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J Exp Med. Oct 1, 1994; 180(4): 1295–1306.
PMCID: PMC2191708

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

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.

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Selected References

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  • Couser WG, Salant DJ, Madaio MP, Adler S, Groggel GC. Factors influencing glomerular and tubulointerstitial patterns of injury in SLE. Am J Kidney Dis. 1982 Jul;2(1 Suppl 1):126–134. [PubMed]
  • Foster MH, Cizman B, Madaio MP. Nephritogenic autoantibodies in systemic lupus erythematosus: immunochemical properties, mechanisms of immune deposition, and genetic origins. Lab Invest. 1993 Nov;69(5):494–507. [PubMed]
  • Kelley VR, Diaz-Gallo C, Jevnikar AM, Singer GG. Renal tubular epithelial and T cell interactions in autoimmune renal disease. Kidney Int Suppl. 1993 Jan;39:S108–S115. [PubMed]
  • Dixon FJ, Oldstone MB, 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]
  • Vlahakos DV, Foster MH, Adams S, Katz M, Ucci AA, Barrett KJ, Datta SK, Madaio MP. Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites. Kidney Int. 1992 Jun;41(6):1690–1700. [PubMed]
  • Jabs DA, Prendergast RA. 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. [PMC free article] [PubMed]
  • Moyer CF, Strandberg JD, Reinisch CL. 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]
  • Katagiri T, Cohen PL, Eisenberg RA. The lpr gene causes an intrinsic T cell abnormality that is required for hyperproliferation. J Exp Med. 1988 Mar 1;167(3):741–751. [PMC free article] [PubMed]
  • Taurog JD, Raveche ES, Smathers PA, Glimcher LH, Huston DP, Hansen CT, Steinberg AD. T cell abnormalities in NZB mice occur independently of autoantibody production. J Exp Med. 1981 Feb 1;153(2):221–234. [PMC free article] [PubMed]
  • Steinberg AD, Roths JB, Murphy ED, Steinberg RT, Raveche ES. 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]
  • Wofsy D, Ledbetter JA, Hendler PL, Seaman WE. Treatment of murine lupus with monoclonal anti-T cell antibody. J Immunol. 1985 Feb;134(2):852–857. [PubMed]
  • Santoro TJ, Portanova JP, Kotzin BL. 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. [PMC free article] [PubMed]
  • Rajagopalan S, Zordan T, Tsokos GC, Datta SK. 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. [PMC free article] [PubMed]
  • Díaz Gallo C, Jevnikar AM, Brennan DC, Florquin S, Pacheco-Silva A, Kelley VR. Autoreactive kidney-infiltrating T-cell clones in murine lupus nephritis. Kidney Int. 1992 Oct;42(4):851–859. [PubMed]
  • Dang H, Harbeck RJ. 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. [PubMed]
  • Pankewycz OG, Migliorini P, Madaio MP. Polyreactive autoantibodies are nephritogenic in murine lupus nephritis. J Immunol. 1987 Nov 15;139(10):3287–3294. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Lin RH, Mamula MJ, Hardin JA, Janeway CA., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. [PMC free article] [PubMed]
  • Mamula MJ, Lin RH, Janeway CA, Jr, Hardin JA. 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]
  • Herron LR, Coffman RL, Kotzin BL. 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. [PubMed]
  • Klinman DM, Steinberg AD. Proliferation of anti-DNA-producing NZB B cells in a non-autoimmune environment. J Immunol. 1986 Jul 1;137(1):69–75. [PubMed]
  • Sobel ES, Katagiri T, Katagiri K, Morris SC, Cohen PL, Eisenberg RA. 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. [PMC free article] [PubMed]
  • 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]
  • Raveche ES, Novotny EA, Hansen CT, Tjio JH, Steinberg AD. 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. [PMC free article] [PubMed]
  • Eastcott JW, Schwartz RS, Datta SK. 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]
  • Cerny A, Kimoto M, Hügin AW, 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]
  • Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ, Murphy ED, Roths JB, Dixon FJ. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978 Nov 1;148(5):1198–1215. [PMC free article] [PubMed]
  • Izui S, Kelley VE, Masuda K, Yoshida H, Roths JB, Murphy ED. Induction of various autoantibodies by mutant gene lpr in several strains of mice. J Immunol. 1984 Jul;133(1):227–233. [PubMed]
  • Wofsy D, Hardy RR, Seaman WE. 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]
  • Davidson WF, Dumont FJ, Bedigian HG, Fowlkes BJ, Morse HC., 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]
  • Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. [PubMed]
  • 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. [PubMed]
  • Watanabe-Fukunaga R, Brannan CI, Itoh N, Yonehara S, Copeland NG, Jenkins NA, Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol. 1992 Feb 15;148(4):1274–1279. [PubMed]
  • Drappa J, Brot N, Elkon KB. 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. [PMC free article] [PubMed]
  • Chen J, Trounstine M, Alt FW, Young F, Kurahara C, Loring JF, 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. [PubMed]
  • Shlomchik MJ, Zharhary D, Saunders T, Camper SA, Weigert MG. A rheumatoid factor transgenic mouse model of autoantibody regulation. Int Immunol. 1993 Oct;5(10):1329–1341. [PubMed]
  • Kincade PW, Lee G, Sun L, Watanabe T. Monoclonal rat antibodies to murine IgM determinants. J Immunol Methods. 1981;42(1):17–26. [PubMed]
  • Coffman RL, Weissman IL. A monoclonal antibody that recognizes B cells and B cell precursors in mice. J Exp Med. 1981 Feb 1;153(2):269–279. [PMC free article] [PubMed]
  • Dialynas DP, Quan ZS, Wall KA, Pierres A, Quintáns J, Loken MR, Pierres M, Fitch FW. 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]
  • Vlahakos D, Foster MH, Ucci AA, Barrett KJ, Datta SK, Madaio MP. 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. [PubMed]
  • Madaio MP, 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]
  • Austin HA, 3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int. 1984 Apr;25(4):689–695. [PubMed]
  • 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]
  • Janeway CA, Jr, Ron J, Katz ME. The B cell is the initiating antigen-presenting cell in peripheral lymph nodes. J Immunol. 1987 Feb 15;138(4):1051–1055. [PubMed]
  • Budd RC, Schreyer M, Miescher GC, MacDonald HR. 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]
  • 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]
  • Zhou T, Bluethmann H, Eldridge J, Berry K, Mountz JD. 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]
  • Shlomchik MJ, Marshak-Rothstein A, Wolfowicz CB, Rothstein TL, Weigert MG. The role of clonal selection and somatic mutation in autoimmunity. Nature. 328(6133):805–811. [PubMed]
  • Levine J, Hartwell D, Beller DI. Imbalanced cytokine production by macrophages from autoimmune-prone mice. Immunol Lett. 1991 Oct;30(2):183–192. [PubMed]
  • Bloom RD, Florquin S, Singer GG, Brennan DC, Kelley VR. Colony stimulating factor-1 in the induction of lupus nephritis. Kidney Int. 1993 May;43(5):1000–1009. [PubMed]
  • Rubin Kelley V, Bloom RD, Yui MA, Martin C, Price D. Pivotal role of colony stimulating factor-1 in lupus nephritis. Kidney Int Suppl. 1994 Feb;45:S83–S85. [PubMed]
  • Halloran PF, 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]
  • Yee J, Kuncio GS, Neilson EG. Tubulointerstitial injury following glomerulonephritis. Semin Nephrol. 1991 May;11(3):361–366. [PubMed]
  • Berden JH, Hang L, McConahey PJ, Dixon FJ. Analysis of vascular lesions in murine SLE. I. Association with serologic abnormalities. J Immunol. 1983 Apr;130(4):1699–1705. [PubMed]
  • 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]
  • Huang L, Sye K, Crispe IN. 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. [PubMed]
  • Miyama-Inaba M, Kuma S, Inaba K, Ogata H, Iwai H, Yasumizu R, Muramatsu S, Steinman RM, Ikehara S. Unusual phenotype of B cells in the thymus of normal mice. J Exp Med. 1988 Aug 1;168(2):811–816. [PMC free article] [PubMed]
  • Watson ML, Rao JK, Gilkeson GS, Ruiz P, Eicher EM, Pisetsky DS, Matsuzawa A, Rochelle JM, Seldin MF. 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. [PMC free article] [PubMed]
  • Jevnikar AM, Grusby MJ, Glimcher LH. Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. J Exp Med. 1994 Apr 1;179(4):1137–1143. [PMC free article] [PubMed]

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