Trail/trail receptor expression on T-cell subtypes in patients with myasthenia gravis

Year 2025, Volume: 42 Issue: 3, 257 - 265, 30.09.2025

Ali Dincer , Dilek İşcan , Atıl Bişgin , Filiz Koç

Abstract

Anti- acetylcholine receptor (Anti-AChR) is the most commonly seen and well known antibody among Myasthenia Gravis (MG) related antibodies and it is produced by B lymphocytes; however,,T-lymphocytes also contribute to the development of the autoimmune response. Apoptosis, programmed cell death, regulates the activities of central and peripheral T cells during immune response. In this regard, the goal of this study was to determine T cell related TNF-related apoptosis-inducing ligand (TRAIL) receptor and ligand composition; and TRAIL’s role in the development and progression of the disease in MG patients. Thus, we aimed to understand how TRAIL and its receptors affect T cell function in the pathophysiological mechanism of MG. This study included a total of 25 patients (13 females and 12 males), who were admitted to the department of neurology and diagnosed with MG according to clinical, electrophysiological and laboratory data, and 16 age- and sex-matched healthy volunteers. The expression profile of TRAIL and its receptors on CD3+ CD4+ and CD3+ CD8+ T lymphocytes were investigated with flow cytometry in peripheral blood samples. Furthermore, the relationship between TRAIL/TRAIL receptor expression and clinical findings and , treatment protocol of the patients were analyzed with Spearman’s Rho. It was detected that TRAIL/TRAIL receptor expression on both CD4+ and CD8+ T cells were significantly higher in MG patients compared to control group. In MG patients, while death receptor-4 (DR4) and decoy receptors (DcR), DcR1 and DcR2, were correlated with CD8+ T cells, they were not correlated with CD4+ T cells. In this study, which evaluated TRAIL/TRAIL receptor expression on T cell subtypes in MG patients, we showed that TNF and TRAIL/TRAIL receptor system play a significant role in MG and concluded that these data will contribute to the development of new gene therapies.

Keywords

Myasthenia Gravis , thymus , TRAIL , apoptosis , CD4+ , CD8+

Ethical Statement

Çukurova Üniversitesi Tıp Fakültesi Girişimsel Olmayan Klinik Araştırmalar Etik kurulu, toplantı sayısı 19, Tarih 2 mayıs 2013, karar no :11

Supporting Institution

YOK

Thanks

-

References

• Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008; 37(2):141-149.
• Punga AR, Maddison P, Heckmann JM, Guptill JT, Evoli, A. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. The Lancet Neurology, 2022;21(2), 176-188.
• Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W et al. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry. 2007; 78(4):386-390.
• Li V, Jasinarachchi M, Butler E. Epidemiology, symptomatology and treatment of patients with myasthenia gravis in an Australian hospital. Intern Med J. 2019; 49(12):1537-1540.
• Mantegazza R, Cavalcante P. Diagnosis and treatment of myasthenia gravis. Curr Opin Rheumatol. 2019; 31(6):623-33.
• Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol. 2002; 2(5):336-345.
• Godfrey DI, Berzins SP. Control points in NKT-cell development. Nat Rev Immunol. 2007; 7(7): 505-518.
• Niu L, Jiang J, Yin Y, Hu B. LncRNA XLOC_003810 modulates thymic Th17/Treg balance in myasthenia gravis with thymoma. Clin Exp Pharmacol Physiol. 2020 Feb 11. doi: 10.1111/1440-1681.13280.
• Kashii Y, Giorda R, Herberman RB, Whiteside TL, Vujanovic NL. Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. J Immunol. 1999; 163(10):5358-5366.
• Chernajovsky Y, Gould D, Annenkov A, Dreja H, Daly G, Rabinovich GA, et al. Immunotherapy of auto-immune diseases by gene transfer. Biochem Soc Trans. 1999; 27(6):869-873.
• Yang J, Marden JJ, Fan C, Sanlioglu S, Weiss RM, Ritchie TC, et al. Genetic redox preconditioning differentially modulates AP-1 and NF kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis. Mol Ther, 2003; 7(1):341-353.
• Bernard D, Quatannens B, Vandenbunder B, Abbadie C. Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1. J Biol Chem, 2001; 276(29):27322-273228.
• Ravi R, Bedi GC, Engstrom LW, et al. Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB. Nat Cell Biol. 2001; 3(4): 409-416.
• Wajant H, Moosmayer D, Wüest T, Bartke T, Gerlach E, Schönherr U, et al. Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative. Oncogene, 2001; 20(30):4101-6.
• Sheikh MS, Fornace AJ JR. Death and decoy receptors and p53-mediated apoptosis. Leukemia, 2000; 14(8):1509- 1513.
• Meng RD, McDonald ER 3rd, Sheikh MS, Fornace AJ Jr, El-Deiry WS. The TRAIL decoy receptor TRUNDD (DcR2, TRAIL- R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. Mol Ther, 2000; 1(2):130-144.
• Song K, Chen Y, Göke R, Wilmen A, Seidel C, Göke A et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med. 2000; 191(7): 1095-1104.
• Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, Peschon J, Chen YH. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/- mice. Nat Immunol. 2003; 4(3): 255-260.
• Oligino T, Ghivizzani S, Wolfe D, Lechman E, Krisky D, Mi Z, et al. Intra-articular delivery of a herpes simplex virus IL- 1Ra gene vector reduces inflammation in a rabbit model of arthritis. Gene Ther. 1999; 6(10):1713-1720.
• Robinson JP, Ostafe R, Iyengar SN, Rajwa B, Fischer R. Flow cytometry: the next revolution. Cells, 2023; 12(14), 1875.
• Sanlioglu AD, Koksal IT, Ciftcioglu A, Baykara A, Lüleci G, Şanlıoğlu S. Differential expression of TRAIL and its receptors in benign and malignant prostate tissues. J Urol. 2007; 177(1): 359-364.
• Aydin C, Sanlioglu AD, Karacay B, Özbilim G, Dertsiz L, Özbudak Ö, et al. Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells. Hum Gene Ther. 2007;18(1):39-50.
• Terzioglu E, Bisgin A, Sanlioglu AD, Ülker M, Yazısız V, Tüzüner S, et al. Concurrent gene therapy strategies effectively destroy synoviocytes of patients with rheumatoid arthritis. Rheumatology (Oxford). 2007; 46(5):783-789.
• Sanlioglu AD, Koksal IT, Ciftcioglu A, Baykara M, Lüleci G, Şanlıoğlu S. Differential expression of TRAIL and its receptors in benign and malignant prostate tissues. J Urol. 2007; 177(1): 359-364.
• Li JY, Ling YJ, Bao WH, Zhang WN, Han XM, Zheng XC, et al. Exploring the causal relationship between inflammatory cytokines and myasthenia gravis: A two-way Mendelian randomization study. Cytokine, 2025; 186, 156843
• Liu XX, Hsu HC, Tousson A, et al. Mountz JD. CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis. J Clin Invest. 2003; 112(9):1332-1341.
• Lamhamedi-Cherradi, S.E., Zheng SJ, Maguschak KA, Peschon J, Chen YH., Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/- mice. Nat Immunol, 2003; 4:255-60.
• Tsokos GC, Tsokos M. The TRAIL to arthritis. J Clin Invest. 2003; 112(9):1315-1317.
• Koksal IT, Sanlioglu AD, Karacay B, Griffith TS, Şanlıoğlu S. Tumor necrosis factor-related apoptosis inducing ligand-R4 decoy receptor expression is correlated with high Gleason scores, prostate-specific antigen recurrence, and decreased survival in patients with prostate carcinoma. Urol Oncol. 2008; 26(2):158-265.
• Sanlioglu AD, Dirice E, Elpek O, Korcum AF, Özdoğan M, Süleymanlar İ, et al. High TRAIL Death Receptor 4 and Decoy Receptor 2 Expression Correlates With Significant Cell Death in Pancreatic Ductal Adenocarcinoma Patients. Pancreas. 2009; 38(2):154-160.
• Bisgin A, Terzioglu E, Aydin C, Yoldaş B, Yazısız V, Balcı N, et al. TRAIL death receptor-4, decoy receptor-1 and decoy receptor-2 expression on CD8+ T cells correlate with the disease severity in patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2010; 27;11:192.
• Kanatli I, Akkaya B, Uysal H, Kahraman S, Sanlioglu AD. (2017). Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis. Neuromuscular Disorders, 27(2), 128- 135.
• Wendling U. Walczak H, Dörr J, Jaboci C, Weller B, Krammer FP, et al. Expression of TRAIL receptors in human autoreactive and foreign antigen-specific T cells. Cell Death Differ. 2000; 7(7):637-644.