Experimental myositis: an optimised version of C-protein-induced myositis

Author:

Giannini MORCID,Rovito D,Oulad-Abdelghani M,Messaddeq N,Debrut L,Kessler P,Charles AL,Geny B,Metzger D,Laverny G,Meyer A

Abstract

IntroductionInflammatory myopathies (IM) are a group of severe autoimmune diseases, sharing some similarities, whose cause is unknown and treatment is empirical. While C-protein-induced myositis (CIM), the most currently used model of IM, has removed some roadblock to understand and improve the treatment of IM, it has only been partially characterised and its generation limited by reproducibility issues. This study aimed at optimising the generation and the characterisation of CIM.MethodsIn silicoanalysis was run to identify the top-3 specific and immunogenic regions of C-protein. The cognate polypeptides were synthetised and used to immunise C57BL/6N mice. Grip strength, walking ability, serum creatine-kinase levels and muscle pathology (histological and electron microscopic features) were assessed. Immune cell proportions and interferon signature in muscles were also determined.ResultsAmong the three C-protein polypeptides with the highest immunogenic score, amino acids 965-991 induced the most severe phenotype (i.e., 37% decrease in strength, 36% increase in hind base width, 45% increase in serum creatine-kinase level, 80% increase in histological inflammatory score) from day (D) 14 to at least D31 after immunisation [experimental myositis (EM)]. Optical and electron microscopy revealed mononuclear cell infiltrate, myofibre necrosis, atrophy, MHC-I expression as well as sarcolemmal, sarcomeric and mitochondrial abnormalities. Proinflammatory T-lymphocytes, macrophages, type-I and II interferon-stimulated transcripts were found within the muscle of EM mice.ConclusionEM recapitulates the common hallmarks of IM. This costless, high throughput, reproducible and stable model, generated in the most commonly used background for genetically engineered mice, may foster pre-clinical research in IM.Key messagesWhat is already known on this topicC-protein-induced myositis is currently the most used model of inflammatory myopathies but has been partially characterised and its generation is limited by reproducibility issues.What this study adds.Immunisation against the polypeptide encompassing C-protein amino acids 965-991 induces a costless, high throughput, reproducible and stable model of myositis (experimental myositis) that recapitulates the common hallmarks of inflammatory myopathies.How this study might affect research, practice or policyExperimental myositis, generated in the most used background for genetically engineered mice (C57BL/6N), might foster pre-clinical research in IM.

Publisher

Cold Spring Harbor Laboratory

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