Assessment of cytotoxic T-lymphocyte antigen-4 (CD152) Levels Associated with HBV in Patients with Diabetes Mellitus
Main Article Content
Abstract
Background: Diabetes mellitus is a chronic disease characterized by an imbalance in glucose homeostasis. The hepatitis B virus is a liver-attacking virus that can cause viral hepatitis, cirrhosis, and liver cancer. A cytotoxic T-lymphocyte antigen-4 called CTLA-4 is an immune checkpoint protein that is necessary for T cells to control immune responses and stop the HBV infection from spreading. It does this by acting as an inhibitory receptor, limiting liver damage during an acute infection, and making it easier for the infection to stay in the body during a chronic case.
Objective: The study aims to assess CTLA-4 levels in relation to HBV infection in diabetes mellitus patients.
Subjects and methods: A cross-sectional study was conducted from July to October 2023. The serum was obtained from 200 diabetic patients who were Iraqis. All of the patients were tested using an ELISA technique for CTLA-4 and HBc IgG. They were tested using a five-panel kit for HBsAb, HBsAg, HBcAb, HBeAg, and HBeAb and measured blood sugar levels. The statistical analysis approach was conducted using SPSS version 26.
Results: Serum CTLA-4 levels were correlated with serum HBc IgG positivity (P = 0.000), total HBc Ab positivity (P = 0.000), and HBs Ab positivity (P = 0.000), and CTLA-4 level was correlated with diabetes mellitus (P = 0.034).
Conclusions: The study concluded that elevated serum CTLA-4 levels in diabetic patients with HBV infection and type I diabetes compared to type II diabetes. This suggests that diabetes affects the immune system's response to HBV.
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References
I. Rachdaoui, N. Insulin: the friend and the foe in the development of type 2 diabetes mellitus. International journal of molecular sciences.2020; 21(5): 1–21.
II. Aghaei Zarch SM, Dehghan Tezerjani M, Talebi M, Vahidi Mehrjardi MY. Molecular biomarkers in diabetes mellitus (DM). Med J Islam Repub Iran. Apr, 2020,1;34:28.
III. Liu Z, Song Z, Sun J, Sun F, Li C, Sun J, Xu L. Association between CTLA-4 rs231775 polymorphism and hepatocellular carcinoma susceptibility. Int J Clin Exp Pathol. Nov, 2015, 1;8(11):15118-22.
IV. Zheng, J. R., Wang, Z. L., & Feng, B. Hepatitis B functional cure and immune response. Frontiers in Immunology.2022; 13, 1075916.
V. Lazarevic, I., Banko, A., Miljanovic, D., & Cupic, M. Clinical Utility of Quantitative HBV Core Antibodies for Solving Diagnostic Dilemmas. Viruses . 2023;15(2), 373.
VI. Cholongitas E, Haidich AB, Apostolidou-Kiouti F, Chalevas P, Papatheodoridis GV. Hepatitis B virus reactivation in HBsAg-negative, anti-HBc-positive patients receiving immunosuppressive therapy: a systematic review. Ann Gastroenterol. Jul-Aug, 2018; 31(4):480-490.
VII. Raimondo, G.; Locarnini, S.; Pollicino, T.; Levrero, M.; Zoulim, F.; Lok, A.S.;et al. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J. Hepatol. 2019, 71(2), 397–408.
VIII. Raimondo, G., Allain, J. P., Brunetto, M. R., Buendia, M. A., Chen, D. S., Colombo, M., et al .Statements from the Taormina expert meeting on occult hepatitis B virus infection. Journal of hepatology, 2008, 49(4), 652-657.
IX. Park, J. J., Wong, D. K., Wahed, A. S., Lee, W. M., Feld, J. J., Terrault, N.,et al . Hepatitis B virus–specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology, 2016; 150 (3), 684-695.
X. Zoulim F, Durantel D. Antiviral therapies and prospects for a cure of chronic hepatitis B. Cold Spring Harb Perspect Med. Apr, 2015, 1;5(4):a021501.
XI. Wang L, Li N, Fan X, Wang X, Zhang X, Zhang K,et al. Circulating CTLA-4 levels and CTLA4 polymorphism associate with disease condition and progession and hepatocellular carcinoma patients’ survival in chronic hepatitis B virus infection. Int Immunopharmacol. 2020; 82:106377.
XII. Ye, B., Liu, X., Li, X. et al. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis (2015).6, e1694.
XIII. Wagner MJ, Othus M, Patel SP, Ryan, C., Sangal, A., Powers, et al. Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). Journal for Immunotherapy of Cance r. 2021; 9(8) , e002990.
XIV. Bertoletti, A., & Ferrari, C. Adaptive immunity in HBV infection. Journal of hepatology.2016; 64(1), S71-S83.
XV. Wykes, M. N., & Lewin, S. R. Immune checkpoint blockade in infectious diseases. Nature Reviews Immunology (2018); 18(2), 91-104.
XVI. Sato S, Fujimoto M, Hasegawa M, et al. Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis. Rheumatology.2004 , 43(10):1261–1266.
XVII. Ryden A, Bolmeson C, Jonson CO, Cilio CM, Faresjo M. Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from type 1 diabetic children. Diabetes Metab Res Rev.2012, 28:84–96.
XVIII. Alshareef SA, Omar SM, Hamdan HZ, and Adam I. Cytotoxic T lymphocyte antigen 4 +49A/G polymorphisms in Sudanese adults with type 1 diabetes and latent autoimmune diabetes. BMC Res Notes. 2019;12:769.
XIX. Clark M, Kroger CJ, Tisch RM.Type 1 diabetes: a chronic anti-Self-Inflammatory response. Front Immunol .2017, 8:1898.
XX. Ren, D., He, L., & Pang, X. Association of CLTA-4 Gene Polymorphisms with Diabetes Mellitus: A Study Based on the Han Population of Northern China. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2022; 2705-2712.
XXI. Schott, E., Witt, H., Hinrichsen, H., Neumann, K., Weich, V., Bergk, A., Halangk, J., Müller, T., Tinjala, S., Puhl, G., Neuhaus, P., Wiedenmann, B., & Berg, T. Gender-dependent association of CTLA4 polymorphisms with resolution of hepatitis C virus infection. Journal of hepatology. 2007, 46(3), 372–380.
XXII. Canaday, D. H., Parker, K. E., Aung, H., Chen, H. E., Nunez-Medina, D., & Burant, C. J. Age-dependent changes in the expression of regulatory cell surface ligands in activated human T-cells. BMC immunology, (2013).14, 1-5.
XXIII. Al-Hakami A. Serum sCTLA-4 level is not associated with type 1 diabetes or the coexistence of autoantibodies in children and adolescent patients from the southern region of Saudi Arabia. Auto- immunity highlights. 2020; 11 (1), 19.
XXIV. Cao, H., Zhang, R., & Zhang, W. CTLA‑4 interferes with the HBV‑specific T cell immune response. International Journal of Molecular Medicine.2018; 42(2), 703-712.
XXV. Arrelias CCA, Rodrigues FB,Torquato MTDCG, Teixeira CRS, Rodrigues FFL, Zanetti ML. Prevalence of serological markers for hepatitis and potential associated factors in patients with diabetes mellitus. Rev Lat Am Enfermagem. Nov, 2018, 29; 26:e3085.
XXVI. Caviglia, G. P., Olivero, A., Ciancio, A., Tandoi, F., Troshina, G., Rosso, C et al ., Analytical and clinical evaluation of a novel assay for anti-HBc IgG measurement in serum of subjects with overt and occult HBV infection. Diagnostic Microbiology and Infectious Disease (2020), 96(4), 114985.
XXVII. Yan L, Zhang H, Ma H, Liu D, Li W, Kang Y, et al. Deep sequencing of hepatitis B virus basal core promoter and precore mutants in HBeAg-positive chronic hepatitis B patients. Sci Rep. 2015;5:17950.
XXVIII. Pollicino, T., and Caminiti, G. HBV-integration studies in the clinic: role in the natural history of infection. Viruses (2021),13 (3), 368.
XXIX. Wang C, Xue R, Wang X, Xiao L and Xian J High-sensitivity HBV DNA test for the diagnosis of occult HBV infection: commonly used but not reliable. Front. Cell. Infect. Microbiol (2023),13:1186877.
XXX. Lu J, Hou X, Tu H, Tang Z, Xiang Y, Bao Y, et al. Chronic hepatitis B virus infection status is more prevalent in patients with type 2 diabetes. J Diabetes Investig (2017): 8(4):619–625.
XXXI. Ndako JA, Nwankiti OO, Olorundare JO, Ojo SKS, Okolie CE, Olatinsu O, Dojumo VT. Studies on the serological markers for hepatitis B virus infection among type 2 diabetic patients. J Clin Lab Anal. Jan; 2021: 35(1):e23464.
XXXII. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patient's recovery from acute viral hepatitis despite active maintenance of a cytotoxic T‐lymphocyte response. Nat Med Journal, 1996: 2:1104‐1108.
XXXIII. Madhava n A, Sachu A, Balakrishnan AK, Balakrishnan S, Vasudevapanicker J. Prevalence of Anti-HBc Antibodies among HBsAg Negative Individuals and Its Association with Occult Hepatitis B. J Lab Physicians. Mar. 2021:13(1):1-5.
XXXIV. Liu Y, Cheng LS, Wu SD, Wang SQ, Li L, She WM, Li J, Wang JY and Jiang W.IL‑10‑producing regulatory B‑cells suppressed effector T‑cells but enhanced regulatory T‑cells in chronic HBV infection. Clin Sci (2016):130: 907‑919.
XXXV. Darmadi D, Lindarto D, Siregar J, Widyawati T, Rusda M, Amin MM, et al.Association Between Serum Cytotoxic T Lymphocyte Antigen (CTLA)-4 Level and Disease Progression in Patients With Chronic Hepatitis B. Med Arch. Apr; 2023,77(2):142-145.
XXXVI. Zhang, H., Wang, Z., Zhang, J., Zhang, X., Gui, Z., Sun, L. & Gu, M. The synergism of B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) attenuated acute T-cell mediated rejection and prolonged renal graft survival. Translational Andrology and Urology, (2020): 9(5), 1990.
XXXVII. Tang ZS, Hao YH, Zhang EJ, Xu CL, Zhou Y, Zheng X and Yang DL: CD28 family of receptors on T cells in chronic HBV infection: Expression characteristics, clinical significance and correlations with PD‑1 blockade. Mol Med Rep (2016) .14: 1107‑1116.
XXXVIII. Peng G, Luo B, Li J, Zhaod, Wu W, chen F;et al. Hepatitis B e‑antigen persistency is associated with the properties of HBV‑specific CD8 T cells in CHB patients. J Clin Immunol . 2011; 31, 195‑204.