Skip to main content
Log in

Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis

  • Original Papers
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Collagen-induced arthritis (CIA) is an animal model of auto immune polyarthritis, sharing similarities with rheumatoid arthritis (RA). Paradoxally, susceptibility to mouse CIA is controlled by the H2A loci (DQ homologous) while RA is linked to HLA.DR genes (H2E homologous). We recently showed that the Eβd molecule prevents CIA development in susceptible H2 q mice. We addressed the question of whether H2Eb polymorphism will influence CIA incidence as HLA.DRB1 polymorphism does in RA. In F1 mice, only H2Ebd and H2Ebs molecules showed protection. Using recombinant B10.RDD (Eb d/b) mice, we found that CIA protection was mediated by the first domain of the Eβd molecule. Using peptides covering the third hypervariable region of the Eβ chain, we found a perfect correlation between presentation of Eβ peptides by the H2Aq molecule and protection on CIA. Therefore, the mechanism by which H2Eb protects against CIA seems to rely on the affinity of Eβ peptides for the H2Aq molecule.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Begovich, A. B., Vu, T. H., and Jones, P. P. Characterization of the molecular defects in the mouse Eβf and Eβq genes. Implications for the origin of MHC polymorphism. J Immunol 144: 1957–1964, 1990

    Google Scholar 

  • Bill, J., Kanagawa, O., Woodland, D. L., and Palmer, E. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of Vβ11-bearing T cells. J Exp Med 169: 1405–1419, 1989

    Google Scholar 

  • Brunsberg, U., Gustafsson, K., Jansson, L., Michaelsson, E., Ahrlund-Ritcher, L., Pettersson, S., Mattsson, R., and Holmdahl, R. Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur J Immunol 24: 1698–1702, 1994

    Google Scholar 

  • Donovan, K. A., Singh, S. K., David, C. S., and Pease, L. R. Molecular analysis and repair of a defective Eαf gene. J Immunol 142: 4034–4040, 1989

    Google Scholar 

  • Gonzalez-Gay, M. A., Nabozny, G. H., Bull, M. J., Zanelli, E., Douhan, III, J., Griffiths, M. M., Glimcher, L. H., Luthra, H. S., and David, C. S. Protective role of MHC class II Ebd transgene on collagen-induced arthritis. J Exp Med 180: 1559–1564, 1994

    Google Scholar 

  • Gregersen, P. K., Silver, J., and Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30: 1205–1213, 1987

    Google Scholar 

  • Gustafsson, K., Karlsson, M., Andersson, L., and Holmdahl, R. Structures on the I-A molecule predisposing for susceptibility to type II collagen-induced autoimmune arthritis. Eur J Immunol 20: 2127–2131, 1990

    Google Scholar 

  • Hirose, S., Zhang, D., Nozawa, S., Nishimura, H., and Shirai, T. The E-linked subregion of the major histocompatibility complex down-regulates autoimmunity in NZB × NZW F1 mice. Immunogenetics 40: 150–153, 1994

    Google Scholar 

  • Holmdahl, R., Karlsson, M., Andersson, M. E., Rask, L., and Andersson, L. Localization of a critical restriction site on the I-Ab chain that determines susceptibility to collagen-induced arthritis in mice. Proc Natl Acad Sci USA 86: 9475–9479, 1989

    Google Scholar 

  • Hood, L., Steinmetz, M., and Malissen, B. Genes of the major histocompatibility complex of the mouse. Annu Rev Immunol 1: 529–568, 1983

    Google Scholar 

  • Jones, P. P., Murphy, D. B., and McDevitt, H. O. Variable synthesis and expression of Eα and Aβ(Eβ) Ia polypeptide chains in mice of different H-2 haplotypes. Immunogenetics 12: 321–337, 1981

    Google Scholar 

  • Kobori, J. A., Strauss, E., Minard, K., and Hood, L. Molecular analysis of the hotspot of recombination in the murine major histocompatibility complex. Science 234: 173–179, 1986

    Google Scholar 

  • Krco, C. J., Beito, T. G., and David, C. S. Determination of tolerance to self Eα peptides by clonal elimination of H-2E reactive T cells and antigen presentation by H-2A molecules. Transplantation 54: 920–923, 1992

    Google Scholar 

  • Lerner, E. A., Matis, L. A., Janeway Jr., C. A., Jones, P. P., Schwartz, R. H., and Murphy, D. B. Monoclonal antibody against an Ir gene product. J Exp Med 152: 1085–1101, 1980

    Google Scholar 

  • Lund, T., O'Reilly, L., Hutchings, P., Kanagawa, O., Simpson, E., Gravely, R., Chandler, P., Dyson, J., Picard, J. K., Edwards, A., Kioussis, D., and Cooke, A. Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A chain or normal I-E chain. Nature 345: 727–729, 1990

    Google Scholar 

  • Mathis, D. J., Benoist, C., Wiliams II, V. E., Kanter, M., and McDevitt, H. O. Several mechanisms can account for deffective Eα gene expression in different mouse haplotypes. Proc Natl Acad Sci USA 80: 273–277, 1983

    Google Scholar 

  • Merino, R., Fossati, L., Lacour, M., Lemoine, R., Higaki, M., and Izui, S. H-2 linked control of the Yaa gene-induced acceleration of lupus-like autoimmune disease in BXSB mice. Eur J Immunol 22: 295–299, 1992

    Google Scholar 

  • Merino, R., Iwamoto, M., Fossati, L., Muniesa, P., Araki, K., Takahashi, S., Huarte, J., Yamamura, K.-I., Vassalli, J. D., and Izui, S. Prevention of systemic lupus erythematosus in autoimmune BXSB mice by a transgene encoding I-Eα chain. J Exp Med 178: 1189–1197, 1993

    Google Scholar 

  • Nepom, G. T. and Erlich, H. MHC class II molecules and autoimmunity. Annu Rev Immunol 9: 493–525, 1991

    Google Scholar 

  • Nishimoto, H., Kikutani, H., Yamamura, K., and Kishimoto, T. Prevention of autoimmune insulinitis by expression of I-E molecules in NOD mice. Nature 328: 432–434, 1987

    Google Scholar 

  • Nizetic, D., Figueroa, F., and Klein, J. Evolutionary relationship between the t and H-2 haplotypes in the house mouse. Immunogenetics 19: 311–320, 1984

    Google Scholar 

  • Ollier, W. and Thomson, W. Population genetics of rheumatoid arthritis. Rheum Dis Clin North Am 18: 741–759, 1992

    Google Scholar 

  • Ozato, K., Mayer, N., and Sachs, D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol 124: 533–540, 1980

    Google Scholar 

  • Ozato, K., Mayer, N. M., and Sachs, D. H. Monoclonal antibodies to mouse major histocompatibility complex antigens. IV. A series of hybridoma clones producing anti-H-2d antibodies and a examination of expression of H-2d antigens on the surface of these cells. Transplantation 34: 113–120, 1982

    Google Scholar 

  • Podolin, P. L., Pressey, A., DeLarato, N. H., Fischer, P. A., Peterson, L. B., and Wicker, L. S. I-E+ nonobese diabetic mice develop insulinitis and diabetes. J Exp Med 178: 793–803, 1993

    Google Scholar 

  • Reinsmoen, N. L. and Batch, F. H. Structural model for T-cell recognition of HLA class II-associated alloepitopes. Hum Immunol 27: 51–72, 1990

    Google Scholar 

  • Roudier, J., Sette, A., Lamont, A., Albani, S., Karras, J. G., and Carson, D. Tolerance to a self peptide from the third hypervariable region of the Eβs chain. Implications for molecular mimicry model of autoimmune disease. Eur J Immunol 21: 2063–2067, 1991

    Google Scholar 

  • Salvat, S., Auger, I., Rochelle, L., Begovich, A., Geburher, L., Sette, A., and Roudier, J. Tolerance to a self-peptide from the third hypervariable region of HLA DRB1*0401 in rheumatoid arthritis patients and normal subjects. J Immunol 153: 5321–5329, 1994

    Google Scholar 

  • Trentham, D. E. Collagen induced arthritis as a relevant model for rheumatoid arthritis. Evidence pro and co. Arthritis Rheum 25: 911–914, 1982

    Google Scholar 

  • Uehira, M., Uno, M., Kurner, T., Kikutani, H., Mori, K., Inomoto, T., Ueda, T., Miyakazi, J., Nishimoto, H., Kishimoto, T., and Yamamura, K. Development of autoimmune insulinitis is prevented in Ed but not in Ak NOD transgenic mice. Int Immunol 1: 209–213, 1989

    Google Scholar 

  • Weyand, C. M., Yie, C., and Goronzy, J. J. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest 89: 2033–2039, 1992

    Google Scholar 

  • Winchester, R., Dwyer, E., and Rose, S. The genetic basis of rheumatoid arthritis. The shared epitope hypothesis. Rheum Dis Clin North Am 18: 761–783, 1992

    Google Scholar 

  • Woodland, D., Happ, J. P., Bill, J., and Palmer, E. Requirement for cotolerogenic gene products in clonal deletion of I-E reactive T cells. Science 247: 964–967, 1990

    Google Scholar 

  • Wooley, P. H., Luthra, H. S., Griffiths, M. M., Stuart, J. M., Huse, A., and 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 135: 2443–2451, 1985

    Google Scholar 

  • Wooley, P. H., Luthra, H. S., Stuart, J. M., and David, C. S. Type II collagen induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med 154: 688–700, 1981

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonzalez-Gay, M.A., Zanelli, E., Krco, C.J. et al. Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis. Immunogenetics 42, 35–40 (1995). https://doi.org/10.1007/BF00164985

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00164985

Keywords

Navigation