Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1983 Mar;51(3):579–586.

Induction of autoimmunity in normal mice by thymectomy and administration of polyclonal B cell activators: association with contrasuppressor function.

H R Smith, D R Green, P A Smathers, R K Gershon, E S Raveche, A D Steinberg
PMCID: PMC1536771  PMID: 6602021

Abstract

In order to gain insight into the role of polyclonal B cell activation in the development of autoimmunity, non-autoimmune mice were given chronic injections of polyclonal B cell activators (PBA). In addition, to assess the contribution of T cell regulation of such PBA-induced B cell hyperactivity, the additional effect of postnatal thymectomy was studied. Mice that were postnatally thymectomized and given PBA (LPS +/- poly rI X rC) thrice weekly were found to have elevated levels of IgG and significantly increased serum concentrations of anti-ssDNA. This anti-DNA production was greater than that observed with PBA alone or with thymectomy alone. The entire experiment was repeated with different non-autoimmune mice with the same result. Numbers of proliferating cells in the spleens of the mice in the various groups were analysed by flow cytometry. The number of cells in S+G2+M phases of the cell cycle was significantly increased by PBA or thymectomy alone as well as by the combination. As a result, B cell proliferation was not sufficient to result in maximal anti-ssDNA; an additional T cell defect was required. This was further studied in an in vitro assay for suppressor and contrasuppressor activity. In three separate experiments, mice which were clinically autoimmune were found to have defective suppressor function and the presence of abnormal contrasuppressor activity, whereas non-autoimmune controls had normal suppressor function and no contrasuppressor function. These results indicate that the combination of PBA and thymectomy can most easily induce autoimmunity. The autoimmune state so induced in non-autoimmune strains was associated with a failure of normal suppressor function and the abnormal presence of contrasuppressor function. These results have important implications for spontaneously occurring autoimmune diseases.

Full text

PDF
579

Selected References

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

  1. Blanchard D., Bach M. A. Thymic function in NZB mice. III. Impairment of the activity of specific suppressor cells involved in the regulation of antibody production against sheep red blood cells. Clin Exp Immunol. 1980 Oct;42(1):1–9. [PMC free article] [PubMed] [Google Scholar]
  2. Burns F. D., Marrack P. C., Kappler J. W., Janeway C. A., Jr Functional heterogeneity among the T-derived lymphocytes of the mouse. IV. Nature of spontaneously induced suppressor cells. J Immunol. 1975 Apr;114(4):1345–1347. [PubMed] [Google Scholar]
  3. Cantor H., Gershon R. K. Immunological circuits: cellular composition. Fed Proc. 1979 Jun;38(7):2058–2064. [PubMed] [Google Scholar]
  4. Carpenter D. F., Steinberg A. D., Schur P. H., Talal N. The pathogenesis of autoimmunity in New Zealand mice. II. Acceleration of glomerulonephritis by polyinosinic-polycytidylic acid. Lab Invest. 1970 Dec;23(6):628–634. [PubMed] [Google Scholar]
  5. Chiller J. M., Weigle W. O. Termination of tolerance to human gamma globulin in mice by antigen and bacterial lipopolysaccharide (endotoxin). J Exp Med. 1973 Mar 1;137(3):740–750. doi: 10.1084/jem.137.3.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cunningham A. J., Szenberg A. Further improvements in the plaque technique for detecting single antibody-forming cells. Immunology. 1968 Apr;14(4):599–600. [PMC free article] [PubMed] [Google Scholar]
  7. Dresser D. W., Popham A. M. Induction of an IgM anti-(bovine)-IgG response in mice by bacterial lipopolysaccharide. Nature. 1976 Dec 9;264(5586):552–554. doi: 10.1038/264552a0. [DOI] [PubMed] [Google Scholar]
  8. Fish F., Ziff M. The in vitro and in vivo induction of anti-double-stranded DNA antibodies in normal and autoimmune mice. J Immunol. 1982 Jan;128(1):409–414. [PubMed] [Google Scholar]
  9. Fournié G. J., Lambert P. H., Meischer P. A. Release of DNA in circulating blood and induction of anti-DNA antibodies after injection of bacterial lipopolysaccharides. J Exp Med. 1974 Nov 1;140(5):1189–1206. doi: 10.1084/jem.140.5.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. GOOD R. A., DALMASSO A. P., MARTINEZ C., ARCHER O. K., PIERCE J. C., PAPERMASTER B. W. The role of the thymus in development of immunologic capacity in rabbits and mice. J Exp Med. 1962 Nov 1;116:773–796. doi: 10.1084/jem.116.5.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gerber N. L., Hardin J. A., Chused T. M., Steinberg A. D. Loss with age in NZB-W mice of thymic suppressor cells in the graft-vs-host reaction. J Immunol. 1974 Nov;113(5):1618–1625. [PubMed] [Google Scholar]
  12. Gershon R. K., Eardley D. D., Durum S., Green D. R., Shen F. W., Yamauchi K., Cantor H., Murphy D. B. Contrasuppression. A novel immunoregulatory activity. J Exp Med. 1981 Jun 1;153(6):1533–1546. doi: 10.1084/jem.153.6.1533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gershwin M. E., Castles J. J., Erickson K., Ahmed A. Studies of congenitally immunologic mutant New Zealand mice. II. Absence of T cell progenitor populations and B cell defects of congenitally athymic (nude) New Zealand Black (NZB) mice. J Immunol. 1979 May;122(5):2020–2025. [PubMed] [Google Scholar]
  14. Green D. R., Eardley D. D., Kimura A., Murphy D. B., Yamauchi K., Gershon R. K. Immunoregulatory circuits which modulate responsiveness to suppressor cell signals: characterization of an effector cell in the contrasuppressor circuit. Eur J Immunol. 1981 Dec;11(12):973–980. doi: 10.1002/eji.1830111205. [DOI] [PubMed] [Google Scholar]
  15. HELYER B. J., HOWIE J. B. THE THYMUS AND AUTOIMMUNE DISEASE. Lancet. 1963 Nov 16;2(7316):1026–1029. doi: 10.1016/s0140-6736(63)90003-5. [DOI] [PubMed] [Google Scholar]
  16. Hodes R. J., Hathcock K. S. In vitro generation of suppressor cell activity: suppression of in vitro induction if cell-mediated cytotoxicity. J Immunol. 1976 Jan;116(1):167–177. [PubMed] [Google Scholar]
  17. 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]
  18. Izui S., Lambert P. H., Fournié G. J., Türler H., Miescher P. A. Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identificantion of circulating DNA and renal localization of DNA-anti-DNA complexes. J Exp Med. 1977 May 1;145(5):1115–1130. doi: 10.1084/jem.145.5.1115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Krishan A. Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining. J Cell Biol. 1975 Jul;66(1):188–193. doi: 10.1083/jcb.66.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Laskin C. A., Smathers P. A., Reeves J. P., Steinberg A. D. Studies of defective tolerance induction in NZB mice. Evidence for a marrow pre-T cell defect. J Exp Med. 1982 Apr 1;155(4):1025–1036. doi: 10.1084/jem.155.4.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Laskin C. A., Taurog J. D., Smathers P. A., Steinberg A. D. Studies of defective tolerance in murine lupus. J Immunol. 1981 Nov;127(5):1743–1747. [PubMed] [Google Scholar]
  23. Mishell R. I., Dutton R. W. Immunization of dissociated spleen cell cultures from normal mice. J Exp Med. 1967 Sep 1;126(3):423–442. doi: 10.1084/jem.126.3.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Moutsopoulos H. M., Boehm-Truitt M., Kassan S. S., Chused T. M. 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] [Google Scholar]
  25. Parish C. R. Appearance of non-specific suppressor T cells during in vitro culture. Immunology. 1977 Oct;33(4):597–603. [PMC free article] [PubMed] [Google Scholar]
  26. Powell D. E., Steinberg A. D. The pathogenesis of autoimmunity in New Zealand mice. IV. Independent stimulation of antibodies to DNA and RNA. Clin Exp Immunol. 1972 Nov;12(3):419–427. [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Reeves J. P., Taurog J. D., Steinberg A. D. Polyclonal B-cell activation of autoantibodies (CBA/N x NZB)F1 mice by polyinosinic polycytidylic acid. Clin Immunol Immunopathol. 1981 May;19(2):170–180. doi: 10.1016/0090-1229(81)90060-x. [DOI] [PubMed] [Google Scholar]
  29. Sawada S., Talal N. Characteristics of in vitro production of antibodies to DNA in normal and autoimmune mice. J Immunol. 1979 Jun;122(6):2309–2313. [PubMed] [Google Scholar]
  30. Silverman D. A., Rose N. R. Neonatal thymectomy increases the incidence of spontaneous and methylcholanthrene-enhanced thyroiditis in rats. Science. 1974 Apr 12;184(4133):162–163. doi: 10.1126/science.184.4133.162. [DOI] [PubMed] [Google Scholar]
  31. Smathers P. A., Steinberg B. J., Reeves J. P., Steinberg A. D. Effects of polyclonal immune stimulators upon NZB.xid congenic mice. J Immunol. 1982 Mar;128(3):1414–1419. [PubMed] [Google Scholar]
  32. Smith H. R., Green D. R., Raveche E. S., Smathers P. A., Gershon R. K., Steinberg A. D. Studies of the induction of anti-DNA in normal mice. J Immunol. 1982 Dec;129(6):2332–2334. [PubMed] [Google Scholar]
  33. Steinberg A. D., Baron S., Talal N. The pathogenesis of autoimmunity in New Zealand mice, I. Induction of antinucleic acid antibodies by polyinosinic-polycytidylic acid. Proc Natl Acad Sci U S A. 1969 Aug;63(4):1102–1107. doi: 10.1073/pnas.63.4.1102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Steinberg A. D., Law L. D., Talal N. The role of NZB-NZW F1 thymus in experimental tolerance and auto-immunity. Arthritis Rheum. 1970 Jul-Aug;13(4):369–377. doi: 10.1002/art.1780130402. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. 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]
  38. 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]
  39. 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]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES