CD4+ and CD8+ CD28<sup>null</sup> T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Pandya, Jayesh M.; Venalis, Paulius; Al-Khalili, Lubna; Hossain, Mohammad Shahadat; Stache, Vanessa; Lundberg, Ingrid E.; Malmström, Vivianne; Fasth, Andreas E. R.

doi:10.1002/art.39650

Cited by 38 publications

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References 48 publications

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“…In conclusion, after revisiting our old results we found that they were quite consistent with the findings described by Pandya et al (1), corroborating the hypothesis that muscle damage is unique in PM and is induced by an expansion of circulating CD81CD28 null T cytotoxic cells, which are activated to migrate through the vessel walls into muscle and adhere to kill myofibers upon perforin polarization. Finally, a further issue is whether peripheral CD81CD28 null T cytotoxic cells might be considered a biomarker for PM; longitudinal studies on larger cohorts of patients are needed in order to test the sensitivity of changes in CD81CD28 null cell levels as a predictor of disease activity and response to treatment.…”

supporting

confidence: 92%

Circulating CD8+CD28^null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Iannone

Cauli

Lopalco

et al. 2016

Arthritis & Rheumatology

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We read with interest the recent report by Pandya et al on the cytotoxic effects of CD28 null T cells on myocytes from patients with polymyositis (PM) (1). They cocultured autologous muscle cells with purified peripheral blood CD81 and CD41 T cells from 5 patients with PM and showed that CD28 null T cells exerted myotoxic activity by increasing the secretion of granzyme B, whereas CD281 T cells did not. The activation of this intracellular pathway was further corroborated by the results of experiments in which perforin polarization was down-regulated by treatment with selective inhibitors.Many years ago we also focused on this topic, investigating whether CD81 T cytotoxic cells circulating in the peripheral blood might differentiate PM from dermatomyositis (DM) (2). By that time in the early 1990s, reported findings from some studies suggested that CD28 antigen expression on the cell surface might identify T cells with cytotoxic functions (3,4). Therefore, in our study we investigated, by flow cytometry, for possible differences in CD81CD281 circulating T cells between PM patients (n 5 12), DM patients (n 5 10), and compared to healthy donors (n 5 16). We found meaningful differences in the distribution of CD81 T cell subsets across groups, but we misinterpreted the implications of our results since we started with the assumption that the CD81 CD281 T cells were the cytotoxic ones (2). In light of more recent studies providing evidence that the lack of CD28 surface antigen defines T cytotoxic cells (5,6) and after reading the article by Pandya et al (1), we reviewed our old data.PM patients displayed the highest percentage of peripheral blood CD81CD28 null T cells (mean 6 SD 13.1 6 2%, versus 5.8 6 1% in patients with DM [P , 0.05] and 6.4 6 2% in healthy controls [P , 0.05]). Similar differences were also detected when absolute numbers of CD81CD28 null T cells were measured. We also investigated the state of functional activation, namely, the migratory phenotype of CD81 T cells, by assessing the coexpression of CD25 and HLA-DR surface antigen, which are up-regulated upon T cell activation, and lymphocyte function-associated antigen 1 (LFA-1), which promotes migration of activated T cells through endothelial cells into extravascular tissue, and adhesion to the target cells (7). Compared to healthy donors, CD81HLA-DR1 T cells were significantly increased in myositis patients, but with no significant difference between the PM and DM groups (mean 6 SD 16.3 6 2% and 16.0 6 1%, respectively).Upon T cell activation, LFA-1 shows a bimodal expression, and a "dim" or "bright" LFA-1 phenotype can be easily recognized based on mean fluorescence intensity seen on flow cytometry. Indeed, the proportion of CD81LFA-1 bright T cells was significantly higher among patients with PM (mean 6 SD 73.4 6 7%) than among patients with DM (45.5 6 9%) or healthy controls (40.2 6 10%) (both P , 0.05), suggesting that activated peripheral blood CD81 T cells are more prone to leak from blood streaming into PM muscles. To investigate this wor...

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supporting

confidence: 92%

Circulating CD8+CD28^null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Iannone

Cauli

Lopalco

et al. 2016

Arthritis & Rheumatology

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“…However, a significant age effect was present. The high frequency of elevated TC levels is of particular interest as previous studies indicate that patients with RA are rarely screened for lipid abnormalities [24], and that patients with RA [6, 25], and with axSpA or PsA [6], are undertreated in terms of lipid-associated CVD risk.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…First, selection bias is indicated by the high rate of use of bDMARDs (especially in axSpA) and the inclusion rate in NOCAR of 41% among all eligible patients [6]. Patients included in NOCAR appear to have had lower disease activity at the time of inclusion and, overall, older age compared to eligible but non-included patients [6]. Since high disease activity is associated with increased risk of CVD [39], our results may thus underestimate the actual CVD risk in patients with IJD with high disease activity.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the European League Against Rheumatism (EULAR) recommendations for CVD risk management advocate that CVD risk assessments should be undertaken every 5 years for patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) [5]. In the Norwegian Collaboration on Atherosclerotic disease in patients with Rheumatic joint diseases (NOCAR) project, systematic CVD risk assessment has been implemented into clinical practice in rheumatology outpatient clinics [6]. …”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular disease risk profiles in inflammatory joint disease entities

et al. 2017

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BackgroundPatients with inflammatory joint diseases (IJD) have increased risk of cardiovascular disease (CVD). Our aim was to compare CVD risk profiles in patients with IJD, including rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) and evaluate the future risk of CVD.MethodsThe prevalence and numbers of major CVD risk factors (CVD-RFs) (hypertension, elevated cholesterol, obesity, smoking, and diabetes mellitus) were estimated in patients with RA, axSpA and PsA. Relative and absolute risk of CVD according to Systematic Coronary Risk Evaluation (SCORE) was calculated.ResultsIn total, 3791 patients were included. CVD was present in 274 patients (7.2%). Of those without established CVD; hypertension and elevated cholesterol were the most frequent CVD-RFs, occurring in 49.8% and 32.8% of patients. Patients with PsA were more often hypertensive and obese. Overall, 73.6% of patients had a minimum of one CVD-RF, which increased from 53.2% among patients aged 30 to <45 years, to 86.2% of patients aged 60 to ≤80 years. Most patients (93.5%) had low/moderate estimated risk of CVD according to SCORE. According to relative risk estimations, 35.2% and 24.7% of patients had two or three times risk or higher, respectively, compared to individuals with no CVD-RFs.ConclusionsIn this nationwide Norwegian project, we have shown for the first time that prevalence and numbers of CVD-RFs were relatively comparable across the three major IJD entities. Furthermore, estimated absolute CVD risk was low, but the relative risk of CVD was markedly high in patients with IJD. Our findings indicate the need for CVD risk assessment in all patients with IJD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1358-1) contains supplementary material, which is available to authorized users.

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Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Peng

Zhang

Liang

et al. 2022

Arthritis & Rheumatology

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Objective Myofiber necrosis is a significant pathologic characteristic of idiopathic inflammatory myopathies (IIMs), and its molecular mechanism is largely unknown. Necroptosis is a recently identified form of regulated necrotic cell death, and its activation might have crucial biologic consequences. The aim of the present study was to investigate the role of necroptosis in IIM muscle damage. Methods Western blot and immunohistochemistry analyses were performed to examine the expression of receptor‐interacting protein 3 (RIP‐3) and mixed‐lineage kinase domain–like (MLKL) proteins in 26 IIM patients and 4 healthy controls, as well as necroptosis‐related damage–associated molecular pattern molecules. Tumor necrosis factor (TNF) was used to stimulate cultured C2C12 myoblasts, and the involvement of necroptosis in cell death of C2C12 cells was studied in vitro. Results The expression of RIP‐3 and MLKL proteins and their phosphorylated forms was significantly increased in the muscle tissue of IIM patients compared to that of healthy controls. The expression levels of RIP‐3 and MLKL proteins were associated with the severity of muscle damage in patients with IIM. Significant colocalization of MLKL with high mobility group box chromosomal protein 1 in necrotizing myofibers was observed in muscle biopsy tissue from patients with IIM. Stimulation of C2C12 myoblasts with TNF and a pan‐caspase inhibitor, Z‐VAD, resulted in the overactivation of necroptosis and significantly increased necrotic cell death. Strategies involving either inhibition of necroptosis with necrostatin‐1 or knockdown of MLKL expression successfully prevented necroptosis‐induced cell death of C2C12 cells. Conclusion These findings demonstrate that overactivated necroptosis contributes to muscle damage in IIMs and suggest that necroptosis inhibitors could represent a new therapeutic target in the treatment of IIMs.

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CD4+ and CD8+ CD28^null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Cited by 38 publications

References 48 publications

Circulating CD8+CD28^null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Circulating CD8+CD28^null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Cardiovascular disease risk profiles in inflammatory joint disease entities

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

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CD4+ and CD8+ CD28null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Cited by 38 publications

References 48 publications

Circulating CD8+CD28null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Circulating CD8+CD28null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Cardiovascular disease risk profiles in inflammatory joint disease entities

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

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Product

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CD4+ and CD8+ CD28^null T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis

Circulating CD8+CD28^null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al

Circulating CD8+CD28^null T Cytotoxic Cells in Polymyositis—A Possible Biomarker? Comment on the Article by Pandya et al