, but, in contrast to ICOS −/− NOD mice, no gene variant previously reported as associated to NOD diabetes. Therefore, we aimed at providing a detailed characterization of the ICOSL −/− NOD model. The phenotype observed in ICOSL −/− NOD mice is globally similar to that observed in ICOS −/− and ICOS −/− ICOSL −/− double-knockout NOD mice, manifested by a progressive locomotor disability rst affecting the front paws as observed by catwalk analysis and a decrease in grip test performance. The pathology remains limited to peripheral nerve and striated muscle. The muscle disease is characterized by myoober necrosis/regeneration and an innammatory innltrate composed of CD4 + T-cells, CD8 + T-cells, and myeloid cells, resembling human myositis. Autoimmune neuromyopa-thy can be transferred to NOD.scid recipients by CD4 + but not by CD8 + T-cells isolated from 40-week-old female ICOSL −/− NOD mice. The predominant role of CD4 + T-cells is further demonstrated by the observation that neuromyopathy does not develop in CIITA −/− ICOSL −/− NOD in contrast to β2microglobulin −/− ICOSL −/− NOD mice. Also, the cytokine proole of CD4 + T-cells innltrating muscle and nerve of ICOSL −/− NOD mice is biased toward a Th1 pattern. Finally, adoptive transfer experiments show that diabetes development requires expression of ICOSL, in contrast to neuromyopathy. Altogether, the deviation of autoimmunity from the pancreas to skeletal muscles in the absence of ICOS/ICOSL signaling in NOD mice is strictly dependent on CD4 + T-cells, leads to myoober necrosis and regeneration. It provides the rst mouse model of spontaneous autoimmune myopathy akin to human myositis.
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Submitted on : Wednesday, May 24, 2017 - 3:58:47 PM
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Claire Briet, Gwladys Bourdenet, Ute C. Rogner, Chantal Becourt, Isabelle Tardivel, et al.. The Spontaneous Autoimmune Neuromyopathy in ICOSL−/− NOD Mice Is CD4+ T-Cell and Interferon-γ Dependent. Frontiers in Immunology, Frontiers, 2017, 8, pp.287. ⟨10.3389/fimmu.2017.00287⟩. ⟨inserm-01527587⟩



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