Abstract
Fifty-one patients with autoimmune hepatitis have been studied for HLA association by conventional serology and also by modified polymerase chain reaction-restriction fragment lenght polymorphism (PCR-RFLP) genoty**.HLA-DR4 was significantly associated with autoimmmune hepatitis (46 of 51 patients, 90.2%). DNA ty** of the DRB1 gene for 43 DR4-positive patients by using the PCR-RFLP technique revealed that of 43 patients, 33 had DRB1 * 0405 (Dw15), five had DRB1 * 0406 (DwKT2), four had DRB1 * 0403 (Dw13a), two had DRB1 * 0401 (Dw4), two of 43 had DRB1 * 0407 (Dw13b) and one had DRB1 * 0408 (Dw14b). Thus, there was no significant difference in Dw frequencies between DR4-positive patients and DR4-positive healthy subjects. These findings suggest that the DR4-specific sequence (Val 11 and His 13 at amino acid positions 11 and 13, respectively), but not particular Dw-associated DR4 sequence, in the first domain of the DRB1 chain contributes to susceptibility to autoimmune hepatitis among Japanese. Interestingly, all five of the DR4-negative patients had the DR2 specificity (DRB1 1502 or 1601). Taken together, these results imply that the basic amino acids at position 13, which is present only on the DR2 and DR4 B1 molecules (Arg on DR2 and His on DR4), are most important for determining the predisposition to autoimmune hepatitis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baisch, J. M., Weeks, T., Giles, R., Hoover, M., Stastng, P., and Capra, J. D.: Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Eng J Med 322: 1836–1841, 1990
Bevan, M. J.: Interactions antigens detected by cytotoxic T cells with the major histocompatibility complex as modifier. Nature 256: 419–421, 1975
Brown, J. H., Jardetzky, T., Saper, M. A., Samraoui, B., Bjorkman, P. I., and Wiley, D. C.: A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature 332: 845–850, 1988
Dunn, O. J.: Multiple comparisons among means. Am J Stat Assoc 56: 52–64, 1961
Edwards, J. H.: HLA-A and disease. The detection of associations. J Immunogenet 1: 249–257, 1974
Gregersen, P. K., Goyert, S. M., Song, Q., and Silver, J.: Microheterogeneity of HLA-DR4 haplotypes: DNA sequence analysis of LD“KT2” and LD“TAS” haplotypes. Hum Immunol 19: 287–292, 1987b
Gregersen, P. K., Shen, M., Song, Q.-L., Merryman, P., Degar, S., Seki, T., Maccari, J., Goldberg, D., Murphy, H., Schwenzer, J., Wang, C., Winchester, R., Nepom, G., and Silver, J.: Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci USA 83: 2642–2646, 1986
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, 1987a
Inoko, H., Ando, A., Ito, M., and Tsuji, K.: Southern hybridization analysis of DNA polymorphism in the HLA-D region. Hum Immunol 16: 304–313, 1986
Lepage, V., Degos, F., Carella, G., De Lima, M., Giraud, M. C., and Degos, L.: HLA-Cw7 and HBs Ag negative chronic active hepatitis. Tissue Antigens 18: 105–107, 1981
Lundin, K. E. A., Rønningen, K. S., Aono, S., Spurkland, A., Gaudernack, G., Isshiki, G., and Thorsby, E.: HLA-DQ antigens and DQβ amino acid 57 of Japanese patients with insulin-dependent diabetes mellitus: detection of a DRw8DQw8 haplotype. Tissue Antigens 34: 233–241, 1989
Mackay, I. R. and Morris, P. J.: Association of autoimmune active chronic hepatitis with HLA-A1,8. Lancet 2: 793–795, 1972
Mackay, I. R. and Tait, B. D.: HLA association with autoimmune-type chronic active hepatitis: identification of B8-DRw3 haplotype by family studies. Gastroenterology 79: 95–98, 1980
Mackay, I. R. and Wood, T. Y.: Lupoid hepatitis — A comparison of 22 cases with other types of chronic liver disease. Quant J Med 31: 485–507, 1962
Maeda, M., Murayama, H., Ishii, N., Uryu, N., Ota, M., Tsuji, K., and Inoko, H.: A simple and rapid method for HLA-DQA1 genoty** by digestion of PCR-amplified DNA with allele specific restriction endonucleases. Tissue Antigens 34: 290–298, 1989a
Maeda, M., Uryu, N., Murayama, N., Ishii, H., Ota, M., Tsuji, K., and Inoko, H.: A simple and rapid method for HLA-DP genoty** by digestion of PCR-amplified DNA with allele specific restriction endonucleases. Human Immunol 27: 111–121, 1989b
Marsh, S. G. E. and Bodmer, J. G.: HLA Class II nucleotide sequences, 1991. Tissue Antigens 37: 181–189, 1991
Nepom, G. T., Hausen, J. A., and Nepom, B. S.: The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol 7: 1–7, 1987
Nomura, N., Ota, M., Tsuji, K., and Inoko, H.: HLA-DQB1 genoty** by modified PCR-RFLP method combined with allele-specific primers. Tissue Antigens 38: 53–59, 1991
Opelz, G., Vogten, A. J., Summerskill, W. H., Schalm, S. W., and Terasaki, P. I.: HLA determinants in chronic active liver disease: possible relation of HLA-Dw3 to prognosis. Tissue Antigens 9: 36–40, 1977
Ota, M., Seki, T., Nomura, N., Sugimura, K., Mizuki, N., Fukushima, H., Tsuji, K., and Inoko, H.: Modified PCR-RFLP method for HLA-DPB1 and-DQA1 genoty**. Tissue Antigens 38: 60–71, 1991
Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S. J., Higuchi, R., Horn, G. T., Mullis, K. B., and Erlich, H. A.: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239: 487–491, 1988
Scharf, S. J., Freidmann, A., Steinman, L., Brautbar, C., and Erlich, H. A.: Specific HLA-DQβ and HLA-DRB1 alleles confer susceptibility to pemphigus vulgaris. Proc Natl Acad Sci USA 86: 6215–6219, 1989
Seki, T., Kiyosawa, K., Inoko, H., and Ota, M.: Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology 12: 1300–1304, 1990
Sollid, L. M., Markussen, G., Ek, J., Gjerde, H., Vartdal, F., and Thorsby, E.: Evidence for a primary association of celiac disease to a particular HLA-DQα/β heterodimer. J Exp Med 169: 345–350, 1989
Svejgaard, A., Jersild, C., Nielsen, S. L., and Bodmer, W. F.: HLA-A antigens and disease statistical and genetical considerations. Tissue Antigens 4: 95–105, 1974
Svejgaard, A., Platz, P., and Ryder, L. P.: HLA and Disease 1982 —a survey. Immunol Rev 70: 193–218, 1989
Tiwari, J. L. and Terasaki, P. I.: HLA and Disease Associations, pp. 167–173, Springer, New York, 1985a
Tiwari, J. L. and Terasaki, P. I.: HLA and Disease Associations, pp. 214–220, Springer, New York, 1985b
Todd, J. A., Bell, J. I., and McDevitt, H. O.: HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604, 1987
Todd, J. A., Bell, J. I., and McDevitt, H. O.: A molecular basis for genetic susceptibility to insulin-dependent diabetes mellitus. Immunol Today 4: 129–134, 1988a
Todd, J. A., Acha-Orbea, H., Bell, J. I., Chao, N., Fronek, Z., Jacob, C. O., McDermott, M., Shinha, A. A., Timmerman, L., Steinman, L., and McDevitt, H. O.: A molecular basis for MHC class II-associated autoimmunity. Science 240: 1003–1009, 1988b
Uryu, N., Maeda, M., Ota, M., Tsuji, K., and Inoko, H.: A simple and rapid method for HLA-DRB and-DQB ty** by digestion of PCR-amplified DNA with allele specific restriction endonucleases. Tissue Antigens 35: 20–31, 1990
Wordsworth, B. P., Lanchbury, J. S. S., Sakkas, L. I., Welsh, K. I., Panayi, G. S., and Bell, J. I.: HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci USA 86: 10049–10053, 1989
Zinkernagel, R. M. and Doherty, P. C.: MHC-restrict cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction specificity, function and responsiveness. Adv Immunol 27: 52–77, 1979
Author information
Authors and Affiliations
Additional information
Address correspondence and offprint requests to: M. Ota.
Rights and permissions
About this article
Cite this article
Ota, M., Seki, T., Kiyosawa, K. et al. A possible association between basic amino acids of position 13 of DRB1 chains and autoimmune hepatitis. Immunogenetics 36, 49–55 (1992). https://doi.org/10.1007/BF00209292
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00209292