PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
 
J Exp Med. 1991 June 1; 173(6): 1441–1449.
PMCID: PMC2190844

An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity

Abstract

Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of anti-Thy 1.2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice. Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the lpr phenotype but not to the same extent. A similar experiment using B6/lpr-Igha recipients confirmed these findings. Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6.C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented, autoantibodies were only of the lpr allotype. In addition, in the presence of lpr B cells, normal B cells showed little response to an exogenous, T cell-dependent antigen. The data thus indicate that lpr B cells manifest an intrinsic abnormality which is essential for autoantibody production in the lpr model.

Full Text

The Full Text of this article is available as a PDF (903K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Nemazee DA, Studer S, Steinmetz M, Dembić Z, Kiefer M. The lymphoproliferating cells of MRL-lpr/lpr mice are a polyclonal population that bear the T lymphocyte receptor for antigen. Eur J Immunol. 1985 Aug;15(8):760–764. [PubMed]
  • Lewis DE, Giorgi JV, Warner NL. Flow cytometry analysis of T cells and continuous T-cell lines from autoimmune MRL/l mice. Nature. 1981 Jan 22;289(5795):298–300. [PubMed]
  • Dumont FJ, Habbersett RC, Coker LZ, Nichols EA, Treffinger JA. High level expression of the plasma cell antigen PC.1 on the T-cell subset expanding in MRL/MpJ-lpr/lpr mice: detection with a xenogeneic monoclonal antibody and alloantisera. Cell Immunol. 1985 Dec;96(2):327–337. [PubMed]
  • Katagiri K, Katagiri T, Eisenberg RA, Ting J, Cohen PL. Interleukin 2 responses of lpr and normal L3T4-/Lyt-2- T cells induced by TPA plus A23187. J Immunol. 1987 Jan 1;138(1):149–156. [PubMed]
  • Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. [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]
  • 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]
  • Monroe JG, Cambier JC, Mody EA, Pisetsky DS. Hyper-Ia antigen expression on B cells from B6-lpr/lpr mice correlates with manifestations of the autoimmune state. Clin Immunol Immunopathol. 1985 Jan;34(1):124–129. [PubMed]
  • Tsunetsugu Y, Fujiwara M. Resistance of tolerance induction in B cells of autoimmune mice--abnormal expansion of low affinity IgG-producing B-cell population. Cell Immunol. 1982 Aug;71(2):303–314. [PubMed]
  • Mosbach-Ozmen L, Gaveriaux C, Montecino-Rodriguez E, Loor F. The C57B1/6 nu/nu, lpr/lpr mouse. III. Autoimmunity status. Thymus. 1986;8(1-2):59–75. [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. [PubMed]
  • Perkins DL, Glaser RM, Mahon CA, Michaelson J, Marshak-Rothstein A. Evidence for an intrinsic B cell defect in lpr/lpr mice apparent in neonatal chimeras. J Immunol. 1990 Jul 15;145(2):549–555. [PubMed]
  • Morris SC, Cheek RL, Cohen PL, Eisenberg RA. Autoantibodies in chronic graft versus host result from cognate T-B interactions. J Exp Med. 1990 Feb 1;171(2):503–517. [PMC free article] [PubMed]
  • Kung JT, Sharrow SO, Sieckmann DG, Lieberman R, Paul WE. A mouse IgM allotypic determinant (Igh-6.5) recognized by a monoclonal rat antibody. J Immunol. 1981 Sep;127(3):873–876. [PubMed]
  • Stall AM, Loken MR. Allotypic specificities of murine IgD and IgM recognized by monoclonal antibodies. J Immunol. 1984 Feb;132(2):787–795. [PubMed]
  • Fisher CL, Eisenberg RA, Cohen PL. Quantitation and IgG subclass distribution of antichromatin autoantibodies in SLE mice. Clin Immunol Immunopathol. 1988 Feb;46(2):205–213. [PubMed]
  • Harmon RC, Stein N, Frelinger JA. Monoclonal antibodies reactive with H-2 determinants. Immunogenetics. 1983;18(5):541–545. [PubMed]
  • Ozato K, Mayer N, Sachs DH. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed]
  • Perkins DL, Michaelson J, Marshak-Rothstein A. The lpr gene is associated with resistance to engraftment by lymphoid but not erythroid stem cells from normal mice. J Immunol. 1987 Jan 15;138(2):466–469. [PubMed]
  • Rokutan K, Hosokawa T, Nakamura K, Koyama K, Aoike A, Kawai K. Increased superoxide anion production and glutathione peroxidase activity in peritoneal macrophages from autoimmune-prone MRL/Mp-Ipr/lpr mice. Int Arch Allergy Appl Immunol. 1988;87(2):113–119. [PubMed]
  • Fujiwara M, Kariyone A. One-way occurrence of graft-versus-host disease in bone marrow chimaeras between congenic MRL mice. Immunology. 1984 Oct;53(2):251–256. [PubMed]
  • Dziarski R. Comparison of in vitro and in vivo mitogenic and polyclonal antibody and autoantibody responses to peptidoglycan, LPS, protein A, PWM, PHA and Con A in normal and autoimmune mice. J Clin Lab Immunol. 1985 Feb;16(2):93–109. [PubMed]

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