Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Oct 1;180(4):1559–1564. doi: 10.1084/jem.180.4.1559

Protective role of major histocompatibility complex class II Ebd transgene on collagen-induced arthritis

PMCID: PMC2191685  PMID: 7931088

Abstract

Collagen-induced arthritis (CIA) is an animal model of autoimmune inflammatory polyarthritis that has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC), H-2, and restricted to the H-2q and H-2r haplotypes. Whereas the role of the H-2A molecule in susceptibility to CIA is well established, little is known about the role of H-2E molecule in the disease. In this study, we analyzed the effect of a transgenic E beta d molecule on CIA susceptibility in a recombinant mouse B10.RQB3, which expresses the CIA susceptible Aq genes and an Eak gene, but does not produce an E molecule since Ebq is nonfunctional. In the presence of an Ebd transgene, a viable E molecule is generated. Whereas B10.RQB3 were susceptible to CIA, B10.RQB3-E beta d+ showed a dramatic reduction in the incidence of arthritis as well as a decrease in the level of anti-mouse and anti-bovine CII antibodies in their serum. No clear cut differences in the expression of T cell receptor (TCR) V beta was observed between E beta d+ and E beta d- transgenic mice. Mechanisms underlying the protective effect of E beta d transgenic molecule on CIA may shed light on how HLA-DR molecules influence human RA.

Full Text

The Full Text of this article is available as a PDF (521.7 KB).

Selected References

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

  1. Anderson G. D., David C. S. In vivo expression and function of hybrid Ia dimers (E alpha A beta) in recombinant and transgenic mice. J Exp Med. 1989 Sep 1;170(3):1003–1008. doi: 10.1084/jem.170.3.1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Begovich A. B., Vu T. H., Jones P. P. Characterization of the molecular defects in the mouse E beta f and E beta q genes. Implications for the origin of MHC polymorphism. J Immunol. 1990 Mar 1;144(5):1957–1964. [PubMed] [Google Scholar]
  3. Bill J., Kanagawa O., Woodland D. L., Palmer E. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells. J Exp Med. 1989 Apr 1;169(4):1405–1419. doi: 10.1084/jem.169.4.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Christadoss P., David C. S., Shenoy M., Keve S. Ek alpha transgene in B10 mice suppresses the development of myasthenia gravis. Immunogenetics. 1990;31(4):241–244. doi: 10.1007/BF00204895. [DOI] [PubMed] [Google Scholar]
  5. Folsom V., Gay D., Tonegawa S. The beta 1 domain of the mouse E beta chain is important for restricted antigen presentation to helper T-cell hybridomas. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1678–1682. doi: 10.1073/pnas.82.6.1678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Glimcher L. H., Kara C. J. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol. 1992;10:13–49. doi: 10.1146/annurev.iy.10.040192.000305. [DOI] [PubMed] [Google Scholar]
  7. Griffiths M. M., Cremer M. A., Harper D. S., McCall S., Cannon G. W. Immunogenetics of collagen-induced arthritis in rats. Both MHC and non-MHC gene products determine the epitope specificity of immune response to bovine and chick type II collagens. J Immunol. 1992 Jul 1;149(1):309–316. [PubMed] [Google Scholar]
  8. Holmdahl R., Karlsson M., Andersson M. E., Rask L., Andersson L. Localization of a critical restriction site on the I-A beta chain that determines susceptibility to collagen-induced arthritis in mice. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9475–9479. doi: 10.1073/pnas.86.23.9475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hood L., Steinmetz M., Malissen B. Genes of the major histocompatibility complex of the mouse. Annu Rev Immunol. 1983;1:529–568. doi: 10.1146/annurev.iy.01.040183.002525. [DOI] [PubMed] [Google Scholar]
  10. Hunt D. F., Michel H., Dickinson T. A., Shabanowitz J., Cox A. L., Sakaguchi K., Appella E., Grey H. M., Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science. 1992 Jun 26;256(5065):1817–1820. doi: 10.1126/science.1319610. [DOI] [PubMed] [Google Scholar]
  11. Lund T., O'Reilly L., Hutchings P., Kanagawa O., Simpson E., Gravely R., Chandler P., Dyson J., Picard J. K., Edwards A. Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature. 1990 Jun 21;345(6277):727–729. doi: 10.1038/345727a0. [DOI] [PubMed] [Google Scholar]
  12. Marcelletti J. F., Ohara J., Katz D. H. Collagen-induced arthritis in mice. Relationship of collagen-specific and total IgE synthesis to disease. J Immunol. 1991 Dec 15;147(12):4185–4191. [PubMed] [Google Scholar]
  13. Mathis D. J., Benoist C., Williams V. E., 2nd, Kanter M., McDevitt H. O. Several mechanisms can account for defective E alpha gene expression in different mouse haplotypes. Proc Natl Acad Sci U S A. 1983 Jan;80(1):273–277. doi: 10.1073/pnas.80.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Merino R., Fossati L., Lacour M., Lemoine R., Higaki M., Izui S. H-2-linked control of the Yaa gene-induced acceleration of lupus-like autoimmune disease in BXSB mice. Eur J Immunol. 1992 Feb;22(2):295–299. doi: 10.1002/eji.1830220202. [DOI] [PubMed] [Google Scholar]
  15. Merino R., Iwamoto M., Fossati L., Muniesa P., Araki K., Takahashi S., Huarte J., Yamamura K., Vassalli J. D., Izui S. Prevention of systemic lupus erythematosus in autoimmune BXSB mice by a transgene encoding I-E alpha chain. J Exp Med. 1993 Oct 1;178(4):1189–1197. doi: 10.1084/jem.178.4.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nabozny G. H., Bull M. J., Hanson J., Griffiths M. M., Luthra H. S., David C. S. Collagen-induced arthritis in T cell receptor V beta congenic B10.Q mice. J Exp Med. 1994 Aug 1;180(2):517–524. doi: 10.1084/jem.180.2.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nepom G. T., Nepom B. S. Prediction of susceptibility to rheumatoid arthritis by human leukocyte antigen genotyping. Rheum Dis Clin North Am. 1992 Nov;18(4):785–792. [PubMed] [Google Scholar]
  18. Nishimoto H., Kikutani H., Yamamura K., Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. 1987 Jul 30-Aug 5Nature. 328(6129):432–434. doi: 10.1038/328432a0. [DOI] [PubMed] [Google Scholar]
  19. Podolin P. L., Pressey A., DeLarato N. H., Fischer P. A., Peterson L. B., Wicker L. S. I-E+ nonobese diabetic mice develop insulitis and diabetes. J Exp Med. 1993 Sep 1;178(3):793–803. doi: 10.1084/jem.178.3.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. doi: 10.1056/NEJM197804202981602. [DOI] [PubMed] [Google Scholar]
  21. Trentham D. E. Collagen arthritis as a relevant model for rheumatoid arthritis. Arthritis Rheum. 1982 Aug;25(8):911–916. doi: 10.1002/art.1780250801. [DOI] [PubMed] [Google Scholar]
  22. Trentham D. E., Townes A. S., Kang A. H., David J. R. Humoral and cellular sensitivity to collagen in type II collagen-induced arthritis in rats. J Clin Invest. 1978 Jan;61(1):89–96. doi: 10.1172/JCI108929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Uehira M., Uno M., Kürner T., Kikutani H., Mori K., Inomoto T., Uede T., Miyazaki J., Nishimoto H., Kishimoto T. Development of autoimmune insulitis is prevented in E alpha d but not in A beta k NOD transgenic mice. Int Immunol. 1989;1(2):209–213. doi: 10.1093/intimm/1.2.209. [DOI] [PubMed] [Google Scholar]
  24. Weyand C. M., Goronzy J. J. Prognosis in rheumatoid arthritis: applying new technologies to old questions. J Rheumatol. 1993 Nov;20(11):1817–1820. [PubMed] [Google Scholar]
  25. Winchester R., Dwyer E., Rose S. The genetic basis of rheumatoid arthritis. The shared epitope hypothesis. Rheum Dis Clin North Am. 1992 Nov;18(4):761–783. [PubMed] [Google Scholar]
  26. Woodland D., Happ M. P., Bill J., Palmer E. Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells. Science. 1990 Feb 23;247(4945):964–967. doi: 10.1126/science.1968289. [DOI] [PubMed] [Google Scholar]
  27. Wooley P. H., Luthra H. S., Griffiths M. M., Stuart J. M., Huse A., David C. S. Type II collagen-induced arthritis in mice. IV. Variations in immunogenetic regulation provide evidence for multiple arthritogenic epitopes on the collagen molecule. J Immunol. 1985 Oct;135(4):2443–2451. [PubMed] [Google Scholar]
  28. Wooley P. H., Luthra H. S., Stuart J. M., David C. S. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med. 1981 Sep 1;154(3):688–700. doi: 10.1084/jem.154.3.688. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES