Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1995 Mar;69(3):1895–1902. doi: 10.1128/jvi.69.3.1895-1902.1995

Bone marrow is a major site of long-term antibody production after acute viral infection.

M K Slifka 1, M Matloubian 1, R Ahmed 1
PMCID: PMC188803  PMID: 7853531

Abstract

Antiviral antibody production is often sustained for long periods after resolution of an acute viral infection. Despite extensive documentation of this phenomenon, the mechanisms involved in maintaining long-term antibody production remain poorly defined. As a first step towards understanding the nature of long-term humoral immunity, we examined the anatomical location of antibody-producing cells during acute viral infection. Using the lymphocytic choriomeningitis virus (LCMV) model, we found that after resolution of the acute infection, when antiviral plasma cells in the spleen decline, a population of virus-specific plasma cells appears in the bone marrow and constitutes the major source of long-term antibody production. Following infection of adult mice, LCMV-specific antibody-secreting cells (ASC) peaked in the spleen at 8 days postinfection but were undetectable in the bone marrow at that time. The infection was essentially cleared by 15 days, and the ASC numbers in the spleen rapidly declined while an increasing population of LCMV-specific ASC began to appear in the bone marrow. Compared with the peak response at 8 days postinfection, time points from 30 days to more than 1 year later demonstrated greater-than-10-fold reductions in splenic ASC. In contrast, LCMV-specific plasma cell numbers in the bone marrow remained high and correlated with the high levels of antiviral serum antibody. The presence of LCMV-specific plasma cells in the bone marrow was not due to persistent infection at this site, since the virus was cleared from both the spleen and bone marrow with similar kinetics as determined by infectivity and PCR assays. The immunoglobulin G subclass profile of antibody-secreting cells derived from bone marrow and the spleen correlated with the immunoglobulin G subclass distribution of LCMV-specific antibody in the serum. Upon rechallenge with LCMV, the spleen exhibited a substantial increase in virus-specific plasma cell numbers during the early phase of the secondary response, followed by an equally sharp decline. Bone marrow ASC populations and LCMV-specific antibody levels in the serum did not change during the early phase of the reinfection, but both increased about two-fold by 15 days postchallenge. After both primary and secondary viral infections, LCMV-specific plasma cells were maintained in the bone marrow, showing that the bone marrow is a major site of long-term antibody production after acute viral infection. These results documenting long-term persistence of plasma cells in the bone marrow suggest a reexamination of our current notions regarding the half-life of plasma cells.

Full Text

The Full Text of this article is available as a PDF (325.3 KB).

Selected References

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

  1. Ahmed R., Butler L. D., Bhatti L. T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. J Virol. 1988 Jun;62(6):2102–2106. doi: 10.1128/jvi.62.6.2102-2106.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmed R. Immunological memory against viruses. Semin Immunol. 1992 Apr;4(2):105–109. [PubMed] [Google Scholar]
  3. Ahmed R., Salmi A., Butler L. D., Chiller J. M., Oldstone M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med. 1984 Aug 1;160(2):521–540. doi: 10.1084/jem.160.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. BLACK F. L., ROSEN L. Patterns of measles antibodies in residents of Tahiti and their stability in the absence of re-exposure. J Immunol. 1962 Jun;88:725–731. [PubMed] [Google Scholar]
  5. Bachmann M. F., Kündig T. M., Kalberer C. P., Hengartner H., Zinkernagel R. M. How many specific B cells are needed to protect against a virus? J Immunol. 1994 May 1;152(9):4235–4241. [PubMed] [Google Scholar]
  6. Benner R., Hijmans W., Haaijman J. J. The bone marrow: the major source of serum immunoglobulins, but still a neglected site of antibody formation. Clin Exp Immunol. 1981 Oct;46(1):1–8. [PMC free article] [PubMed] [Google Scholar]
  7. Benner R., Meima F., van der Meulen G. M., van Muiswinkel W. B. Antibody formation in mouse bone marrow. I. Evidence for the development of plaque-forming cells in situ. Immunology. 1974 Feb;26(2):247–255. [PMC free article] [PubMed] [Google Scholar]
  8. Braunstein H., Thomas S., Ito R. Immunity to measles in a large population of varying age. Significance with respect to vaccination. Am J Dis Child. 1990 Mar;144(3):296–298. doi: 10.1001/archpedi.1990.02150270046024. [DOI] [PubMed] [Google Scholar]
  9. Buchmeier M. J., Welsh R. M., Dutko F. J., Oldstone M. B. The virology and immunobiology of lymphocytic choriomeningitis virus infection. Adv Immunol. 1980;30:275–331. doi: 10.1016/s0065-2776(08)60197-2. [DOI] [PubMed] [Google Scholar]
  10. Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  12. Cooney E. L., Collier A. C., Greenberg P. D., Coombs R. W., Zarling J., Arditti D. E., Hoffman M. C., Hu S. L., Corey L. Safety of and immunological response to a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein. Lancet. 1991 Mar 9;337(8741):567–572. doi: 10.1016/0140-6736(91)91636-9. [DOI] [PubMed] [Google Scholar]
  13. Dilosa R. M., Maeda K., Masuda A., Szakal A. K., Tew J. G. Germinal center B cells and antibody production in the bone marrow. J Immunol. 1991 Jun 15;146(12):4071–4077. [PubMed] [Google Scholar]
  14. Doherty P. C., Allan W., Eichelberger M., Carding S. R. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annu Rev Immunol. 1992;10:123–151. doi: 10.1146/annurev.iy.10.040192.001011. [DOI] [PubMed] [Google Scholar]
  15. Eriksson K., Nordström I., Horal P., Jeansson S., Svennerholm B., Vahlne A., Holmgren J., Czerkinsky C. Amplified ELISPOT assay for the detection of HIV-specific antibody-secreting cells in subhuman primates. J Immunol Methods. 1992 Aug 30;153(1-2):107–113. doi: 10.1016/0022-1759(92)90312-h. [DOI] [PubMed] [Google Scholar]
  16. FAHEY J. L., SELL S. THE IMMUNOGLOBULINS OF MICE. V. THE METABOLIC (CATABOLIC) PROPERTIES OF FIVE IMMUNOGLOBULIN CLASSES. J Exp Med. 1965 Jul 1;122:41–58. doi: 10.1084/jem.122.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gray D. Immunological memory. Annu Rev Immunol. 1993;11:49–77. doi: 10.1146/annurev.iy.11.040193.000405. [DOI] [PubMed] [Google Scholar]
  18. Grob J. P., Grundy J. E., Prentice H. G., Griffiths P. D., Hoffbrand A. V., Hughes M. D., Tate T., Wimperis J. Z., Brenner M. K. Immune donors can protect marrow-transplant recipients from severe cytomegalovirus infections. Lancet. 1987 Apr 4;1(8536):774–776. doi: 10.1016/s0140-6736(87)92800-5. [DOI] [PubMed] [Google Scholar]
  19. Hill S. W. Distribution of plaque-forming cells in the mouse for a protein antigen. Evidence for highly active parathymic lymph nodes following intraperitoneal injection of hen lysozyme. Immunology. 1976 Jun;30(6):895–906. [PMC free article] [PubMed] [Google Scholar]
  20. Ho F., Lortan J. E., MacLennan I. C., Khan M. Distinct short-lived and long-lived antibody-producing cell populations. Eur J Immunol. 1986 Oct;16(10):1297–1301. doi: 10.1002/eji.1830161018. [DOI] [PubMed] [Google Scholar]
  21. Hyland L., Hou S., Coleclough C., Takimoto T., Doherty P. C. Mice lacking CD8+ T cells develop greater numbers of IgA-producing cells in response to a respiratory virus infection. Virology. 1994 Oct;204(1):234–241. doi: 10.1006/viro.1994.1527. [DOI] [PubMed] [Google Scholar]
  22. Hyland L., Sangster M., Sealy R., Coleclough C. Respiratory virus infection of mice provokes a permanent humoral immune response. J Virol. 1994 Sep;68(9):6083–6086. doi: 10.1128/jvi.68.9.6083-6086.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jamieson B. D., Butler L. D., Ahmed R. Effective clearance of a persistent viral infection requires cooperation between virus-specific Lyt2+ T cells and nonspecific bone marrow-derived cells. J Virol. 1987 Dec;61(12):3930–3937. doi: 10.1128/jvi.61.12.3930-3937.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koch G., Osmond D. G., Julius M. H., Benner R. The mechanism of thymus-dependent antibody formation in bone marrow. J Immunol. 1981 Apr;126(4):1447–1451. [PubMed] [Google Scholar]
  25. Lau L. L., Jamieson B. D., Somasundaram T., Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994 Jun 23;369(6482):648–652. doi: 10.1038/369648a0. [DOI] [PubMed] [Google Scholar]
  26. Lehmann-Grube F., Moskophidis D., Löhler J. Recovery from acute virus infection. Role of cytotoxic T lymphocytes in the elimination of lymphocytic choriomeningitis virus from spleens of mice. Ann N Y Acad Sci. 1988;532:238–256. doi: 10.1111/j.1749-6632.1988.tb36343.x. [DOI] [PubMed] [Google Scholar]
  27. Lycke N. A sensitive method for the detection of specific antibody production in different isotypes from single lamina propria plasma cells. Scand J Immunol. 1986 Oct;24(4):393–403. doi: 10.1111/j.1365-3083.1986.tb02127.x. [DOI] [PubMed] [Google Scholar]
  28. MacLennan I. C., Liu Y. J., Johnson G. D. Maturation and dispersal of B-cell clones during T cell-dependent antibody responses. Immunol Rev. 1992 Apr;126:143–161. doi: 10.1111/j.1600-065x.1992.tb00635.x. [DOI] [PubMed] [Google Scholar]
  29. MacLennan I. C., Liu Y. J., Oldfield S., Zhang J., Lane P. J. The evolution of B-cell clones. Curr Top Microbiol Immunol. 1990;159:37–63. doi: 10.1007/978-3-642-75244-5_3. [DOI] [PubMed] [Google Scholar]
  30. Moskophidis D., Cobbold S. P., Waldmann H., Lehmann-Grube F. Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response. J Virol. 1987 Jun;61(6):1867–1874. doi: 10.1128/jvi.61.6.1867-1874.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moskophidis D., Lehmann-Grube F. The immune response of the mouse to lymphocytic choriomeningitis virus. IV. Enumeration of antibody-producing cells in spleens during acute and persistent infection. J Immunol. 1984 Dec;133(6):3366–3370. [PubMed] [Google Scholar]
  32. Möller S. A., Borrebaeck C. A. A filter immuno-plaque assay for the detection of antibody-secreting cells in vitro. J Immunol Methods. 1985 May 23;79(2):195–204. doi: 10.1016/0022-1759(85)90099-7. [DOI] [PubMed] [Google Scholar]
  33. Nieuwenhuis P., Opstelten D. Functional anatomy of germinal centers. Am J Anat. 1984 Jul;170(3):421–435. doi: 10.1002/aja.1001700315. [DOI] [PubMed] [Google Scholar]
  34. Oldstone M. B., Ahmed R., Byrne J., Buchmeier M. J., Riviere Y., Southern P. Virus and immune responses: lymphocytic choriomeningitis virus as a prototype model of viral pathogenesis. Br Med Bull. 1985 Jan;41(1):70–74. doi: 10.1093/oxfordjournals.bmb.a072029. [DOI] [PubMed] [Google Scholar]
  35. PAUL J. R., RIORDAN J. T., MELNICK J. L. Antibodies to three different antigenic types of poliomyelitis virus in sera from North Alaskan Eskimos. Am J Hyg. 1951 Sep;54(2):275–285. doi: 10.1093/oxfordjournals.aje.a119485. [DOI] [PubMed] [Google Scholar]
  36. Roldán E., García-Pardo A., Brieva J. A. VLA-4-fibronectin interaction is required for the terminal differentiation of human bone marrow cells capable of spontaneous and high rate immunoglobulin secretion. J Exp Med. 1992 Jun 1;175(6):1739–1747. doi: 10.1084/jem.175.6.1739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Salvato M., Shimomaye E., Southern P., Oldstone M. B. Virus-lymphocyte interactions. IV. Molecular characterization of LCMV Armstrong (CTL+) small genomic segment and that of its variant, Clone 13 (CTL-). Virology. 1988 Jun;164(2):517–522. doi: 10.1016/0042-6822(88)90566-1. [DOI] [PubMed] [Google Scholar]
  38. Saxon A., Mitsuyasu R., Stevens R., Champlin R. E., Kimata H., Gale R. P. Designed transfer of specific immune responses with bone marrow transplantation. J Clin Invest. 1986 Oct;78(4):959–967. doi: 10.1172/JCI112686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sha B. E., Harris A. A., Benson C. A., Atkinson W. L., Urbanski P. A., Stewart J. A., Williams W. W., Murphy R. L., Phair J. P., Levin S. A. Prevalence of measles antibodies in asymptomatic human immunodeficiency virus-infected adults. J Infect Dis. 1991 Nov;164(5):973–975. doi: 10.1093/infdis/164.5.973. [DOI] [PubMed] [Google Scholar]
  40. Tew J. G., DiLosa R. M., Burton G. F., Kosco M. H., Kupp L. I., Masuda A., Szakal A. K. Germinal centers and antibody production in bone marrow. Immunol Rev. 1992 Apr;126:99–112. doi: 10.1111/j.1600-065x.1992.tb00633.x. [DOI] [PubMed] [Google Scholar]
  41. Thomsen A. R., Volkert M., Marker O. Different isotype profiles of virus-specific antibodies in acute and persistent lymphocytic choriomeningitis virus infection in mice. Immunology. 1985 Jun;55(2):213–223. [PMC free article] [PubMed] [Google Scholar]
  42. Tishon A., Salmi A., Ahmed R., Oldstone M. B. Role of viral strains and host genes in determining levels of immune complexes in a model system: implications for HIV infection. AIDS Res Hum Retroviruses. 1991 Dec;7(12):963–969. doi: 10.1089/aid.1991.7.963. [DOI] [PubMed] [Google Scholar]
  43. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES