Abstract
Vaccination is the most effective way to prevent Hepatitis B (HB) infection. The goal of vaccination is to induce immunological memory. Hence, determining the frequency of memory B-cell (MBC) subsets is an important indicator of vaccine efficacy. This study aimed to evaluate the frequency of different B-cell subpopulations and the expression of PD-1 on B-cell subsets in low responders (LR) and high responders (HR) to HB vaccine. According to our findings, the expression level of PD-1 was significantly higher on atypical MBC (atMBC) than that of naive B cell and classical MBC (cMBC) in LR and HR groups. Moreover, cMBCs had a significant higher PD-1 expression than naive B cells in LR group. No significant differences were found in the frequency of various B-cell subpopulations and the expression level of PD-1 on B-cell subsets between LR and HR groups. We observed a negative correlation between age and HBsAb titer and a positive correlation between age and PD-1 expression level on cMBC in LR group. It can be concluded that inadequate specific memory B-cell response, rather than total memory B-cell deficiency, may be implicated in low responsive rate to HB vaccine in healthy individuals.
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References
Lai A, Sagnelli C, Lo Presti A, Cella E, Angeletti S, Spoto S et al (2018) What is changed in HBV molecular epidemiology in Italy? J Med Virol 90(5):786–795. https://doi.org/10.1002/jmv.25027
Chemin I, Pujol FH (2022) Special issue: “updates on HBV infection”. Microorganisms 10(3): 580. https://doi.org/10.3390/microorganisms10030580
Kumar M, Pahuja S, Khare P, Kumar A (2023) Current challenges and future perspectives of diagnosis of hepatitis B virus. Diagnostics (Basel) 13(3): 368. https://doi.org/10.3390/diagnostics13030368.
Stasi C, Silvestri C, Voller F (2017) Emerging trends in epidemiology of hepatitis B virus infection. J Clin Transl Hepatol 5(3):272. https://doi.org/10.14218/JCTH.2017.00010
Doedée A, Kannegieter N, Öztürk K, van Loveren H, Janssen R, Buisman A-M (2016) Higher numbers of memory B-cells and Th2-cytokine skewing in high responders to hepatitis B vaccination. Vaccine 34(19):2281–2289. https://doi.org/10.1016/j.vaccine.2015.12.027
Borzooy Z, Streinu-Cercel A, Mirshafiey A, Khamseh A, Mahmoudie MK, Navabi SS et al (2016) IL-17 and IL-22 genetic polymorphisms in HBV vaccine non-and low-responders among healthcare workers. Germs 6(1):14. https://doi.org/10.11599/germs.2016.1084
Kao J-H (2015) Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29(6):907–917. https://doi.org/10.1016/j.bpg.2015.09.011
Hummel IB, Zitzmann A, Erl M, Wenzel JJ, Jilg W (2016) Characteristics of immune memory 10–15 years after primary hepatitis B vaccination. Vaccine 34(5):636–642. https://doi.org/10.1016/j.vaccine.2015.12.033
Seifert M, Küppers R (2016) Human memory B cells. Leukemia 30(12):2283–2292. https://doi.org/10.1038/leu.2016.226
Sebina I, Pepper M (2018) Humoral immune responses to infection: common mechanisms and unique strategies to combat pathogen immune evasion tactics. Curr Opin Immunol 51:46–54. https://doi.org/10.1016/j.coi.2018.02.001
Peeridogaheh H, Meshkat Z, Habibzadeh S, Arzanlou M, Shahi JM, Rostami S et al (2018) Current concepts on immunopathogenesis of hepatitis B virus infection. Virus Res 245:29–43. https://doi.org/10.1016/j.virusres.2017.12.007
Bertoletti A, Ferrari C (2016) Adaptive immunity in HBV infection. J Hepatol 64(1):S71–S83. https://doi.org/10.1016/j.jhep.2016.01.026
Kusumoto S, Tanaka Y, Ueda R, Mizokami M (2011) Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy. J Gastroenterol 46(1):9–16. https://doi.org/10.1007/s00535-010-0331-4
Imkeller K, Wardemann H (2018) Assessing human B cell repertoire diversity and convergence. Immunol Rev 284(1):51–66. https://doi.org/10.1111/imr.12670
Illingworth J, Butler NS, Roetynck S, Mwacharo J, Pierce SK, Bejon P et al (2013) Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J Immunol 190(3):1038–1047. https://doi.org/10.4049/jimmunol.1202438
Hu Z, Luo Z, Wan Z, Wu H, Li W, Zhang T et al (2015) HIV-associated memory B cell perturbations. Vaccine 33(22):2524–2529. https://doi.org/10.1016/j.vaccine.2015.04.008
Salimzadeh L, Le Bert N, Dutertre C-A, Gill US, Newell EW, Frey C et al (2018) PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Investig 128(10):4573–4587. https://doi.org/10.1172/JCI121957
Rath S, Devey M (1988) IgG subclass composition of antibodies to HBsAg in circulating immune complexes from patients with hepatitis B virus infections. Clin Exp Immunol 72(1):164–167
Pupovac A, Good-Jacobson KL (2017) An antigen to remember: regulation of B cell memory in health and disease. Curr Opin Immunol 45:89–96. https://doi.org/10.1016/j.coi.2017.03.004
Portugal S, Obeng-Adjei N, Moir S, Crompton PD, Pierce SK (2017) Atypical memory B cells in human chronic infectious diseases: an interim report. Cell Immunol 321:18–25. https://doi.org/10.1016/j.cellimm.2017.07.003
Akkaya M, Kwak K, Pierce SK (2020) B cell memory: building two walls of protection against pathogens. Nat Rev Immunol 20(4):229–238. https://doi.org/10.1038/s41577-019-0244-2
Burton AR, Maini MK (2021) Human antiviral B cell responses: emerging lessons from hepatitis B and COVID-19. Immunol Rev 299(1):108–117. https://doi.org/10.1111/imr.12953
Milich DR, Leroux-Roels GG (2003) Immunogenetics of the response to HBsAg vaccination. Autoimmun Rev 2(5):248–257. https://doi.org/10.1016/s1568-9972(03)00031-4
Rosado MM, Scarsella M, Pandolfi E, Cascioli S, Giorda E, Chionne P et al (2011) Switched memory B cells maintain specific memory independently of serum antibodies: the hepatitis B example. Eur J Immunol 41(6):1800–1808. https://doi.org/10.1002/eji.201041187
Shokrgozar MA, Mahmoodzadeh-Niknam H, Shokri F (2002) Distribution of circulating immune cells in responder and non-responder individuals to hepatitis B vaccine. Iran Biomed J 6(1):1–5
Shokrgozar MA, Shokri F (2001) Enumeration of hepatitis B surface antigen-specific B lymphocytes in responder and non-responder normal individuals vaccinated with recombinant hepatitis B surface antigen. Immunology 104(1):75–79. https://doi.org/10.1046/j.1365-2567.2001.01273.x
Lømo J, Blomhoff HK, Jacobsen SE, Krajewski S, Reed JC, Smeland EB (1997) Interleukin-13 in combination with CD40 ligand potently inhibits apoptosis in human B lymphocytes: upregulation of Bcl-xL and Mcl-1. Blood J Am Soc Hematol 89(12):4415–4424
Doi H, Yoshio S, Yoneyama K, Kawai H, Sakamoto Y, Shimagaki T, et al (2019) Immune determinants in the acquisition and maintenance of antibody to hepatitis B surface antigen in adults after first‐time hepatitis B vaccination. Hepatol Commun 3(6): 812–824. https://doi.org/10.1002/hep4.1357
Tsai Y-F, Yang C-I, Du J-S, Lin M-H, Tang S-H, Wang H-C et al (2019) Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study. PeerJ 7: e7481. https://doi.org/10.7717/peerj.7481
Garner-Spitzer E, Wagner A, Paulke-Korinek M, Kollaritsch H, Heinz FX, Redlberger-Fritz M et al (2013) Tick-borne encephalitis (TBE) and hepatitis B nonresponders feature different immunologic mechanisms in response to TBE and influenza vaccination with involvement of regulatory T and B cells and IL-10. J Immunol 191(5):2426–2436. https://doi.org/10.4049/jimmunol.1300293
Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L et al (2018) Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Investig 128(10):4588–4603. https://doi.org/10.1172/JCI121960
Knox JJ, Buggert M, Kardava L, Seaton KE, Eller MA, Canaday DH, et al (2017) T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response. JCI Insight 2(8). https://doi.org/10.1172/jci.insight.92943
Jubel JM, Barbati ZR, Burger C, Wirtz DC, Schildberg FA (2020) The role of PD-1 in acute and chronic infection. Front Immunol 11:487. https://doi.org/10.3389/fimmu.2020.00487
Amu S, Lavy-Shahaf G, Cagigi A, Hejdeman B, Nozza S, Lopalco L et al (2014) Frequency and phenotype of B cell subpopulations in young and aged HIV-1 infected patients receiving ART. Retrovirology 11(1):1–13. https://doi.org/10.1186/s12977-014-0076-x
Wilson JK, Zhao Y, Singer M, Spencer J, Shankar-Hari M (2018) Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis-pilot study. Crit Care 22(1):1–7. https://doi.org/10.1186/s13054-018-2020-2
Lu Y, Zhu Q, Li Y, Wang Q, Jiang C, Li Z et al (2020) Aberrant expression of PD-1 on B cells and its association with the clinical parameters of systemic lupus erythematosus. https://doi.org/10.21203/rs.2.17942/v2
Poonia B, Ayithan N, Nandi M, Masur H, Kottilil S (2018) HBV induces inhibitory FcRL receptor on B cells and dysregulates B cell-T follicular helper cell axis. Sci Rep 8(1):1–14. https://doi.org/10.1038/s41598-018-33719-x
Thibult M-L, Mamessier E, Gertner-Dardenne J, Pastor S, Just-Landi S, Xerri L et al (2013) PD-1 is a novel regulator of human B-cell activation. Int Immunol 25(2):129–137. https://doi.org/10.1093/intimm/dxs098
Roe K, Shu GL, Draves KE, Giordano D, Pepper M, Clark EA (2019) Targeting antigens to CD180 but not CD40 programs immature and mature B cell subsets to become efficient APCs. J Immunol 203(7):1715–1729. https://doi.org/10.4049/jimmunol.1900549
Chung JB, Silverman M, Monroe JG (2003) Transitional B cells: step by step towards immune competence. Trends Immunol 24(6):342–348. https://doi.org/10.1016/s1471-4906(03)00119-4
Perez-Andres M, Paiva B, Nieto WG, Caraux A, Schmitz A, Almeida J et al (2010) Human peripheral blood B-cell compartments: a crossroad in B-cell traffic. Cytometry B Clin Cytom 78(S1):S47–S60. https://doi.org/10.1002/cyto.b.20547
Weinberg A, Lindsey J, Bosch R, Persaud D, Sato P, Ogwu A et al (2018) B and T cell phenotypic profiles of African HIV-infected and HIV-exposed uninfected infants: associations with antibody responses to the pentavalent rotavirus vaccine. Front Immunol 8:2002. https://doi.org/10.3389/fimmu.2017.02002
Schmidlin H, Diehl SA, Blom B (2009) New insights into the regulation of human B-cell differentiation. Trends Immunol 30(6):277–285. https://doi.org/10.1016/j.it.2009.03.008
Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB (2019) Immunosenescence and human vaccine immune responses. Immun Ageing 16(1):1–16. https://doi.org/10.1186/s12979-019-0164-9
Notarte KI, Ver AT, Velasco JV, Pastrana A, Catahay JA, Salvagno GL et al (2021) Effects of age, sex, serostatus and underlying comorbidities on humoral response post-SARS-CoV-2 Pfizer-BioNTech vaccination: a systematic review. medRxiv. https://doi.org/10.1080/10408363.2022.2038539
Müller L, Andrée M, Moskorz W, Drexler I, Walotka L, Grothmann R et al (2021) Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination. MedRxiv. https://doi.org/10.1093/cid/ciab381
Colonna-Romano G, Bulati M, Aquino A, Pellicano M, Vitello S, Lio D et al (2009) A double-negative (IgD− CD27−) B cell population is increased in the peripheral blood of elderly people. Mech Ageing Dev 130(10):681–690. https://doi.org/10.1016/j.mad.2009.08.003
Dunn-Walters DK, Stewart AT, Sinclair EL, Serangeli I (2020) Age-related changes in B cells relevant to vaccine responses. Interdiscip Top Gerontol Geriatr 43:56–72. https://doi.org/10.1159/000504479
Ubillos I, Campo JJ, Requena P, Ome-Kaius M, Hanieh S, Rose H et al (2017) Chronic exposure to malaria is associated with inhibitory and activation markers on atypical memory B cells and marginal zone-like B cells. Front Immunol 8:966. https://doi.org/10.3389/fimmu.2017.00966
Yang S, Tian G, Cui Y, Ding C, Deng M, Yu C et al (2016) Factors influencing immunologic response to hepatitis B vaccine in adults. Sci Rep 6(1):1–12. https://doi.org/10.1038/srep27251
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This study was a part of MSc project of Zahra Saleh, Department of Immunology Shiraz University of Medical Sciences and was financially supported by Shiraz University of Medical Sciences (Grant no 21740).
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KK designed the project, ZS performed the experiments, analyzed the data, prepared all figures and tables, and wrote the manuscript; KK, FM, MA, MH, and DK reviewed and edited the manuscript. All authors have read and approved the final paper.
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Saleh, Z., Mehdipour, F., Ataollahi, M.R. et al. Frequency of B-Cell Subpopulations in Low Responders in Comparison with High Responders to Hepatitis B Vaccine Among Health Care Workers. Curr Microbiol 80, 296 (2023). https://doi.org/10.1007/s00284-023-03367-0
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DOI: https://doi.org/10.1007/s00284-023-03367-0