Icos gene disruption in non‐obese diabetic mice elicits myositis associated with anti‐troponin T3 autoantibodies. Issue 1 (22nd February 2023)

• Record Type: Journal Article
• Authors: Bourdenet, Gwladys; Pileyre, Baptiste; Drouot, Laurent; Martinet, Jérémie; Bécourt, Chantal; Carrette, Marion; Riou, Gaétan; Bergua, Cécile; Jaworski, Thara; Chan, Philippe; Jean, Laetitia; Fréret, Manuel; Cosette, Pascal; Boitard, Christian; Abad, Catalina; Boyer, Olivier
• Is Part Of: Neuropathology & applied neurobiology. Volume 49:Issue 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-22
• Subjects: autoantibody -- ICOS -- idiopathic inflammatory myopathies (IIM) -- mouse -- myositis -- NOD -- TNNT3; Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12889
• Languages: English
• ISSNs: 0305-1846

Abstract

Abstract: Aims: Idiopathic inflammatory myopathies (IIM) are autoimmune inflammatory disorders leading to skeletal muscle weakness and disability. The pathophysiology of IIM is poorly understood due to the scarcity of animal disease models. Genetic deletion of Icos or Icosl (inducible T cell co‐stimulator/ligand) in non‐obese diabetic (NOD) mice leads to muscle disease. Our aim was to characterise Icos −/− NOD myopathy and to search for novel autoantibodies (aAbs) in this model. Methods: Diabetes, weight, myopathy incidence/clinical score and grip strength were assessed over time. Locomotor activity was analysed with the Catwalk XT gait analysis system. Muscle histology was evaluated in haematoxylin/eosin and Sirius red‐stained sections, and immune infiltrates were characterised by immunofluorescence and flow cytometry. 2D gel electrophoresis of muscle protein extracts and mass spectrometry were used to identify novel aAbs. NOD mice were immunised with troponin T3 (TNNT3) in incomplete Freund's adjuvant (IFA) and R848. An addressable laser bead immunoassay (ALBIA) was developed to measure aAb IgG serum levels. Results: Icos −/− NOD mice did not exhibit diabetes but developed spontaneous progressive myositis with decreased muscle strength and altered locomotor activity. Muscle from these mice exhibited myofibre necrosis, myophagocytosis, central nuclei, fibrosis and perimysial and endomysial cell infiltrates with macrophages and T cells. We identified anti‐TNNT3 aAbs in diseased mice. Immunisation of NOD mice with murine TNNT3 protein led to myositis development, supporting its pathophysiological role. Conclusions: These data show that Icos −/− NOD mice represent a spontaneous model of myositis and the discovery of anti‐TNNT3 aAb suggests a new autoantigen in this model. Abstract : Icos +/+ NOD mice develop a pancreatic β cell‐specific autoimmune response and subsequently diabetes. Icos −/− NOD mice are protected from diabetes but instead develop myositis with the presence of antibodies against the muscle troponin T3 (TNNT3) protein. Immunisation of Icos +/+ NOD mice with TNNT3 leads to myositis, confirming the role of this autoantigen in disease pathogenesis.