Document Type : Research articles
Authors
- Jila Masrour-Roudsari 1
- Mohammad Reza Hasanjani Roushan 2
- Yousef Yahyapour 2
- Rahim Barari Savadkoohi 2
- Ali Bijani 3
- Mousa Mohammadnia-Afrouzi 4
1 1- Student Research Committee, Babol University of Medical Sciences, Babol, Iran 2- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
2 Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
3 Social Determinants Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
4 1- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran 2- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
Abstract
Background: Hepatitis B is a viral disease that can be chronic. The Treg population during hepatitis appears to have an important role in controlling disease progression.
Objectives: The present study aimed to determine the level of Tregs in patients with chronic hepatitis B (CHB) at different stages of the disease.
Methods: This study was carried out on 90 patients with CHB followed-up for an average of 10 years and divided into hepatitis B surface antigen (HBs Ag+), seroconverted (HBs Ag- and hepatitis B surface antibody [HBs Ab+]), and serocleared (HBs Ag- and HBs Ab-) groups. Then, 5 ml of the blood sample was taken, and the peripheral blood mononuclear cells (PBMCs) were separated using Ficoll. The surface markers, including CD4, CD25, and CD127, and FoxP3 intracellular marker were measured in the PBMCs. Isotype was considered the control for each sample. The samples were read by the FACSCalibur 4-color flow cytometer (BD Biosciences, San Jose, CA, USA) and analyzed using FlowJo software (version 7.6.1). The levels of aspartate aminotransferase, alanine transaminase, ?-fetoprotein, platelets, white blood cells, and hemoglobin were extracted from the patients records.
Results: The mean age values of the HBs Ag+ (n=35), seroclearance (n=27), and seroconversion (n=28) groups were 43.97±11.86, 47.26±12.95, and 47.39±10.40 years, respectively. The frequency of CD4+ CD25+ FoxP3+ (Treg) was higher in the HBs Ag+ group than that reported for the other two groups. The Treg population demonstrated a significant difference between the serocleared and seroconverted groups; however, the Treg frequency was higher in the seroconverted group in comparison to that of the other two groups. The Treg/T-Activator ratio was significantly higher in the HBs Ag+ group than those reported for the two other groups.
Conclusion: CD4+ CD25+ FoxP3+ T cells are the important subgroups of Treg cells affecting immune suppression.
Keywords
- De Clercq E, Férir G, Kaptein S, Neyts J. Antiviral treatment of chronic hepatitis b virus (HBV) infections. Viruses. 2010;2(6):1279-305. doi: 10.3390/v2061279.
- Uyar Y, Cabar C, Balci A. Eroprevalence of hepatitis B virus among pregnant women in Northern Turkey. Hapat Mon. 2009;9(2):146-9.
- Mohammadizad H, Shahbazi M, Hasanjani Roushan MR, Soltanzadeh-Yamchi M, Mohammadnia-Afrouzi M. TIM-3 as a marker of exhaustion in CD8+ T cells of active chronic hepatitis B patients. Microb Pathog. 2019;128:323-8. doi: 10.1016/j.micpath.2019.01.026. [PubMed: 30660734].
- Xue-Song L, Cheng-Zhong L, Ying Z, Mo-Bin W. Changes of Treg and Th17 cells balance in the development of acute and chronic hepatitis B virus infection. BMC Gastroenterol.2012;12:43. doi: 10.1186/1471-230X-12-43. [PubMed: 22548790].
- Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, et al. IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 2012;122(2):529-37. doi: 10.1172/JCI58847. [PubMed: 22251702].
- Cai D, Mills C, Yu W, Yan R, Aldrich CE, Saputelli JR, et al. Identification of disubstituted sulfonamide Compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation. Antimicrob Agents Chemother. 2012;56(8):4277–88. doi: 10.1128/AAC.00473-12. [PubMed: 22644022].
- Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343(6176):1221-8. doi: 10.1126/science.1243462. [PubMed: 24557838].
- Tavakolpour S. Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients. Immunol Lett. 2016;171:70-1. doi: 10.1016/j.imlet.2015.12.007. [PubMed: 26730847].
- Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis. 2015;6:e1694. doi: 10.038/cddis.2015.42. [PubMed: 25789969].
- Aalaei-Andabili SH, Alavian SM. Regulatory T cells are the most important determinant factor of hepatitis B infection prognosis: A systematic review and meta-analysis. Vaccine. 2012;30:5595-602. doi: 10.1016/j.vaccine.2012.06.063. [PubMed: 22781305].
- Peng G, Li S, Wu W, Sun Z, Chen Y, Chen Z. Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection. Immunology. 2008;123(57-65). doi: 10.1111/j.1365-2567.2007.02691.x. [PubMed: 17764450].
- Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005;41(4):771-8. doi: 10.1002/hep.20649. [PubMed: 15791617].
- TrehanPati N, Kotillil S, Hissar SS, Shrivastava S, Khanam A, Sukriti S, et al. Circulating Tregs correlate with viral load reduction in chronic HBV-treated patients with tenofovir disoproxil fumarate. J Clin Immunol. 2011;31(509-20). doi: 10.1007/s10875-011-9509-7. [PubMed: 21305387].
- Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis 2007;7(12):804-13. doi: 10.1016/S1473-3099(07)70289-X. [PubMed: 18045563].
- Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 2006;177(1):739-47. doi: 10.4049/jimmunol.177.1.739.[PubMed: 16785573].
- Wang R, Xie R,. Circulating regulatory Tfh cells are enriched in patients with chronic hepatitis B infection and induce the differentiation of regulatory B cells. Exp Cell Res. 2018;365(2):171-6. doi: 10.1016/j.yexcr.2018.02.031. [PubMed: 29501568].
- Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41(4):529-42. doi: 10.1016/j.immuni.2014.10.004. [PubMed: 25367570].
- Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, et al. International AIDS vaccine initiative protocol C principal, investigators PP, shane crotty. human circulating PD-1+CXCR3−CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758-69. doi: 10.1016/j.immuni.2013.08.031.
- Jung MK, Shin EC. Regulatory T cells in hepatitis B and C virus infections. Immun Netw. 2016;16(6):330-6. doi: 10.4110/in.2016.16.6.330. [PubMed: 28035208].
- El-Badawy O, Sayed D, Badary MS, Abd-Alrahman ME, El-Feky MA, Thabit AG. Relations of regulatory T cells with hepatitis markers in chronic hepatitis B virus infection. Human Immunol. 2012;73(4):335-41. doi: 10.1016/j.humimm.2012.01.014. [PubMed: 22342871].
- Dietze KK, Schimmer S, Kretzmer F, Wang J, Lin Y, Huang X, et al. Characterization of the treg response in the hepatitis B virus hydrodynamic injection mouse model. PLoS One. 2016;11(3)e0151717. doi: 10.1371/journal.pone.0151717. [PubMed: 26986976].
- Hasanjani RM, Bayani M, Soleimani AS, Mohammadnia-Afrouzi M, Nouri HR, Ebrahimpour S. Evaluation of CD4+CD25+foxp3+ regulatory T cells during treatment of patients with brucellosis. J Biol Regul Homeost Agents. 2016;30(3):675-82. [PubMed: 27655484].
- Kosinska AD, Pishraft‐Sabet L, Wu W, Fang Z, Lenart M, Chen J, et al. Low hepatitis B virus–specific t-cell response in males correlates with high regulatory T-cell numbers in murine models. Hepatology. 2017;66(1):69-83. doi: 10.1002/hep.29155. [PubMed: 28295453].
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