Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Oct 1;180(4):1295–1306. doi: 10.1084/jem.180.4.1295

The role of B cells in lpr/lpr-induced autoimmunity

PMCID: PMC2191708  PMID: 7931063

Abstract

The primary roles of T cells and B cells in the initiation of systemic autoimmunity are unclear. To investigate the role of B cells, we crossed the "Jh knockout" mutation onto the autoimmune lpr/lpr background. Animals homozygous for both traits were obtained. As expected, these animals lack B cells. These animals also show no signs of autoimmune kidney destruction nor vasculitis, in spite of carrying the lpr/lpr mutation. In contrast, lpr/lpr littermates that had B cells had severe nephritis and vasculitis, as well as autoantibodies. These results demonstrate a primary role for B cells and/or (auto)antibodies in initiating several types of autoimmune-mediated tissue destruction. The implications of this finding for models and therapy of autoimmunity are discussed.

Full Text

The Full Text of this article is available as a PDF (1.9 MB).

Selected References

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

  1. Andrews B. S., Eisenberg R. A., Theofilopoulos A. N., Izui S., Wilson C. B., McConahey P. J., Murphy E. D., Roths J. B., Dixon F. J. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978 Nov 1;148(5):1198–1215. doi: 10.1084/jem.148.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Austin H. A., 3rd, Muenz L. R., Joyce K. M., Antonovych T. T., Balow J. E. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int. 1984 Apr;25(4):689–695. doi: 10.1038/ki.1984.75. [DOI] [PubMed] [Google Scholar]
  3. Berden J. H., Hang L., McConahey P. J., Dixon F. J. Analysis of vascular lesions in murine SLE. I. Association with serologic abnormalities. J Immunol. 1983 Apr;130(4):1699–1705. [PubMed] [Google Scholar]
  4. Bloom R. D., Florquin S., Singer G. G., Brennan D. C., Kelley V. R. Colony stimulating factor-1 in the induction of lupus nephritis. Kidney Int. 1993 May;43(5):1000–1009. doi: 10.1038/ki.1993.141. [DOI] [PubMed] [Google Scholar]
  5. Budd R. C., Schreyer M., Miescher G. C., MacDonald H. R. T cell lineages in the thymus of lpr/lpr mice. Evidence for parallel pathways of normal and abnormal T cell development. J Immunol. 1987 Oct 1;139(7):2200–2210. [PubMed] [Google Scholar]
  6. Cerny A., Kimoto M., Hügin A. W., Merino R., Izui S. Anti-IgM treatment of C57BL/6-1pr/1pr mice: depletion of B cells reduces 1pr gene-induced lymphoproliferation and mononuclear cell vasculitis. Clin Exp Immunol. 1989 Jul;77(1):124–129. [PMC free article] [PubMed] [Google Scholar]
  7. Chen J., Trounstine M., Alt F. W., Young F., Kurahara C., Loring J. F., Huszar D. Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int Immunol. 1993 Jun;5(6):647–656. doi: 10.1093/intimm/5.6.647. [DOI] [PubMed] [Google Scholar]
  8. Coffman R. L., Weissman I. L. A monoclonal antibody that recognizes B cells and B cell precursors in mice. J Exp Med. 1981 Feb 1;153(2):269–279. doi: 10.1084/jem.153.2.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Couser W. G., Salant D. J., Madaio M. P., Adler S., Groggel G. C. Factors influencing glomerular and tubulointerstitial patterns of injury in SLE. Am J Kidney Dis. 1982 Jul;2(1 Suppl 1):126–134. [PubMed] [Google Scholar]
  10. Dang H., Harbeck R. J. The in vivo and in vitro glomerular deposition of isolated anti-double-stranded-DNA antibodies in NZB/W mice. Clin Immunol Immunopathol. 1984 Feb;30(2):265–278. doi: 10.1016/0090-1229(84)90061-8. [DOI] [PubMed] [Google Scholar]
  11. Davidson W. F., Dumont F. J., Bedigian H. G., Fowlkes B. J., Morse H. C., 3rd Phenotypic, functional, and molecular genetic comparisons of the abnormal lymphoid cells of C3H-lpr/lpr and C3H-gld/gld mice. J Immunol. 1986 Jun 1;136(11):4075–4084. [PubMed] [Google Scholar]
  12. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
  13. Dixon F. J., Oldstone M. B., Tonietti G. Pathogenesis of immune complex glomerulonephritis of new zealand mice. J Exp Med. 1971 Sep 1;134(3):65–71. [PMC free article] [PubMed] [Google Scholar]
  14. Drappa J., Brot N., Elkon K. B. The Fas protein is expressed at high levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10340–10344. doi: 10.1073/pnas.90.21.10340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Díaz Gallo C., Jevnikar A. M., Brennan D. C., Florquin S., Pacheco-Silva A., Kelley V. R. Autoreactive kidney-infiltrating T-cell clones in murine lupus nephritis. Kidney Int. 1992 Oct;42(4):851–859. doi: 10.1038/ki.1992.360. [DOI] [PubMed] [Google Scholar]
  16. Eastcott J. W., Schwartz R. S., Datta S. K. Genetic analysis of the inheritance of B cell hyperactivity in relation to the development of autoantibodies and glomerulonephritis in NZB x SWR crosses. J Immunol. 1983 Nov;131(5):2232–2239. [PubMed] [Google Scholar]
  17. Foster M. H., Cizman B., Madaio M. P. Nephritogenic autoantibodies in systemic lupus erythematosus: immunochemical properties, mechanisms of immune deposition, and genetic origins. Lab Invest. 1993 Nov;69(5):494–507. [PubMed] [Google Scholar]
  18. Halloran P. F., Urmson J., Ramassar V., Laskin C., Autenried P. Increased class I and class II MHC products and mRNA in kidneys of MRL-lpr/lpr mice during autoimmune nephritis and inhibition by cyclosporine. J Immunol. 1988 Oct 1;141(7):2303–2312. [PubMed] [Google Scholar]
  19. Herron L. R., Coffman R. L., Kotzin B. L. Enhanced response of autoantibody-secreting B cells from young NZB/NZW mice to T-cell-derived differentiation signals. Clin Immunol Immunopathol. 1988 Feb;46(2):314–327. doi: 10.1016/0090-1229(88)90193-6. [DOI] [PubMed] [Google Scholar]
  20. Huang L., Sye K., Crispe I. N. Proliferation and apoptosis of B220+CD4-CD8-TCR alpha beta intermediate T cells in the liver of normal adult mice: implication for lpr pathogenesis. Int Immunol. 1994 Apr;6(4):533–540. doi: 10.1093/intimm/6.4.533. [DOI] [PubMed] [Google Scholar]
  21. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  22. Izui S., Kelley V. E., Masuda K., Yoshida H., Roths J. B., Murphy E. D. Induction of various autoantibodies by mutant gene lpr in several strains of mice. J Immunol. 1984 Jul;133(1):227–233. [PubMed] [Google Scholar]
  23. Jabs D. A., Prendergast R. A. Reactive lymphocytes in lacrimal gland and vasculitic renal lesions of autoimmune MRL/lpr mice express L3T4. J Exp Med. 1987 Oct 1;166(4):1198–1203. doi: 10.1084/jem.166.4.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Janeway C. A., Jr, Ron J., Katz M. E. The B cell is the initiating antigen-presenting cell in peripheral lymph nodes. J Immunol. 1987 Feb 15;138(4):1051–1055. [PubMed] [Google Scholar]
  25. Jevnikar A. M., Grusby M. J., Glimcher L. H. Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. J Exp Med. 1994 Apr 1;179(4):1137–1143. doi: 10.1084/jem.179.4.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Katagiri T., Cohen P. L., Eisenberg R. A. The lpr gene causes an intrinsic T cell abnormality that is required for hyperproliferation. J Exp Med. 1988 Mar 1;167(3):741–751. doi: 10.1084/jem.167.3.741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kelley V. R., Diaz-Gallo C., Jevnikar A. M., Singer G. G. Renal tubular epithelial and T cell interactions in autoimmune renal disease. Kidney Int Suppl. 1993 Jan;39:S108–S115. [PubMed] [Google Scholar]
  28. Kincade P. W., Lee G., Sun L., Watanabe T. Monoclonal rat antibodies to murine IgM determinants. J Immunol Methods. 1981;42(1):17–26. doi: 10.1016/0022-1759(81)90220-9. [DOI] [PubMed] [Google Scholar]
  29. Klinman D. M., Steinberg A. D. Proliferation of anti-DNA-producing NZB B cells in a non-autoimmune environment. J Immunol. 1986 Jul 1;137(1):69–75. [PubMed] [Google Scholar]
  30. Levine J., Hartwell D., Beller D. I. Imbalanced cytokine production by macrophages from autoimmune-prone mice. Immunol Lett. 1991 Oct;30(2):183–192. doi: 10.1016/0165-2478(91)90023-4. [DOI] [PubMed] [Google Scholar]
  31. Lin R. H., Mamula M. J., Hardin J. A., Janeway C. A., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. doi: 10.1084/jem.173.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Madaio M. P., Carlson J., Cataldo J., Ucci A., Migliorini P., Pankewycz O. Murine monoclonal anti-DNA antibodies bind directly to glomerular antigens and form immune deposits. J Immunol. 1987 May 1;138(9):2883–2889. [PubMed] [Google Scholar]
  33. Mamula M. J., Lin R. H., Janeway C. A., Jr, Hardin J. A. Breaking T cell tolerance with foreign and self co-immunogens. A study of autoimmune B and T cell epitopes of cytochrome c. J Immunol. 1992 Aug 1;149(3):789–795. [PubMed] [Google Scholar]
  34. Matsuzaki Y., Pannetien C., Kanagawa O., Gachelin G., Nakauchi H. Evidence for the existence of two parallel differentiation pathways in the thymus of MRL lpr/lpr mice. J Immunol. 1992 Aug 1;149(3):1069–1074. [PubMed] [Google Scholar]
  35. Miyama-Inaba M., Kuma S., Inaba K., Ogata H., Iwai H., Yasumizu R., Muramatsu S., Steinman R. M., Ikehara S. Unusual phenotype of B cells in the thymus of normal mice. J Exp Med. 1988 Aug 1;168(2):811–816. doi: 10.1084/jem.168.2.811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Moyer C. F., Strandberg J. D., Reinisch C. L. Systemic mononuclear-cell vasculitis in MRL/Mp-lpr/lpr mice. A histologic and immunocytochemical analysis. Am J Pathol. 1987 May;127(2):229–242. [PMC free article] [PubMed] [Google Scholar]
  37. Nemazee D., Guiet C., Buerki K., Marshak-Rothstein A. B lymphocytes from the autoimmune-prone mouse strain MLR/lpr manifest an intrinsic defect in tetraparental MRL/lpr in equilibrium DBA/2 chimeras. J Immunol. 1991 Oct 15;147(8):2536–2539. [PubMed] [Google Scholar]
  38. Nose M., Nishimura M., Kyogoku M. Analysis of granulomatous arteritis in MRL/Mp autoimmune disease mice bearing lymphoproliferative genes. The use of mouse genetics to dissociate the development of arteritis and glomerulonephritis. Am J Pathol. 1989 Aug;135(2):271–280. [PMC free article] [PubMed] [Google Scholar]
  39. Pankewycz O. G., Migliorini P., Madaio M. P. Polyreactive autoantibodies are nephritogenic in murine lupus nephritis. J Immunol. 1987 Nov 15;139(10):3287–3294. [PubMed] [Google Scholar]
  40. Rajagopalan S., Zordan T., Tsokos G. C., Datta S. K. Pathogenic anti-DNA autoantibody-inducing T helper cell lines from patients with active lupus nephritis: isolation of CD4-8- T helper cell lines that express the gamma delta T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7020–7024. doi: 10.1073/pnas.87.18.7020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. Reininger L., Berney T., Shibata T., Spertini F., Merino R., Izui S. Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms. Proc Natl Acad Sci U S A. 1990 Dec;87(24):10038–10042. doi: 10.1073/pnas.87.24.10038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ron Y., Sprent J. T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes. J Immunol. 1987 May 1;138(9):2848–2856. [PubMed] [Google Scholar]
  44. Rubin Kelley V., Bloom R. D., Yui M. A., Martin C., Price D. Pivotal role of colony stimulating factor-1 in lupus nephritis. Kidney Int Suppl. 1994 Feb;45:S83–S85. [PubMed] [Google Scholar]
  45. Santoro T. J., Portanova J. P., Kotzin B. L. The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice. J Exp Med. 1988 May 1;167(5):1713–1718. doi: 10.1084/jem.167.5.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Shlomchik M. J., Marshak-Rothstein A., Wolfowicz C. B., Rothstein T. L., Weigert M. G. The role of clonal selection and somatic mutation in autoimmunity. 1987 Aug 27-Sep 2Nature. 328(6133):805–811. doi: 10.1038/328805a0. [DOI] [PubMed] [Google Scholar]
  47. Shlomchik M. J., Zharhary D., Saunders T., Camper S. A., Weigert M. G. A rheumatoid factor transgenic mouse model of autoantibody regulation. Int Immunol. 1993 Oct;5(10):1329–1341. doi: 10.1093/intimm/5.10.1329. [DOI] [PubMed] [Google Scholar]
  48. Sobel E. S., Katagiri T., Katagiri K., Morris S. C., Cohen P. L., Eisenberg R. A. An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity. J Exp Med. 1991 Jun 1;173(6):1441–1449. doi: 10.1084/jem.173.6.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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]
  50. Taurog J. D., Raveche E. S., Smathers P. A., Glimcher L. H., Huston D. P., Hansen C. T., Steinberg A. D. T cell abnormalities in NZB mice occur independently of autoantibody production. J Exp Med. 1981 Feb 1;153(2):221–234. doi: 10.1084/jem.153.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Vlahakos D. V., Foster M. H., Adams S., Katz M., Ucci A. A., Barrett K. J., Datta S. K., Madaio M. P. Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites. Kidney Int. 1992 Jun;41(6):1690–1700. doi: 10.1038/ki.1992.242. [DOI] [PubMed] [Google Scholar]
  52. Vlahakos D., Foster M. H., Ucci A. A., Barrett K. J., Datta S. K., Madaio M. P. Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo. J Am Soc Nephrol. 1992 Feb;2(8):1345–1354. doi: 10.1681/ASN.V281345. [DOI] [PubMed] [Google Scholar]
  53. Watanabe-Fukunaga R., Brannan C. I., Copeland N. G., Jenkins N. A., Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. doi: 10.1038/356314a0. [DOI] [PubMed] [Google Scholar]
  54. Watanabe-Fukunaga R., Brannan C. I., Itoh N., Yonehara S., Copeland N. G., Jenkins N. A., Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol. 1992 Feb 15;148(4):1274–1279. [PubMed] [Google Scholar]
  55. Watson M. L., Rao J. K., Gilkeson G. S., Ruiz P., Eicher E. M., Pisetsky D. S., Matsuzawa A., Rochelle J. M., Seldin M. F. Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med. 1992 Dec 1;176(6):1645–1656. doi: 10.1084/jem.176.6.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wofsy D., Hardy R. R., Seaman W. E. The proliferating cells in autoimmune MRL/lpr mice lack L3T4, an antigen on "helper" T cells that is involved in the response to class II major histocompatibility antigens. J Immunol. 1984 Jun;132(6):2686–2689. [PubMed] [Google Scholar]
  57. Wofsy D., Ledbetter J. A., Hendler P. L., Seaman W. E. Treatment of murine lupus with monoclonal anti-T cell antibody. J Immunol. 1985 Feb;134(2):852–857. [PubMed] [Google Scholar]
  58. Yee J., Kuncio G. S., Neilson E. G. Tubulointerstitial injury following glomerulonephritis. Semin Nephrol. 1991 May;11(3):361–366. [PubMed] [Google Scholar]
  59. Zhou T., Bluethmann H., Eldridge J., Berry K., Mountz J. D. Origin of CD4-CD8-B220+ T cells in MRL-lpr/lpr mice. Clues from a T cell receptor beta transgenic mouse. J Immunol. 1993 Apr 15;150(8 Pt 1):3651–3667. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES