• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Nov 1, 1992; 176(5): 1343–1353.
PMCID: PMC2119422

Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells

Abstract

Pre-B cell lines proliferating for several months on stromal cells in the presence of interleukin 7 (IL-7) were established from fetal liver of (NZB x NZW)F1 mice. They express the B lineage-specific markers PB76, B220, and VpreB, but do not express surface immunoglobulin (sIg). Upon removal of IL-7 from the culture, they differentiate to sIg+ B cells that can then be stimulated by lipopolysaccharide to become IgM- secreting cells. Transfer of these pre-B cell lines into SCID mice leads to hypergammaglobulinemia of IgM (600-900 micrograms/ml), IgG2a (1-3 mg/ml), and IgG3 (300-500 micrograms/ml) for the next 3-5 mo. The spleen appears populated with (NZB x NZW)F1-derived pre-B cells, few B cells, and many IgM and/or IgG-producing plasma cells. In contrast, SCID mice populated with pre-B cell lines of normal (C57BL/6 x DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (approximately 100- 300 micrograms/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB x NZW)F1 pre-B cell-populated SCID mice contain elevated serum titers of IgG antinuclear autoantibodies, but no retroviral gp70-specific nor erythrocyte-specific autoantibodies. Up to 20% of the SCID mice develop proteinuria as a consequence of IgG deposits in the kidney glomeruli during a 7-mo period of observation. All signs of autoimmune disease seen in these mice are independent of the sex of the SCID host. This experimental system provides a distinction between the disease-determining (NZB x NZW)F1 genes, which are expressed in the B lymphocyte lineage and cause the development of the disease, from those expressed in other cell lineages which only modulate its progression.

Full Text

The Full Text of this article is available as a PDF (1.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Slack JH, Hang L, Barkley J, Fulton RJ, D'Hoostelaere L, Robinson A, Dixon FJ. Isotypes of spontaneous and mitogen-induced autoantibodies in SLE-prone mice. J Immunol. 1984 Mar;132(3):1271–1275. [PubMed]
  • Lambert PH, Dixon FJ. Pathogenesis of the glomerulonephritis of NZB/W mice. J Exp Med. 1968 Mar 1;127(3):507–522. [PMC free article] [PubMed]
  • Staples PJ, Talal N. Relative inability to induce tolerance in adult NZB and NZB-NZW F1 mice. J Exp Med. 1969 Jan 1;129(1):123–139. [PMC free article] [PubMed]
  • Goldings EA, Cohen PL, McFadden SF, Ziff M, Vitetta ES. Defective B cell tolerance in adult (NZB X MZW)F1 mice. J Exp Med. 1980 Sep 1;152(3):730–735. [PMC free article] [PubMed]
  • Yoshida H, Yoshida M, Izui S, Lambert PH. Distinct clonotypes of anti-DNA antibodies in mice with lupus nephritis. J Clin Invest. 1985 Aug;76(2):685–694. [PMC free article] [PubMed]
  • Howie JB, Helyer BJ. The immunology and pathology of NZB mice. Adv Immunol. 1968;9:215–266. [PubMed]
  • Gioud M, Kotzin BL, Rubin RL, Joslin FG, Tan EM. In vivo and in vitro production of anti-histone antibodies in NZB/NZW mice. J Immunol. 1983 Jul;131(1):269–274. [PubMed]
  • Steward MW, Hay FC. Changes in immunoglobulin class and subclass of anti-DNA antibodies with increasing age in N/ZBW F1 hybrid mice. Clin Exp Immunol. 1976 Nov;26(2):363–370. [PMC free article] [PubMed]
  • Izui S, Elder JH, McConahey PJ, Dixon FJ. Identification of retroviral gp70 and anti-gp70 antibodies involved in circulating immune complexes in NZB X NZW mice. J Exp Med. 1981 May 1;153(5):1151–1160. [PMC free article] [PubMed]
  • Jyonouchi H, Kincade PW. Precocious and enhanced functional maturation of B lineage cells in New Zealand Black mice during embryonic development. J Exp Med. 1984 Apr 1;159(4):1277–1282. [PMC free article] [PubMed]
  • Maruyama N, Furukawa F, Nakai Y, Sasaki Y, Ohta K, Ozaki S, Hirose S, Shirai T. Genetic studies of autoimmunity in New Zealand mice. IV. Contribution of NZB and NZW genes to the spontaneous occurrence of retroviral gp70 immune complexes in (NZB X NZW)F1 hybrid and the correlation to renal disease. J Immunol. 1983 Feb;130(2):740–746. [PubMed]
  • Laskin CA, Taurog JD, Smathers PA, Steinberg AD. Studies of defective tolerance in murine lupus. J Immunol. 1981 Nov;127(5):1743–1747. [PubMed]
  • Hang L, Slack JH, Amundson C, Izui S, Theofilopoulos AN, Dixon FJ. Induction of murine autoimmune disease by chronic polyclonal B cell activation. J Exp Med. 1983 Mar 1;157(3):874–883. [PMC free article] [PubMed]
  • Moutsopoulos HM, Boehm-Truitt M, Kassan SS, Chused TM. Demonstration of activation of B lymphocytes in New Zealand black mice at birth by an immunoradiometric assay for murine IgM. J Immunol. 1977 Nov;119(5):1639–1644. [PubMed]
  • Knight JG, Adams DD. Three genes for lupus nephritis in NZB x NZW mice. J Exp Med. 1978 Jun 1;147(6):1653–1660. [PMC free article] [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]
  • Izui S, McConahey PJ, Clark JP, Hang LM, Hara I, Dixon FJ. Retroviral gp70 immune complexes in NZB x NZW F2 mice with murine lupus nephritis. J Exp Med. 1981 Aug 1;154(2):517–528. [PMC free article] [PubMed]
  • Bocchieri MH, Cooke A, Smith JB, Weigert M, Riblet RJ. Independent segregation of NZB immune abnormalities in NZB x C58 recombinant inbred mice. Eur J Immunol. 1982 Apr;12(4):349–354. [PubMed]
  • Kohno A, Yoshida H, Sekita K, Maruyama N, Ozaki S, Hirose S, Shirai T. Genetic regulation of the class conversion of dsDNA-specific antibodies in (NZB X NZW)F1 hybrid. Immunogenetics. 1983;18(5):513–524. [PubMed]
  • Hirose S, Nagasawa R, Sekikawa I, Hamaoki M, Ishida Y, Sato H, Shirai T. Enhancing effect of H-2-linked NZW gene(s) on the autoimmune traits of (NZB X NZW)F1 mice. J Exp Med. 1983 Jul 1;158(1):228–233. [PMC free article] [PubMed]
  • Kotzin BL, Palmer E. The contribution of NZW genes to lupus-like disease in (NZB x NZW)F1 mice. J Exp Med. 1987 May 1;165(5):1237–1251. [PMC free article] [PubMed]
  • Akizuki M, Reeves JP, Steinberg AD. Expression of autoimmunity by NZB/NZW marrow. Clin Immunol Immunopathol. 1978 Jul;10(3):247–250. [PubMed]
  • Rolink A, Melchers F. Molecular and cellular origins of B lymphocyte diversity. Cell. 1991 Sep 20;66(6):1081–1094. [PubMed]
  • Wofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med. 1985 Feb 1;161(2):378–391. [PMC free article] [PubMed]
  • Babcock SK, Appel VB, Schiff M, Palmer E, Kotzin BL. Genetic analysis of the imperfect association of H-2 haplotype with lupus-like autoimmune disease. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7552–7555. [PMC free article] [PubMed]
  • Rolink A, Kudo A, Karasuyama H, Kikuchi Y, Melchers F. Long-term proliferating early pre B cell lines and clones with the potential to develop to surface Ig-positive, mitogen reactive B cells in vitro and in vivo. EMBO J. 1991 Feb;10(2):327–336. [PMC free article] [PubMed]
  • Strasser A. PB76: a novel surface glycoprotein preferentially expressed on mouse pre-B cells and plasma cells detected by the monoclonal antibody G-5-2. Eur J Immunol. 1988 Nov;18(11):1803–1810. [PubMed]
  • Kincade PW, Lee G, Watanabe T, Sun L, Scheid MP. Antigens displayed on murine B lymphocyte precursors. J Immunol. 1981 Dec;127(6):2262–2268. [PubMed]
  • Leptin M. Monoclonal antibodies specific for murine IgM. II. Activation of B lymphocytes by monoclonal antibodies specific for the four constant domains of IgM. Eur J Immunol. 1985 Feb;15(2):131–137. [PubMed]
  • Yelton DE, Desaymard C, Scharff MD. Use of monoclonal anti-mouse immunoglobulin to detect mouse antibodies. Hybridoma. 1981;1(1):5–11. [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]
  • Ledbetter JA, Herzenberg LA. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. [PubMed]
  • Iscove NN, Melchers F. Complete replacement of serum by albumin, transferrin, and soybean lipid in cultures of lipopolysaccharide-reactive B lymphocytes. J Exp Med. 1978 Mar 1;147(3):923–933. [PMC free article] [PubMed]
  • Gronowicz E, Coutinho A, Melchers F. A plaque assay for all cells secreting Ig of a given type or class. Eur J Immunol. 1976 Aug;6(8):588–590. [PubMed]
  • Rolink AG, Melchers F, Palacios R. Monoclonal antibodies reactive with the mouse interleukin 5 receptor. J Exp Med. 1989 May 1;169(5):1693–1701. [PMC free article] [PubMed]
  • Rolink AG, Radaszkiewicz T, Melchers F. The autoantigen-binding B cell repertoires of normal and of chronically graft-versus-host-diseased mice. J Exp Med. 1987 Jun 1;165(6):1675–1687. [PMC free article] [PubMed]
  • Luzuy S, Merino J, Engers H, Izui S, Lambert PH. Autoimmunity after induction of neonatal tolerance to alloantigens: role of B cell chimerism and F1 donor B cell activation. J Immunol. 1986 Jun 15;136(12):4420–4426. [PubMed]
  • Reininger L, Shibata T, Schurmans S, Merino R, Fossati L, Lacour M, Izui S. Spontaneous production of anti-mouse red blood cell autoantibodies is independent of the polyclonal activation in NZB mice. Eur J Immunol. 1990 Nov;20(11):2405–2410. [PubMed]
  • Evans LH, Morrison RP, Malik FG, Portis J, Britt WJ. A neutralizable epitope common to the envelope glycoproteins of ecotropic, polytropic, xenotropic, and amphotropic murine leukemia viruses. J Virol. 1990 Dec;64(12):6176–6183. [PMC free article] [PubMed]
  • Carroll AM, Hardy RR, Bosma MJ. Occurrence of mature B (IgM+, B220+) and T (CD3+) lymphocytes in scid mice. J Immunol. 1989 Aug 15;143(4):1087–1093. [PubMed]
  • Custer RP, Bosma GC, Bosma MJ. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol. 1985 Sep;120(3):464–477. [PMC free article] [PubMed]
  • Ohsugi Y, Gershwin ME, Ahmed A, Skelly RR, Milich DR. Studies of congenitally immunologic mutant New Zealand mice. VI. Spontaneous and induced autoantibodies to red cells and DNA occur in New Zealand X-linked immunodeficient (Xid) mice without phenotypic alternations of the Xid gene or generalized polyclonal B cell activation. J Immunol. 1982 May;128(5):2220–2227. [PubMed]
  • Steinberg BJ, Smathers PA, Frederiksen K, Steinberg AD. Ability of the xid gene to prevent autoimmunity in (NZB X NZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA. J Clin Invest. 1982 Sep;70(3):587–597. [PMC free article] [PubMed]
  • Scher I. CBA/N immune defective mice; evidence for the failure of a B cell subpopulation to be expressed. Immunol Rev. 1982;64:117–136. [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]
  • Merino R, Fossati L, Lacour M, Izui S. Selective autoantibody production by Yaa+ B cells in autoimmune Yaa(+)-Yaa- bone marrow chimeric mice. J Exp Med. 1991 Nov 1;174(5):1023–1029. [PMC free article] [PubMed]
  • Hang L, Theofilopoulos AN, Balderas RS, Francis SJ, Dixon FJ. The effect of thymectomy on lupus-prone mice. J Immunol. 1984 Apr;132(4):1809–1813. [PubMed]
  • Gershwin ME, Ohsugi Y, Ahmed A, Castles JJ, Scibienski R, Ikeda RM. Studies of congenitally immunologically mutant New Zealand mice. IV. Development of autoimmunity in congenitally athymic (nude) New Zealand Black x White F1 hybrid mice. J Immunol. 1980 Sep;125(3):1189–1195. [PubMed]
  • Mihara M, Ohsugi Y, Saito K, Miyai T, Togashi M, Ono S, Murakami S, Dobashi K, Hirayama F, Hamaoka T. Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals. J Immunol. 1988 Jul 1;141(1):85–90. [PubMed]
  • Frederickson GG, Basch RS. L3T4 antigen expression by hemopoietic precursor cells. J Exp Med. 1989 Apr 1;169(4):1473–1478. [PMC free article] [PubMed]

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

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...