Skip to main content
PMC home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1986 Dec;66(3):497–506.

Selective sensitization of peripheral blood T lymphocytes to hepatitis B core antigen in patients with chronic active hepatitis type B.

C Ferrari, A Penna, P Sansoni, T Giuberti, T M Neri, F V Chisari, F Fiaccadori
PMCID: PMC1542471  PMID: 3494552

Abstract

The proliferative response of peripheral blood T cells to hepatitis B surface antigen (HBsAg), pre-S antigen and hepatitis B core antigen (HBcAg) has been studied in 20 patients with hepatitis B virus induced chronic active hepatitis (CAH) and in 12 control subjects. Eleven of the 20 CAH patients showed a significant T lymphocyte proliferative response to HBcAg, whereas no proliferation was detectable in response to envelope antigens (HBs and pre-S) in any patient. T cell subset fractionation revealed that HBcAg specific proliferation was limited to the CD4+ (helper/inducer) population. CD8+ (suppressor/cytotoxic) T cells were unresponsive to HBcAg and did not suppress the proliferative response of autologous CD4+ cells. The HBcAg specific T cell proliferative response did not correlate with serum anti-core antibody titres or with biochemical evidence of liver disease. The present results show the selective presence of HBcAg-sensitized T cells in the peripheral blood of patients with HBsAg positive CAH and suggest that the peripheral lymphoid compartment may not reflect immunopathogenetically important cellular events operative at the site of tissue injury.

Full text

PDF
497

Images in this article

499Fig. 1
on p.499

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aldershvile J., Dietrichson O., Hardt F., Nielsen J. O., Skinhöj P. Humoral and cell-mediated immunity to hepatitis B virus antigens in acute and chronic liver disease. Scand J Gastroenterol. 1977;12(8):917–922. doi: 10.3109/00365527709181350. [DOI] [PubMed] [Google Scholar]
  2. Alexander G. J., Nouri-Aria K. T., Eddleston A. L., Williams R. Contrasting relations between suppressor-cell function and suppressor-cell number in chronic liver disease. Lancet. 1983 Jun 11;1(8337):1291–1293. doi: 10.1016/s0140-6736(83)92410-8. [DOI] [PubMed] [Google Scholar]
  3. Beutner K. R., Tiku M. L., Ogra P. L. Hepatitis B surface antigen-specific cell-mediated immune responses in human chronic hepatitis B surface antigen carriers. Infect Immun. 1978 Aug;21(2):480–488. doi: 10.1128/iai.21.2.480-488.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Celis E., Chang T. W. HBsAg-serum protein complexes stimulate immune T lymphocytes more efficiently than do pure HBsAg. Hepatology. 1984 Nov-Dec;4(6):1116–1123. doi: 10.1002/hep.1840040604. [DOI] [PubMed] [Google Scholar]
  5. Celis E., Kung P. C., Chang T. W. Hepatitis B virus-reactive human T lymphocyte clones: antigen specificity and helper function for antibody synthesis. J Immunol. 1984 Mar;132(3):1511–1516. [PubMed] [Google Scholar]
  6. Chisari F. V., Pinkert C. A., Milich D. R., Filippi P., McLachlan A., Palmiter R. D., Brinster R. L. A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science. 1985 Dec 6;230(4730):1157–1160. doi: 10.1126/science.3865369. [DOI] [PubMed] [Google Scholar]
  7. Damle N. K., Mohagheghpour N., Engleman E. G. Soluble antigen-primed inducer T cells activate antigen-specific suppressor T cells in the absence of antigen-pulsed accessory cells: phenotypic definition of suppressor-inducer and suppressor-effector cells. J Immunol. 1984 Feb;132(2):644–650. [PubMed] [Google Scholar]
  8. Desaules M., Frei P. C., Libanska J., Wuilleret B. Lack of leukocyte migration inhibition by hepatitis B antigen and normal nonspecific immunoreactivity in asymptomatic carriers. J Infect Dis. 1976 Nov;134(5):505–509. doi: 10.1093/infdis/134.5.505. [DOI] [PubMed] [Google Scholar]
  9. Dudley F. J., Giustino V., Sherlock S. Cell-mediated immunity in patients positive for hepatitis-associated antigen. Br Med J. 1972 Dec 30;4(5843):754–756. doi: 10.1136/bmj.4.5843.754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Erard P. Technical study of the leucocyte migration inhibition test in agarose. Application to PPD and to hepatitis B antigen. Clin Exp Immunol. 1974 Nov;18(3):439–448. [PMC free article] [PubMed] [Google Scholar]
  11. Fattovich G., Alberti A., Crivellaro C., Pontisso P., Noventa F., Realdi G. Cellular immunity to the hepatitis B virion in acute hepatitis type B. Clin Exp Immunol. 1983 Sep;53(3):645–650. [PMC free article] [PubMed] [Google Scholar]
  12. Hanson R. G., Hoofnagle J. H., Minuk G. Y., Purcell R. H., Gerin J. L. Cell-mediated immunity to hepatitis B surface antigen in man. Clin Exp Immunol. 1984 Aug;57(2):257–264. [PMC free article] [PubMed] [Google Scholar]
  13. Ibrahim A. B., Vyas G. N., Perkins H. A. Immune response to hepatitis B surface antigen. Infect Immun. 1975 Jan;11(1):137–141. doi: 10.1128/iai.11.1.137-141.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Irwin G. R., Jr, Hierholzer W. J., Jr, Cimis R., McCollum R. W. Delayed hypersensitivity in hepatitis B: clinical correlates of in vitro production of migration inhibition factor. J Infect Dis. 1974 Dec;130(6):580–587. doi: 10.1093/infdis/130.6.580. [DOI] [PubMed] [Google Scholar]
  15. Lee W. M., Reed W. D., Mitchell C. G., Woolf I. L., Dymock I. W., Eddleston A. L., Williams R. Cell-mediated immunity to hepatitis B surface antigen in blood donors with persistent antigenaemia. Gut. 1975 Jun;16(6):416–420. doi: 10.1136/gut.16.6.416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lee W. M., Reed W. D., Osman C. G., Vahrman J., Zuckerman A. J., Eddleston A. L., Williams R. Immune responses to the hepatitis B surface antigen and liver-specific lipoprotein in acute type B hepatitis. Gut. 1977 Mar;18(3):250–257. doi: 10.1136/gut.18.3.250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Machida A., Kishimoto S., Ohnuma H., Miyamoto H., Baba K., Oda K., Nakamura T., Miyakawa Y., Mayumi M. A hepatitis B surface antigen polypeptide (P31) with the receptor for polymerized human as well as chimpanzee albumins. Gastroenterology. 1983 Aug;85(2):268–274. [PubMed] [Google Scholar]
  18. Milich D. R., McLachlan A., Chisari F. V., Kent S. B., Thorton G. B. Immune response to the pre-S(1) region of the hepatitis B surface antigen (HBsAg): a pre-S(1)-specific T cell response can bypass nonresponsiveness to the pre-S(2) and S regions of HBsAg. J Immunol. 1986 Jul 1;137(1):315–322. [PubMed] [Google Scholar]
  19. Milich D. R., McNamara M. K., McLachlan A., Thornton G. B., Chisari F. V. Distinct H-2-linked regulation of T-cell responses to the pre-S and S regions of the same hepatitis B surface antigen polypeptide allows circumvention of nonresponsiveness to the S region. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8168–8172. doi: 10.1073/pnas.82.23.8168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Milich D. R., Thornton G. B., Neurath A. R., Kent S. B., Michel M. L., Tiollais P., Chisari F. V. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science. 1985 Jun 7;228(4704):1195–1199. doi: 10.1126/science.2408336. [DOI] [PubMed] [Google Scholar]
  21. Mogensen C. E. The glomerular permeability determined by dextran clearance using Sephadex gel filtration. Scand J Clin Lab Invest. 1968;21(1):77–82. doi: 10.3109/00365516809076979. [DOI] [PubMed] [Google Scholar]
  22. Mondelli M., Eddleston A. L. Mechanisms of liver cell injury in acute and chronic hepatitis B. Semin Liver Dis. 1984 Feb;4(1):47–58. doi: 10.1055/s-2008-1040645. [DOI] [PubMed] [Google Scholar]
  23. Mondelli M., Vergani G. M., Alberti A., Vergani D., Portmann B., Eddleston A. L., Williams R. Specificity of T lymphocyte cytotoxicity to autologous hepatocytes in chronic hepatitis B virus infection: evidence that T cells are directed against HBV core antigen expressed on hepatocytes. J Immunol. 1982 Dec;129(6):2773–2778. [PubMed] [Google Scholar]
  24. Naumov N. V., Mondelli M., Alexander G. J., Tedder R. S., Eddleston A. L., Williams R. Relationship between expression of hepatitis B virus antigens in isolated hepatocytes and autologous lymphocyte cytotoxicity in patients with chronic hepatitis B virus infection. Hepatology. 1984 Jan-Feb;4(1):63–68. doi: 10.1002/hep.1840040111. [DOI] [PubMed] [Google Scholar]
  25. Neurath A. R., Kent S. B., Strick N. Location and chemical synthesis of a pre-S gene coded immunodominant epitope of hepatitis B virus. Science. 1984 Apr 27;224(4647):392–395. doi: 10.1126/science.6200931. [DOI] [PubMed] [Google Scholar]
  26. Pasek M., Goto T., Gilbert W., Zink B., Schaller H., MacKay P., Leadbetter G., Murray K. Hepatitis B virus genes and their expression in E. coli. Nature. 1979 Dec 6;282(5739):575–579. doi: 10.1038/282575a0. [DOI] [PubMed] [Google Scholar]
  27. Saxon A., Feldhaus J., Robins R. A. Single step separation of human T and B cells using AET treated srbc rosettes. J Immunol Methods. 1976;12(3-4):285–288. doi: 10.1016/0022-1759(76)90050-8. [DOI] [PubMed] [Google Scholar]
  28. Stibbe W., Gerlich W. H. Structural relationships between minor and major proteins of hepatitis B surface antigen. J Virol. 1983 May;46(2):626–628. doi: 10.1128/jvi.46.2.626-628.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Stibbe W., Gerlich W. H. Variable protein composition of hepatitis B surface antigen from different donors. Virology. 1982 Dec;123(2):436–442. doi: 10.1016/0042-6822(82)90275-6. [DOI] [PubMed] [Google Scholar]
  30. Suppressor cell function in chronic liver disease. Lancet. 1983 Aug 6;2(8345):342–343. [PubMed] [Google Scholar]
  31. Sylvan S. P., Hellström U. B., Lundbergh P. R. Detection of cellular and humoral immunity to hepatitis B surface antigen (HBsAg) in asymptomatic HBsAg carriers. Clin Exp Immunol. 1985 Nov;62(2):288–295. [PMC free article] [PubMed] [Google Scholar]
  32. Thomas H. C., Brown D., Routhier G., Janossy G., Kung P. C., Goldstein G., Sherlock S. Inducer and suppressor T-cells in hepatitis B virus-induced liver disease. Hepatology. 1982 Mar-Apr;2(2):202–204. doi: 10.1002/hep.1840020203. [DOI] [PubMed] [Google Scholar]
  33. Thomas J. O., Kornberg R. D. An octamer of histones in chromatin and free in solution. Proc Natl Acad Sci U S A. 1975 Jul;72(7):2626–2630. doi: 10.1073/pnas.72.7.2626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tiku M. L., Beutner K. R., Tiku K., Ogra P. L. Cell-mediated immune response to liver tissue antigen and hepatitis B surface antigen after infection with hepatitis B virus in humans. J Infect Dis. 1978 Nov;138(5):587–596. doi: 10.1093/infdis/138.5.587. [DOI] [PubMed] [Google Scholar]
  35. Trevisan A., Realdi G., Alberti A., Ongaro G., Pornaro E., Meliconi R. Core antigen-specific immunoglobulin G bound to the liver cell membrane in chronic hepatitis B. Gastroenterology. 1982 Feb;82(2):218–222. [PubMed] [Google Scholar]
  36. Vento S., Hegarty J. E., Alberti A., O'Brien C. J., Alexander G. J., Eddleston A. L., Williams R. T lymphocyte sensitization to HBcAg and T cell-mediated unresponsiveness to HBsAg in hepatitis B virus-related chronic liver disease. Hepatology. 1985 Mar-Apr;5(2):192–197. doi: 10.1002/hep.1840050206. [DOI] [PubMed] [Google Scholar]
  37. Wysocki L. J., Sato V. L. "Panning" for lymphocytes: a method for cell selection. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2844–2848. doi: 10.1073/pnas.75.6.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. de Gast G. C., Houwen B., Nieweg H. O. Specific lymphocyte stimulation by purified, heat-inactivated hepatitis-B antigen. Br Med J. 1973 Dec 22;4(5894):707–709. doi: 10.1136/bmj.4.5894.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. de Moura M. C., Vernace S. J., Paronetto F. Cell-mediated immune reactivity to hepatitis B surface antigen in liver diseases. Gastroenterology. 1975 Aug;69(2):310–317. [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES