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⬛ 1. Approaches to address muscle cell attack by cytotoxic T cells

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1). Approaches to address muscle cell attack by cytotoxic T cells.

⬛ 1.1 Summary:

▣ Greenberg, S. A. (2020). Pathogenesis of inclusion body myositis. Current Opinion in Rheumatology,32(6) https://doi.org/10.1097/BOR.0000000000000752

▣ Greenberg (2020) states "IBM is an autoimmune disease. Multiple arms of the immune system are activated, but a direct attack on muscle fibers by highly differentiated T cells drives muscle destruction."

▣ Greenberg (2020) states that IBM is resistant to therapies because of this highly differentiated T-cell population, which is not effectively reduced by corticosteroids.

▣ Greenberg (2020) states "T-cell cytotoxicity directed against myofibers is the only pathogenic mechanism we are certain of for IBM."

▣ Greenberg (2020) states "Five studies over the last decade have shown an increased frequency of highly differentiated CD4 and CD8 T cells in IBM muscle or blood."

▣ Greenberg (2020) states "IBM is unique among muscle diseases for its muscle genomic signature of T-cell cytotoxicity."

▣ Greenberg et al., (2019) described the specific cytotoxic CD8 + T cells responsible for muscle cell destruction in IBM and a marker these cells display (KLRG1). This suggests an optimistic direction to take in the development of a medication to treat IBM. IBM may be the only muscle disease characterized by killer cells of the immune system attacking muscle cells.

⬛ 1.2 Benveniste, O.,& Allenbach, Y. (2019). Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain, 142(9), 2549-2551. https://doi.org/10.1093/brain/awz229

▣ This article is a commentary on the article below, (Greenberg et al., 2019).

▣ They [(Greenberg et al., 2019).] show that IBM is driven by highly differentiated cytotoxic T cells and that this pathogenesis is unique among idiopathic inflammatory myopathies.

▣ Greenberg et al. identified a muscle cytotoxic signature and highly differentiated T cell signature present only in IBM. These cytotoxic and highly differentiated cells were CD8+ and killer cell lectin-like receptor G1 (KLRG1) positive.

▣ KLRG1 is an inhibitory receptor of the C-type lectin-like family. It is used as a marker of terminally differentiated NK and T cells and is strongly induced by chronic viral and other infections. IBM can occur in the setting of viral infection with HIV-1 or human T cell leukaemia virus type 1 (HTLV-1), but in the majority of cases no chronic viral infection is observed. Thus, in IBM, the chronic antigenic stimulation of T cells must come from some as yet unidentified muscle antigens, presumably presented by the myofibres themselves at their surface by major histocompatibility complex (MHC) class I molecules. MHC class I overexpression is in fact one of the hallmarks of IBM pathology. Thus, in IBM it appears that huge antigen stimulation results over time in transformation of naive or early effector memory T cells to TEMRA, which can even give rise to the phenotype of T cell large granular lymphocytic leukaemia.

▣ Circulating anti-cN1A autoantibodies have been identified, for example, while genome-wide studies show marked association (P less than 10 -33 ) with HLADRB1, an autoimmune haplotype.

▣ the study does suggest the value of targeting KLRG1+ cells as an IBM therapeutic. In addition to KLRG1 being a marker of presumed pathogenic cells in IBM muscle, the study demonstrated low expression of KLRG1 on lymphoid tissue central memory T cells, which are of paramount importance for infectious disease defence, and low expression on regulatory T cells that help to suppress autoimmunity (Greenberg et al., 2019). We can thus imagine that a targeted therapy for IBM that aims to deplete TEMRA KLRG1+ presumably effector cells (e.g. with a monoclonal antibody) may have a good safety profile in terms of infections and may efficiently tackle one of the key actors in IBM pathophysiology.

▣ Glossary

⧈ IBM: Inclusion body myositis is the most prevalent myopathy in individuals over 50 years of age. Its unique phenotype with asymmetrical slowly progressive diffuse muscle weakness mainly affecting the quadriceps, hand finger flexors and swallowing muscles is highly indicative of the diagnosis, and should not be confused with a polymyositis (based on inflammatory infiltrates present on muscle biopsy) because of its resistance to corticosteroids.

⧈ KLRG1: Killer cell lectin-like receptor subfamily G member 1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on terminally differentiated effector and effector memory CD8+ T and NK cells.

⧈ TEMRA cells: Terminally differentiated effector memory T cells. Human CD8+ T cells are commonly classified into four subsets based on surface expression of the leucocyte common antigen isoform CD45RA and the lymph node addressin CCR7. Naive T cells (CD45RA+/CCR7+) are thereby distinguished from central memory (TCM, CD45RA—/CCR7+), effector memory (TEM, CD45RA—/CCR7-) and TEMRA (CD45RA+/CCR7-) T cells.

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⬛ 1.3 Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher-allan, C., Amato, A. A., & Dorfman, D. M. (2019). Highly differentiated cytotoxic T cells in inclusion body myositis. Brain, 1-15. https://doi.org/10.1093/brain/awz207

▣ "(Greenberg et al., 2019). — Study"

▣ Inclusion body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantibody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8 + T cell destruction of myofibres. Here, we report on translational studies of inclusion body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with inclusion body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in inclusion body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28870 human tissue samples, and identified the presence of KLRG1 on pathogenic inclusion body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in inclusion body myositis blood. We examined inclusion body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infectionprotective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of inclusion body myositis.

▣ Here, we report on translational studies of IBM patient muscle and blood samples compared with large numbers of muscle samples from other muscle diseases, identifying a unique cytotoxic lymphocyte signature and a highly differentiated T-cell signature in IBM muscle, highlighting the relevance of highly differentiated cytotoxic T cells to the pathogenesis of IBM. In particular, killer cell lectin-like receptor G1 (KLRG1), an inhibitory T- and NK-cell receptor that is known to mark highly differentiated cytotoxic T cells, is identified on IBM blood and muscle-invading T cells.

▣ Evaluation of muscle gene expression across 305 muscle biopsy samples from a wide range of muscle diseases, compared to 106 normal samples, showed a cytotoxic lymphocyte signature in IBM distinct from all other muscle diseases, particularly other forms of inflammatory myopathy, which include dermatomyositis, polymyositis, autoimmune necrotizing myopathy, and non-specific myositis.

▣ To identify potential therapeutic targets that are enriched among human cytotoxic T cells, we examined a genomic dataset (European Bioinformatics Institute, accession ETABM-40) of human blood CD8 + T cell differentiation constructed on sorted CD8 + naive, central memory, effector memory (TEM), and terminally differentiated effector memory (TEMRA) T cells.

▣ This strategy identified KLRG1 as a marker of T cells that could be potential therapeutic targets.

▣ Collectively, the current data and previous studies demonstrate that muscle and blood CD4 + and CD8 + T cells in IBM have been driven to highly differentiated effector T cells defined in various overlapping ways, such as loss of CD28, loss of CD62L on CD45RA + T cells gain of CD244, gain of CD57 and gain of KLRG1. These cells have potent cytokine (e.g. IFN-gamma) secreting and cytotoxic capacities. Specifically, IBM blood CD8 + CD28 - T cells have been shown to be major producers of IFN- gamma. These T-cell phenotypic changes are also seen in T cell large granular lymphocytic leukaemia (LGLL), a treatment-refractory expansion of clonal highly differentiated effector CD8 + T cells previously linked to IBM. LGLL T and NK cell expansions are associated with IL-15, and it is notable that IBM muscle has significantly increased IL15 gene expression.

▣ A major distinction between polymyositis and IBM evident here is the presence of highly differentiated CD8 + CD57 + T cells in IBM muscle but lacking from polymyositis muscle, and the correlation of KLRG1 expression with cytotoxicity present in IBM but not polymyositis.

▣ These studies highlight possible reasons for IBM treatment-refractoriness and the potential value of targeting the highly pathogenic T-cell population. Molecules highly expressed by these cells, but with lower expression by regulatory T cells and central memory T cells are potential favourable targets for an IBM therapeutic

⬛ 1.4 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

▣ "(Greenberg, 2019). — Review"

▣ 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.

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▣ 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.

Critical References

⬛ Benveniste, O.,& Allenbach, Y. (2019). Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain, 142(9), 2549-2551.https://doi.org/10.1093/brain/awz229

⬛ DzanguĆ©-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, 18(4), 325-333. https://doi.org/10.1016/j.autrev.2019.02.003

⬛ Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 1. https://doi.org/10.1038/s41584-019-0186-x

⬛ Greenberg, S. A. (2020). Pathogenesis of inclusion body myositis. Current Opinion in Rheumatology,32(6) https://doi.org/10.1097/BOR.0000000000000752

⬛ Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher-allan, C., Amato, A. A., & Dorfman, D. M. (2019). Highly differentiated cytotoxic T cells in inclusion body myositis. Brain, 1-15. https://doi.org/10.1093/brain/awz207

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