Research News

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(Because of the way articles come out, there is some overlap between years.)

Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 2019, 1. https://doi.org/10.1038/s41584-019-0186-x
Abstract: Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in less than 1 percent of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.



Conclusions: Tremendous progress has been made in the clinical and pathogenic understanding of IBM over the past decade. Major advances in biomarker identification, including the notable whole genome linkage to an HLA autoimmune haplotype, the identification of a specific autoantibody and T cell phenotypical abnormalities, have advanced IBM diagnosis and pathogenic understanding. IBM is unique among muscle diseases owing to its molecular signature involving highly differentiated cytotoxic T cells that have escaped immune regulation. Although viewed as treatment refractory, only very limited therapeutic approaches have been carefully studied to date, and none of these has been rationally directed towards targeting this population of T cells; some treatments (such as corticosteroids and alemtuzumab) have had predictably counterproductive liabilities. Complete understanding of the pathogenesis of IBM, like most acquired diseases in humans, awaits successful therapeutic responses from mechanistically targeted therapies.

Dzangue-Tchoupou, G., Mariampillai, K., Bolko, L., Amelin, D., Mauhin, W., Corneau, A., . .. Benveniste, O. (2019). CD8 + T-bet+ cells as a predominant biomarker for inclusion body myositis. Autoimmunity Reviews. https://doi.org/10.1016/j.autrev.2019.02.003
Conclusion: Using a panel of thirty-six markers by mass cytometry, we identify an activated cell population (CD8+ T-bet+ CD57- CD28 low CD27 low CD127 low CD38+ HLA-DR+) which could play a role in the physiopathology of inclusion body myositis, and identify CD8+ T-bet+ cells as a predominant biomarker of this disease.

Huntley, M. L., Gao, J., Termsarasab, P., Wang, L., Zeng, S., Thammongkolchai, T., ... Wang, X. (2019). Association between TDP-43 and mitochondria in inclusion body myositis. Laboratory Investigation. https://doi.org/10.1038/s41374-019-0233-x

De Paepe, B. (2019). Sporadic inclusion body myositis: An acquired mitochondrial disease with extras. Biomolecules, 9(1), 15. https://doi.org/10.3390/biom9010015
Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition.