Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1982 Aug 1;156(2):567–584. doi: 10.1084/jem.156.2.567

A natural model of immunologic tolerance. Tolerance to murine C5 is mediated by T cells, and antigen is required to maintain unresponsiveness

PMCID: PMC2186765  PMID: 6808076

Abstract

A unique experimental model is described, where natural immunologic tolerance to a well-defined soluble native antigen (murine C5) is examined in congenic strains of mice that differ only by the presence or the absence of C5. A highly sensitive hemolytic assay was developed to detect nanogram amounts of C5 as well as an assay of anti-C5 inhibition of C5 hemolytic activity. The latter was more sensitive than immunodiffusion. Two reciprocal approaches were used to study the cellular basis of tolerance in irradiated hosts of either strain. In the first, lymphoid cells from either strain were transferred to irradiated B10.D2OSN hosts that were lacking C5 and so would not hinder detection of anti-C5 antibody upon challenge with murine C5. Second, lymphoid cells from either strain were transferred to irradiated B10.D2NSN hosts, whose native C5 provided the antigenic stimulus. The immune response of whole nonadherent spleen cell suspension as well as mixtures of T and B cells (separated on the basis of surface immunoglobulin) from either strain were studied. In addition, the duration of tolerance and the antigen requirement to maintain it in irradiated C5-deficient hosts repopulated with C5-sufficient spleen cells was examined. The positive control of irradiated C5-deficient hosts repopulated with syngeneic spleen cells showed a primary and secondary response to immunization. In contrast, C5-sufficient spleen cells failed to respond both in the primary and the secondary response. Because the unresponsiveness was not caused by antigen carryover and was not antigen specific, it represents central tolerance. In C5- sufficient irradiated hosts (where immunization was not required and antigen was present in natural form and physiological concentration), transfer of C5-deficient cells mediated a drop in C5 levels to 10-20% of that noted in unreconstituted controls. T and B cell mixing experiments from the two strains into deficient or sufficient hosts demonstrated that tolerance is T cell dependent and that C5-sufficient or -deficient B cells could cooperate with nontolerant C5-sufficient T cells to produce significant anti-C5 antibody or mediate a significant drop in C5 levels. In addition, the presence of antigen was necessary to maintain tolerance. In conclusion, these results show that (a) natural tolerance to C5 is an active process that is T cell dependent and requires the presence of antigen; (b) in this natural model, clonal abortion does not seem to occur; and (c) both tolerant and nontolerant B cells retain the capacity to produce autoantibody.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Bankhurst A. D., Torrigiani G., Allison A. C. Lymphocytes binding human thyroglobulin in healthy people and its relevance to tolerance for autoantigens. Lancet. 1973 Feb 3;1(7797):226–230. doi: 10.1016/s0140-6736(73)90066-4. [DOI] [PubMed] [Google Scholar]
  2. Barcinski M. A., Rosenthal A. S. Immune response gene control of determinant selection. I. Intramolecular mapping of the immunogenic sites on insulin recognized by guinea pig T and B cells. J Exp Med. 1977 Mar 1;145(3):726–742. doi: 10.1084/jem.145.3.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borel Y., Kilham L., Kurtz S. E., Reinisch C. L. Dichotomy between the induction of suppressor cells and immunologic tolerance by adult thymectomy. J Exp Med. 1980 Mar 1;151(3):743–748. doi: 10.1084/jem.151.3.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borel Y., Reinisch C. L., Schlossman S. F. T and B cell in hapten-specific carrier-determined tolerance. J Exp Med. 1975 Nov 1;142(5):1254–1262. doi: 10.1084/jem.142.5.1254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. CINADER B., DUBISKI S., WARDLAW A. C. DISTRIBUTION, INHERITANCE, AND PROPERTIES OF AN ANTIGEN, MUB1, AND ITS RELATION TO HEMOLYTIC COMPLEMENT. J Exp Med. 1964 Nov 1;120:897–924. doi: 10.1084/jem.120.5.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cambier J. C., Uhr J. W., Kettman J. R., Vitetta E. S. B cell tolerance. I. Analysis of hapten-specific unresponsiveness induced in vitro in adult and neonatal murine spleen cell populations. J Immunol. 1977 Dec;119(6):2054–2059. [PubMed] [Google Scholar]
  7. Chiller J. M., Habicht G. S., Weigle W. O. Kinetic differences in unresponsiveness of thymus and bone marrow cells. Science. 1971 Feb 26;171(3973):813–815. doi: 10.1126/science.171.3973.813. [DOI] [PubMed] [Google Scholar]
  8. Diener E., Kraft N., Lee K. C., Shiozawa C. Antigen recognition. IV. Discrimination by antigen-binding immunocompetent B cells between immunity and tolerance is determined by adherent cells. J Exp Med. 1976 Apr 1;143(4):805–821. doi: 10.1084/jem.143.4.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fearon D. T., Austen K. F. Activation of the alternative complement pathway with rabbit erythrocytes by circumvention of the regulatory action of endogenous control proteins. J Exp Med. 1977 Jul 1;146(1):22–33. doi: 10.1084/jem.146.1.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hammer C. H., Wirtz G. H., Renfer L., Gresham H. D., Tack B. F. Large scale isolation of functionally active components of the human complement system. J Biol Chem. 1981 Apr 25;256(8):3995–4006. [PubMed] [Google Scholar]
  11. Ivanyi J., Salerno A. Cellular mechanisms of escape from immunological tolerance. Immunology. 1972 Feb;22(2):247–257. [PMC free article] [PubMed] [Google Scholar]
  12. Jemmerson R., Margoliash E. Specificity of the antibody response of rabbits to a self-antigen. Nature. 1979 Nov 29;282(5738):468–471. doi: 10.1038/282468a0. [DOI] [PubMed] [Google Scholar]
  13. Klaus G. G., Cross A. M. The influence of epitope density on the immunological properties of hapten-protein conjugates. III. Induction of hapten-specific tolerance by heavily and lightly hapten-substituted serum albumin. Scand J Immunol. 1974;3(6):797–808. doi: 10.1111/j.1365-3083.1974.tb01315.x. [DOI] [PubMed] [Google Scholar]
  14. LEDERBERG J. Genes and antibodies. Science. 1959 Jun 19;129(3364):1649–1653. doi: 10.1126/science.129.3364.1649. [DOI] [PubMed] [Google Scholar]
  15. NOSSAL G. J. The induction of immunological tolerance in rats to foreign erythrocytes. Aust J Exp Biol Med Sci. 1958 Jun;36(3):235–244. doi: 10.1038/icb.1958.25. [DOI] [PubMed] [Google Scholar]
  16. Nossal G. J., Pike B. L. Clonal anergy: persistence in tolerant mice of antigen-binding B lymphocytes incapable of responding to antigen or mitogen. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1602–1606. doi: 10.1073/pnas.77.3.1602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nossal G. J., Pike B. L. Mechanisms of clonal abortion tolerogenesis. I. Response of immature hapten-specific B lymphocytes. J Exp Med. 1978 Nov 1;148(5):1161–1170. doi: 10.1084/jem.148.5.1161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ooi Y. M., Colten H. R. Biosynthesis and post-synthetic modification of a precursor (pro-C5) of the fifth component of mouse complement (C5). J Immunol. 1979 Dec;123(6):2494–2498. [PubMed] [Google Scholar]
  19. Ooi Y. M., Harris D. E., Edelson P. J., Colten H. R. Post-translational control of complement (C5) production by resident and stimulated mouse macrophages. J Immunol. 1980 May;124(5):2077–2081. [PubMed] [Google Scholar]
  20. Parker D. C., Fothergill J. J., Wadsworth D. C. B lymphocyte activation by insoluble anti-immunoglobulin: induction of immunoglobulin secretion by a T cell-dependent soluble factor. J Immunol. 1979 Aug;123(2):931–941. [PubMed] [Google Scholar]
  21. Parks D. E., Doyle M. V., Weigle W. O. Induction and mode of action of suppressor cells generated against human gamma globulin. I. An immunologic unresponsive state devoid of demonstrable suppressor cells. J Exp Med. 1978 Sep 1;148(3):625–638. doi: 10.1084/jem.148.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Primi D., Hammarström L., Smith C. I., Möller G. Characterization of self-reactive B cells by polyclonal B-cell activators. J Exp Med. 1977 Jan 1;145(1):21–30. doi: 10.1084/jem.145.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. ROSENBERG L. T., TACHIBANA D. K. Activity of mouse complement. J Immunol. 1962 Dec;89:861–867. [PubMed] [Google Scholar]
  24. RUOSLAHTI E., Pihko H., Becker M., Mäkelä O. Rabbit alpha-fetoprotein: normal levels and breakage tolerance with haptenated homologous alpha-fetoprotein. Eur J Immunol. 1975 Jan;5(1):7–10. doi: 10.1002/eji.1830050103. [DOI] [PubMed] [Google Scholar]
  25. Rajewsky K., Brenig C. Paralysis to serum albumins in T and B lymphocytes in mice. Dose dependence, specificity and kinetics of escape. Eur J Immunol. 1974 Feb;4(2):120–125. doi: 10.1002/eji.1830040211. [DOI] [PubMed] [Google Scholar]
  26. Reichlin M. Amino acid substitution and the antigenicity of globular proteins. Adv Immunol. 1975;20:71–123. doi: 10.1016/s0065-2776(08)60207-2. [DOI] [PubMed] [Google Scholar]
  27. Rose N. R., Kong Y. C., Okayasu I., Giraldo A. A., Beisel K., Sundick R. S. T-cell regulation in autoimmune thyroiditis. Immunol Rev. 1981;55:299–314. doi: 10.1111/j.1600-065x.1981.tb00346.x. [DOI] [PubMed] [Google Scholar]
  28. Ruoslahti E., Wigzell H. Breakage of tolerance to alpha foetoprotein in monkeys. Nature. 1975 Jun 26;255(5511):716–717. doi: 10.1038/255716a0. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Sundsmo J. S., Götze O. Human monocyte spreading induced by factor Bb of the alternative pathway of complement activation. A possible role for C5 in monocyte spreading. J Exp Med. 1981 Sep 1;154(3):763–777. doi: 10.1084/jem.154.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Teale J. M., Mandel T. E. Ontogenic development of B-lymphocyte function and tolerance susceptibility in vivo and in an in vitro organ culture system. J Exp Med. 1980 Feb 1;151(2):429–445. doi: 10.1084/jem.151.2.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. WEIGLE W. O. THE INDUCTION OF AUTOIMMUNITY IN RABBITS FOLLOWING INJECTION OF HETEROLOGOUS OR ALTERED HOMOLOGOUS THYROGLOBULIN. J Exp Med. 1965 Feb 1;121:289–308. doi: 10.1084/jem.121.2.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Waters C. A., Pilarski L. M., Wegmann T. G., Diener E. Tolerance induction during ontogeny. I. Presence of active suppression in mice rendered tolerant to human gamma-globulin in utero correlates with the breakdown of the tolerant state. J Exp Med. 1979 May 1;149(5):1134–1151. doi: 10.1084/jem.149.5.1134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Weigle W. O. Analysis of autoimmunity through experimental models of thyroiditis and allergic encephalomyelitis. Adv Immunol. 1980;30:159–273. doi: 10.1016/s0065-2776(08)60196-0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES