Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1986 Mar 1;163(3):644–653. doi: 10.1084/jem.163.3.644

Delineation of a defect in T cell receptor beta genes of NZW mice predisposed to autoimmunity

PMCID: PMC2188050  PMID: 3005467

Abstract

In an attempt to determine whether genes involved in T cell antigen recognition are structurally abnormal and thereby promote murine systemic lupus, we analyzed the structural integrity of the D, J, and C region elements of the T cell receptor alpha and beta chain genes in all major lupus strains and several normal strains. Within the limits of restriction fragment length polymorphism analysis, all strains had an identical genomic organization, except the NZW mice, in which a deletion of the C beta 1-D beta 2-J beta 2 elements was found. Sequence analysis of NZW genomic elements containing this deletion placed its probable origin within the first exon of C beta 1, and extending to a complementary region within the first exon of C beta 2. The significance of this abnormality in the pathogenesis of systemic autoimmune disease remains to be determined.

Full Text

The Full Text of this article is available as a PDF (833.0 KB).

Selected References

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

  1. Allison J. P., McIntyre B. W., Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J Immunol. 1982 Nov;129(5):2293–2300. [PubMed] [Google Scholar]
  2. Arden B., Klotz J. L., Siu G., Hood L. E. Diversity and structure of genes of the alpha family of mouse T-cell antigen receptor. 1985 Aug 29-Sep 4Nature. 316(6031):783–787. doi: 10.1038/316783a0. [DOI] [PubMed] [Google Scholar]
  3. Barth R. K., Kim B. S., Lan N. C., Hunkapiller T., Sobieck N., Winoto A., Gershenfeld H., Okada C., Hansburg D., Weissman I. L. The murine T-cell receptor uses a limited repertoire of expressed V beta gene segments. Nature. 1985 Aug 8;316(6028):517–523. doi: 10.1038/316517a0. [DOI] [PubMed] [Google Scholar]
  4. Behlke M. A., Spinella D. G., Chou H. S., Sha W., Hartl D. L., Loh D. Y. T-cell receptor beta-chain expression: dependence on relatively few variable region genes. Science. 1985 Aug 9;229(4713):566–570. doi: 10.1126/science.3875151. [DOI] [PubMed] [Google Scholar]
  5. Birnboim H. C. A rapid alkaline extraction method for the isolation of plasmid DNA. Methods Enzymol. 1983;100:243–255. doi: 10.1016/0076-6879(83)00059-2. [DOI] [PubMed] [Google Scholar]
  6. Dretzen G., Bellard M., Sassone-Corsi P., Chambon P. A reliable method for the recovery of DNA fragments from agarose and acrylamide gels. Anal Biochem. 1981 Apr;112(2):295–298. doi: 10.1016/0003-2697(81)90296-7. [DOI] [PubMed] [Google Scholar]
  7. Epstein R., Roehm N., Marrack P., Kappler J., Davis M., Hedrick S., Cohn M. Genetic markers of the antigen-specific T cell receptor locus. J Exp Med. 1985 May 1;161(5):1219–1224. doi: 10.1084/jem.161.5.1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gascoigne N. R., Chien Y., Becker D. M., Kavaler J., Davis M. M. Genomic organization and sequence of T-cell receptor beta-chain constant- and joining-region genes. Nature. 1984 Aug 2;310(5976):387–391. doi: 10.1038/310387a0. [DOI] [PubMed] [Google Scholar]
  9. HELYER B. J., HOWIE J. B. Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice. Nature. 1963 Jan 12;197:197–197. doi: 10.1038/197197a0. [DOI] [PubMed] [Google Scholar]
  10. Hanahan D., Meselson M. Plasmid screening at high colony density. Gene. 1980 Jun;10(1):63–67. doi: 10.1016/0378-1119(80)90144-4. [DOI] [PubMed] [Google Scholar]
  11. Hang L., Slack J. H., Amundson C., Izui S., Theofilopoulos A. N., Dixon F. J. Induction of murine autoimmune disease by chronic polyclonal B cell activation. J Exp Med. 1983 Mar 1;157(3):874–883. doi: 10.1084/jem.157.3.874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hayday A. C., Diamond D. J., Tanigawa G., Heilig J. S., Folsom V., Saito H., Tonegawa S. Unusual organization and diversity of T-cell receptor alpha-chain genes. 1985 Aug 29-Sep 4Nature. 316(6031):828–832. doi: 10.1038/316828a0. [DOI] [PubMed] [Google Scholar]
  13. Hedrick S. M., Germain R. N., Bevan M. J., Dorf M., Engel I., Fink P., Gascoigne N., Heber-Katz E., Kapp J., Kaufmann Y. Rearrangement and transcription of a T-cell receptor beta-chain gene in different T-cell subsets. Proc Natl Acad Sci U S A. 1985 Jan;82(2):531–535. doi: 10.1073/pnas.82.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hoover M. L., Marks J., Chipman J., Palmer E., Stastny P., Capra J. D. Restriction fragment length polymorphism of the gene encoding the alpha chain of the human T cell receptor. J Exp Med. 1985 Sep 1;162(3):1087–1092. doi: 10.1084/jem.162.3.1087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kappler J., Kubo R., Haskins K., Hannum C., Marrack P., Pigeon M., McIntyre B., Allison J., Trowbridge I. The major histocompatibility complex-restricted antigen receptor on T cells in mouse and man: identification of constant and variable peptides. Cell. 1983 Nov;35(1):295–302. doi: 10.1016/0092-8674(83)90232-5. [DOI] [PubMed] [Google Scholar]
  16. Kofler R., Noonan D. J., Levy D. E., Wilson M. C., Møller N. P., Dixon F. J., Theofilopoulos A. N. Genetic elements used for a murine lupus anti-DNA autoantibody are closely related to those for antibodies to exogenous antigens. J Exp Med. 1985 Apr 1;161(4):805–815. doi: 10.1084/jem.161.4.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kofler R., Perlmutter R. M., Noonan D. J., Dixon F. J., Theofilopoulos A. N. Ig heavy chain variable region gene complex of lupus mice exhibits normal restriction fragment length polymorphism. J Exp Med. 1985 Jul 1;162(1):346–351. doi: 10.1084/jem.162.1.346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kotzin B. L., Barr V. L., Palmer E. A large deletion within the T-cell receptor beta-chain gene complex in New Zealand white mice. Science. 1985 Jul 12;229(4709):167–171. doi: 10.1126/science.2990044. [DOI] [PubMed] [Google Scholar]
  19. Kronenberg M., Goverman J., Haars R., Malissen M., Kraig E., Phillips L., Delovitch T., Suciu-Foca N., Hood L. Rearrangement and transcription of the beta-chain genes of the T-cell antigen receptor in different types of murine lymphocytes. Nature. 1985 Feb 21;313(6004):647–653. doi: 10.1038/313647a0. [DOI] [PubMed] [Google Scholar]
  20. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  21. Park C. L., Balderas R. S., Fieser T. M., Slack J. H., Prud'Homme G. J., Dixon F. J., Theofilopoulos A. N. Isotypic profiles and other fine characteristics of immune responses to exogenous thymus-dependent and -independent antigens by mice with lupus syndromes. J Immunol. 1983 May;130(5):2161–2167. [PubMed] [Google Scholar]
  22. Prud'homme G. J., Balderas R. S., Dixon F. J., Theofilopoulos A. N. B cell dependence on and response to accessory signals in murine lupus strains. J Exp Med. 1983 Jun 1;157(6):1815–1827. doi: 10.1084/jem.157.6.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Robinson M. A., Kindt T. J. Segregation of polymorphic T-cell receptor genes in human families. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3804–3808. doi: 10.1073/pnas.82.11.3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Saito H., Kranz D. M., Takagaki Y., Hayday A. C., Eisen H. N., Tonegawa S. Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. 1984 Jun 28-Jul 4Nature. 309(5971):757–762. doi: 10.1038/309757a0. [DOI] [PubMed] [Google Scholar]
  25. Siu G., Clark S. P., Yoshikai Y., Malissen M., Yanagi Y., Strauss E., Mak T. W., Hood L. The human T cell antigen receptor is encoded by variable, diversity, and joining gene segments that rearrange to generate a complete V gene. Cell. 1984 Jun;37(2):393–401. doi: 10.1016/0092-8674(84)90369-6. [DOI] [PubMed] [Google Scholar]
  26. Siu G., Kronenberg M., Strauss E., Haars R., Mak T. W., Hood L. The structure, rearrangement and expression of D beta gene segments of the murine T-cell antigen receptor. 1984 Sep 27-Oct 3Nature. 311(5984):344–350. doi: 10.1038/311344a0. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Theofilopoulos A. N., Balderas R. S., Shawler D. L., Lee S., Dixon F. J. Influence of thymic genotype on the systemic lupus erythematosus-like disease and T cell proliferation of MRL/Mp-lpr/lpr mice. J Exp Med. 1981 Jun 1;153(6):1405–1414. doi: 10.1084/jem.153.6.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Theofilopoulos A. N., Dixon F. J. Murine models of systemic lupus erythematosus. Adv Immunol. 1985;37:269–390. doi: 10.1016/s0065-2776(08)60342-9. [DOI] [PubMed] [Google Scholar]
  30. Theofilopoulos A. N., Shawler D. L., Balderas R. S., Elder J. H., Katz D. H., Dixon F. J. Specificities of NZB anti-H-2d CML reactions: role of Qa-1 and retroviral gp70 antigens. J Immunol. 1981 Mar;126(3):1154–1159. [PubMed] [Google Scholar]
  31. Tonietti G., Oldstone M. B., Dixon F. J. The effect of induced chronic viral infections on the immunologic diseases of New Zealand mice. J Exp Med. 1970 Jul 1;132(1):89–109. doi: 10.1084/jem.132.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vieira J., Messing J. The pUC plasmids, an M13mp7-derived system for insertion mutagenesis and sequencing with synthetic universal primers. Gene. 1982 Oct;19(3):259–268. doi: 10.1016/0378-1119(82)90015-4. [DOI] [PubMed] [Google Scholar]
  33. Wofsy D., Seaman W. E. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med. 1985 Feb 1;161(2):378–391. doi: 10.1084/jem.161.2.378. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES