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. 1983 Jun 1;157(6):1815–1827. doi: 10.1084/jem.157.6.1815

B cell dependence on and response to accessory signals in murine lupus strains

PMCID: PMC2187057  PMID: 6406639

Abstract

B cell hyperactivity, a feature common to all lupus-prone murine strains, may be caused by hyperresponsiveness to, overproduction of, or bypassing of certain signals required for B cell activation, proliferation, and differentiation. In this study, we have compared the responses of B cells from three lupus-prone strains of mice (BXSB males, MRL and NZB/W females) and normal strains in a number of assays for which two or more signals are required to obtain a response. In medium to low density cultures of B cells from BXSB and NZB/W but not MRL/l lupus mice, the cells' proliferation induced by bacterial lipopolysaccharide (LPS) or anti-mu antibody was much higher than that of B cells from normal controls. At low B cell density, polyclonal activation by these substances and subsequent Ig secretion were dependent on accessory signals present in supernatants of concanavalin A-treated normal lymphocytes (CAS) or on the MRL/l proliferating T cell- derived B cell differentiation factor (L-BCDF) in both lupus-prone and immunologically normal mice. However, the responses of B cells from BXSB and NZB/W, but not MRL/l, mice to these accessory signals were higher than those of normal mice. Ig synthesis by fresh B cells of BXSB and NZB/W mice cultured in the absence of mitogens but in the presence of CAS or L-BCDF was higher than by similar cells from other strains, suggesting an increased frequency of B cells activated in vivo in these two autoimmune strains of mice. The patterns of IgG subclass secretion in response to LPS (without added CAS or L-BCDF) were abnormal in all lupus strains, with a predominance of IgG2b and/or IgG2a and low levels of IgG3, contrary to normal B cells for which IgG3 synthesis predominated. However, IgG1 synthesis in vitro by autoimmune and normal B cells alike was highly dependent on T cell-derived soluble mediators. Antigen-specific responses to SRBC in vitro of B cells from all lupus strains, like those of B cells from normal strains, required a minimum of three signals (antigen, LPS, T cell-derived antigen nonspecific helper factors). Yet, once triggered, B cells of BXSB and NZB/W mice gave higher responses than those of the other strains. We conclude that B cells of lupus mice have signal requirements similar to those of normal mice. Nevertheless, B cells of BXSB and NZB/W, but not MRL/l, lupus mice hyperrespond or process some accessory signals abnormally.

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Selected References

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

  1. Anderson J., Melchers F. T cell-dependent activation of resting B cells: requirement for both nonspecific unrestricted and antigen-specific Ia-restricted soluble factors. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2497–2501. doi: 10.1073/pnas.78.4.2497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andersson J., Coutinho A., Melchers F., Watanabe T. Growth and maturation of single clones of normal murine T and B lymphocytes in vitro. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 1):227–236. doi: 10.1101/sqb.1977.041.01.028. [DOI] [PubMed] [Google Scholar]
  3. Isakson P. C., Puré E., Vitetta E. S., Krammer P. H. T cell-derived B cell differentiation factor(s). Effect on the isotype switch of murine B cells. J Exp Med. 1982 Mar 1;155(3):734–748. doi: 10.1084/jem.155.3.734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Izui S., Eisenberg R. A., Dixon F. J. IgM rheumatoid factors in mice injected with bacterial lipopolysaccharides. J Immunol. 1979 May;122(5):2096–2102. [PubMed] [Google Scholar]
  5. Izui S., McConahey P. J., Dixon F. J. Increased spontaneous polyclonal activation of B lymphocytes in mice with spontaneous autoimmune disease. J Immunol. 1978 Dec;121(6):2213–2219. [PubMed] [Google Scholar]
  6. Julius M. H., von Boehmer H., Sidman C. L. Dissociation of two signals required for activation of resting B cells. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1989–1993. doi: 10.1073/pnas.79.6.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Liebson H. J., Marrack P., Kappler J. B cell helper factors. II. Synergy among three helper factors in the response of T cell- and macrophage-depleted B cells. J Immunol. 1982 Oct;129(4):1398–1402. [PubMed] [Google Scholar]
  8. Marrack P., Graham S. D., Jr, Kushnir E., Leibson H. J., Roehm N., Kappler J. W. Nonspecific factors in B cell responses. Immunol Rev. 1982;63:33–49. doi: 10.1111/j.1600-065x.1982.tb00410.x. [DOI] [PubMed] [Google Scholar]
  9. Martinez-Alonso C., Coutinho A. Immunoglobulin C-gene expression. III. Possible induction of specific genetic events in activated B lymphocytes by the polyclonal stimuli driving clonal expansion. Eur J Immunol. 1982 Jun;12(6):502–506. doi: 10.1002/eji.1830120610. [DOI] [PubMed] [Google Scholar]
  10. McKearn J. P., Paslay J. W., Slack J., Baum C., Davie J. M. B cell subsets and differential responses to mitogens. Immunol Rev. 1982;64:5–23. doi: 10.1111/j.1600-065x.1982.tb00416.x. [DOI] [PubMed] [Google Scholar]
  11. Ohsugi Y., Gershwin M. E. Studies of congenitally immunologic mutant New Zealand mice. III. Growth of B lymphocyte clones in congenitally athymic (nude) and hereditarily asplenic (Dh/+) NZB mice: a primary B cell defect. J Immunol. 1979 Sep;123(3):1260–1265. [PubMed] [Google Scholar]
  12. Parker D. C. Separable helper factors support B cell proliferation and maturation to Ig secretion. J Immunol. 1982 Aug;129(2):469–474. [PubMed] [Google Scholar]
  13. Parker D. C., Wadsworth D. C., Schneider G. B. Activation of murine B lymphocytes by anti-immunoglobulin is an inductive signal leading to immunoglobulin secretion. J Exp Med. 1980 Jul 1;152(1):138–150. doi: 10.1084/jem.152.1.138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Prud'Homme G. J., Park C. L., Fieser T. M., Kofler R., Dixon F. J., Theofilopoulos A. N. Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype. J Exp Med. 1983 Feb 1;157(2):730–742. doi: 10.1084/jem.157.2.730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Prystowsky M. B., Ely J. M., Beller D. I., Eisenberg L., Goldman J., Goldman M., Goldwasser E., Ihle J., Quintans J., Remold H. Alloreactive cloned T cell lines. VI. Multiple lymphokine activities secreted by helper and cytolytic cloned T lymphocytes. J Immunol. 1982 Dec;129(6):2337–2344. [PubMed] [Google Scholar]
  16. Raveche E. S., Novotny E. A., Hansen C. T., Tjio J. H., Steinberg A. D. Genetic studies in NZB mice. V. Recombinant inbred lines demonstrate that separate genes control autoimmune phenotype. J Exp Med. 1981 May 1;153(5):1187–1197. doi: 10.1084/jem.153.5.1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Raveche E. S., Steinberg A. D., DeFranco A. L., Tjio J. H. Cell cycle analysis of lymphocyte activation in normal and autoimmune strains of mice. J Immunol. 1982 Sep;129(3):1219–1226. [PubMed] [Google Scholar]
  18. Roubinian J. R., Papoian R., Talal N. Effects of neonatal thymectomy and splenectomy on survival and regulation of autoantibody formation in NZB/NZW F1 mice. J Immunol. 1977 May;118(5):1524–1529. [PubMed] [Google Scholar]
  19. Steinberg A. D., Huston D. P., Taurog J. D., Cowdery J. S., Ravecheé E. S. The cellular and genetic basis of murine lupus. Immunol Rev. 1981;55:121–154. doi: 10.1111/j.1600-065x.1981.tb00341.x. [DOI] [PubMed] [Google Scholar]
  20. Steinberg A. D., Roths J. B., Murphy E. D., Steinberg R. T., Raveche E. S. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J Immunol. 1980 Aug;125(2):871–873. [PubMed] [Google Scholar]
  21. Swain S. L., Dennert G., Warner J. F., Dutton R. W. Culture supernatants of a stimulated T-cell line have helper activity that acts synergistically with interleukin 2 in the response of B cells to antigen. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2517–2521. doi: 10.1073/pnas.78.4.2517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Swain S. L., Dutton R. W. Production of a B cell growth-promoting activity, (DL)BCGF, from a cloned T cell line and its assay on the BCL1 B cell tumor. J Exp Med. 1982 Dec 1;156(6):1821–1834. doi: 10.1084/jem.156.6.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Theofilopoulos A. N., Balderas R. S., Gozes Y., Fidler J. M., Liu F. T., Ahmed A., Dixon F. J. Surface and functional characteristics of B cells from lupus-prone murine strains. Clin Immunol Immunopathol. 1982 May;23(2):224–244. doi: 10.1016/0090-1229(82)90110-6. [DOI] [PubMed] [Google Scholar]
  24. Theofilopoulos A. N., Balderas R. S., Shawler D. L., Lee S., Dixon F. J. Influence of thymic genotype on the systemic lupus erythematosus-like disease and T cell proliferation of MRL/Mp-lpr/lpr mice. J Exp Med. 1981 Jun 1;153(6):1405–1414. doi: 10.1084/jem.153.6.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Theofilopoulos A. N., Dixon F. J. Etiopathogenesis of murine SLE. Immunol Rev. 1981;55:179–216. doi: 10.1111/j.1600-065x.1981.tb00343.x. [DOI] [PubMed] [Google Scholar]
  26. Theofilopoulos A. N., Eisenberg R. A., Bourdon M., Crowell J. S., Jr, Dixon F. J. Distribution of lymphocytes identified by surface markers in murine strains with systemic lupus erythematosus-like syndromes. J Exp Med. 1979 Feb 1;149(2):516–534. doi: 10.1084/jem.149.2.516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Theofilopoulos A. N., Shawler D. L., Eisenberg R. A., Dixon F. J. Splenic immunoglobulin-secreting cells and their regulation in autoimmune mice. J Exp Med. 1980 Feb 1;151(2):446–466. doi: 10.1084/jem.151.2.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wofsy D., Ledbetter J. A., Roubinian J. R., Seaman W. E., Talal N. Thymic influences on autoimmunity in MRL-lpr mice. Scand J Immunol. 1982 Jul;16(1):51–58. doi: 10.1111/j.1365-3083.1982.tb00698.x. [DOI] [PubMed] [Google Scholar]
  29. Zubler R. H., Glasebrook A. L. Requirement for three signals in "T-independent" (lipopolysaccharide-induced) as well as in T-dependent B cell responses. J Exp Med. 1982 Mar 1;155(3):666–680. doi: 10.1084/jem.155.3.666. [DOI] [PMC free article] [PubMed] [Google Scholar]

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