Cytotoxic T-Lymphocyte-Associated Protein 4 Activity and Epstein-Barr Virus Infection in Thalassemia Patients from Najaf Province: A Cross-Sectional Study
DOI:
https://doi.org/10.63939/dkwph612Keywords:
Thalassemia, Epstein–Barr virus, EBV-DNA positivity, soluble CTLA-4, immune checkpoint, PCRAbstract
Background: Immunological dysregulation secondary to the governing chronic disease burden, repetitive blood transfusions, and ongoing antigenic stimulation exposes patients with thalassemia to enhanced risk of viral persistence or reactivation. Soluble cytotoxic T-lymphocyte-associated protein 4 (sCTLA-4), an important marker associated with immune-checkpoints and physiologically regulating T-cell responses, may be may be elevated due to viral persistence or reactivation of virions that are present as free-floating particles in the serum (also known as viremia) of subjects infected by the Epstein-Barr virus Objective: The aim of this study was evaluation of serum soluble CTLA-4 in thalassemia patients positive and negative for EBV-DNA from Najaf province. Methodology: Cross-sectional study of hundred thalassemia patients. EBV DNA was detected by PCR, while the level of serum soluble CTLA-4 was assessed. This study segregated patients to be either EBV-DNA positive or negative. We analyzed the variables such as age distribution, demographics, clinical features, serum sCTLA-4 levels, logistic regression and correlation, ROC curve. Results: EBV DNA was detected in 45 % of patients. Among patients, EBV-DNA was positive in 56.1% of the population aged between 15–30 years, compared with 30.2% in those aged between 5–15 years. In patients with EBV-DNA, serum soluble CTLA-4 levels were significantly higher than in those without it (56.8 ± 14.9 pg/mL vs 34.7 ± 11.2 pg/mL; P<0.01). Serum sCTLA-4 levels were positively associated with EBV-DNA positivity. Results of logistic regression indicated an increased likelihood of
EBV-DNA testing positive with each 10 pg/mL rise in sCTLA-4. In the ROC study, an area under the curve (AUC) of 0.86 was performed well as a strong classifier. Conclusion: Results: The findings showed that EBV-DNA positive was significantly associated with a high level of serum soluble CTLA-4 in thalassemia patients. Further studies are warranted to confirm serum sCTLA-4 as potential biomarker of EBV-induced immune dysregulation disease of thalassemia, together with quantitative profiling for viral load using an appropriate sampling approach and immunophenotyping.
Downloads
References
1. Farmakis D, Porter J, Taher A, Domenica Cappellini M, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation guidelines for the management of transfusion-dependent thalassemia. HemaSphere. 2022;6(8):e732. doi:10.1097/HS9.0000000000000732.
2. Gluba-Brzózka A, Franczyk B, Olszewski R, Rysz J. Pathomechanisms of immunological disturbances in β-thalassemia. Int J Mol Sci. 2021;22(18):9677. doi:10.3390/ijms22189677.
3. Riaz M, Abbas M, Rasool G, Baig IS, Mahmood Z, Munir N, et al. Prevalence of transfusion-transmitted infections in multiple blood transfusion-dependent thalassemic patients in Asia: a systematic review. Int J Immunopathol Pharmacol. 2022;36:03946320221096909. doi:10.1177/03946320221096909.
4. Zhang L, Wang H, Zhang C, et al. Epstein-Barr virus infection and related diseases in immunocompromised patients. Virol J. 2020;17(1):15. doi:10.1186/s12985-020-01293-x.
5. Dietrich S, Niedrig M, Schönborn V, et al. Epstein-Barr virus reactivation and lymphoproliferation in patients with thalassemia. Int J Hematol. 2021;113(4):507-515. doi:10.1007/s12185-020-02961-3.
6. Waki T, Saito M, Izuno Y, et al. Epstein-Barr virus-associated lymphoproliferative disorders in thalassemia patients after bone marrow transplantation: clinical and molecular characterization. J Clin Oncol. 2021;39(11):1397-1405. doi:10.1200/JCO.20.02779.
7. Wang F, Wu D, Zhou H, et al. Lymphoproliferative disorders and EBV reactivation in patients with thalassemia after hematopoietic stem cell transplantation. Blood Adv. 2020;4(6):1075-1083. doi:10.1182/bloodadvances.2019001294.
8. Papaevangelou G, Karabula C, Tsevrenis H, Kallinikos G. Epstein-Barr virus infection in polytransfused patients with homozygous beta-thalassaemia. Vox Sang. 1979;37(5):305-309. doi:10.1111/j.1423-0410.1979.tb02309.x.
9. Al Taie AA, Ibraheem MA, Fadhil KB. Epstein-Barr virus infection in thalassemia patients related to blood group in Mosul/Iraq. Ann Trop Med Public Health. 2019;22(8):136-145. doi:10.36295/ASRO.2019.220815.
10. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/blood-2017-06-741033.
11. Dahal LN, Basu N, Youssef H, Khanolkar RC, Barker RN, Erwig LP, et al. Immunoregulatory soluble CTLA-4 modifies effector T-cell responses in systemic lupus erythematosus. Arthritis Res Ther. 2016;18:180. doi:10.1186/s13075-016-1075-1.
12. Wang Y, Zhang L, Zhang J, et al. Soluble CTLA-4 levels as a biomarker of immune suppression in viral infections. Clin Immunol. 2017;183:64-72. doi:10.1016/j.clim.2017.07.006.
13. Figueroa-Vega N, Guarner-Argáez V, Sanchez M, et al. The role of soluble CTLA-4 in chronic viral infections. Immunol Lett. 2021;236:26-35. doi:10.1016/j.imlet.2021.01.008.
14. Hwang S, Seo H, Kim Y, et al. Impact of soluble CTLA-4 on immune dysregulation and viral reactivation in immunocompromised patients. J Immunol Res. 2019;2019:6483290. doi:10.1155/2019/6483290.
15. Mandrekar JN. Receiver operating characteristic curve in diagnostic test assessment. J Thorac Oncol. 2010;5(9):1315-1316. doi:10.1097/JTO.0b013e3181ec173d.
16. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: biology and clinical disease. Cell. 2022;185(20):3652-3670. doi:10.1016/j.cell.2022.08.026.
17. Dowd JB, Palermo T, Brite J, McDade TW, Aiello A. Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6–19, 2003–2010. PLoS One. 2013;8(5):e64921. doi:10.1371/journal.pone.0064921.
18. Centers for Disease Control and Prevention. Laboratory testing for Epstein-Barr virus. Atlanta: CDC; 2024.
19. ARUP Consult. Epstein-Barr virus — EBV: choose the right test. Salt Lake City: ARUP Laboratories; 2025.
20. Papaevangelou G, Karabula C, Tsevrenis H, Kallinikos G. Epstein-Barr virus infection in polytransfused patients with homozygous beta-thalassaemia. Vox Sang. 1979;37(5):305-309. doi:10.1111/j.1423-0410.1979.tb02309.x.
21. Al Taie AA, Ibraheem MA, Fadhil KB. Epstein-Barr virus infection in thalassemia patients related to blood group in Mosul/Iraq. Ann Trop Med Public Health. 2019;22(8):136-145. doi:10.36295/ASRO.2019.220815.
22. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/blood-2017-06-741033.
23. Dahal LN, Basu N, Youssef H, Khanolkar RC, Barker RN, Erwig LP, et al. Immunoregulatory soluble CTLA-4 modifies effector T-cell responses in systemic lupus erythematosus. Arthritis Res Ther. 2016;18:180. doi:10.1186/s13075-016-1075-1.
24. Grywalska E, Mielnik M, Podgajna M, Hymos A, Ludian J, Rolińska A, et al. Expression of CTLA-4 and CD86 antigens and Epstein-Barr virus reactivation in chronic lymphocytic leukemia—any link with known prognostic factors? Cancers. 2022;14(3):672. doi:10.3390/cancers14030672.
25. Mertowska P, Mertowski S, Smolak K, et al. Could immune checkpoint disorders and EBV reactivation be connected in the development of hematological malignancies in immunodeficient patients? Cancers. 2023;15(19):4786. doi:10.3390/cancers15194786.
26. Ma SD, Xu X, Jones R, Delecluse HJ, Zumwalde NA, Sharma A, et al. PD-1/CTLA-4 blockade inhibits Epstein-Barr virus-induced lymphoma growth in a cord blood humanized-mouse model. PLoS Pathog. 2016;12(5):e1005642. doi:10.1371/journal.ppat.1005642.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Journal of Progressive Medical Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
