Abstract
The association of HLA A1, B8, and DR3 with generalized myasthenia gravis (GMG) ini Caucasoids is well established, but no particular gene has been implicated and there is still no adequate explanation in functional terms. In study we have taken advantage of sequential genomic markers between B8 and DR3 so as to map the location of susceptibility gene(s) on the A1, B8, DR3 (8.1) ancestral haplotype. By studying 51 patients, we have delineated a region between HLA B and TNF which is shared by 29/29 patients with B8 and DR3, 19/19 patients with B8 but not DR3 and 2/3 patients with DR3 but not B8. The potential importance of this region was confirmed by examining a similar disease induced by D-Penicillamine (D-PenMG) and associated with different HLA class II alleles (DR1 and/or DR7). Among these patients, 7/16 (44%) have B8, often with other markers of 8.1. These results implicate at least two categories of genes in determining susceptibility to MG; one located in the region between HLA B and TNF may be immunoregulatory, whereas the second, located in the class II region, may relate to the inducing factor (e. g., DR1 or DR7 in D-PenMG).
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abraham, L.J., ChinDu, D., Zahedi, K., Dawkins, R. L., and Whiteland, A. S.: Haplotypic polymorphisms of the TNFB gene. Immunogenetics 33: 50–53, 1991
Albert, E. and Mayr, W.: Brief summary of the Ninth International Histocompatibility Workshop. Tissue Antigens 25: 3–10, 1985
Alper, C. A., Boenisch, T., and Watson, L.: Genetic Polymorphism in Human Glycine-rich Glycoprotein. J Exp Med 135: 86–90, 1972
Awdeh, Z. L., Raum, L. D., Yunis, E. J., and Alper, C. A.: Extended HLA/ complement allele haplotypes: evidence for T/t-like complex in man. Proc Natl Acad Sci USA 80: 259–263, 1983
Bell, J., Smoot, S., Newby, C., Toyka, K., Rassenti, L., Smith, K., Hohfeld, R., and McDevitt, H.: HLA-DQ beta-chain polymorphism linked to myasthenia gravis. Lancet: 1058–1060, 1986
Belt, K. T., Carroll, M. C., and Porter, R. R.: The structural basis of the multiple forms of human complement component C4. Cell 36: 907–914, 1984
Bertrams, J., and Baur, M. P.: Insulin-dependent diabetes mellitus. In E. D. Albert (ed.): Histocompatibility Testing 1984, 348–358, Springer, New York, 1984
Carlsson, B., Wallin, J., Pirskanen, R., Matell, G., and Smith, C. I. E.: Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis. Immunogenetics 31: 285–290, 1990
Carroll, M. C., Palsdottir, A., Belt, K. T., and Porter, R. R.: Deletion of complement C4 and steroid 21-hyroxylase genes in the HLA class III region. EMBO J 4: 2547–2552, 1985
Christiansen, F. T., Dawkins, R. L., Uko, G., McCluskey, J., Kay, P. H., and Zilko, P. J.: Complement allotyping in SLE: association with C4A null. Aust N Z J Med 13: 483–488, 1983
Christiansen, F. T., Pollack, M. S., Garlepp, M. J., and Dawkins, R. L.: Myasthenia gravis and HLA antigens in American Blacks and other races. J Neuroimmunol 7: 121–129, 1984
Collier, S., Sinnott, P. J., Dyer, P. A., Price, D. A., Harris, R., and Strachan, T.: Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase deficiency complement C4 gene repeats in 21-hydroxylase dificiency haplotypes. EMBO J 8: 1393–1402, 1989
Dawkins, R. L.: Myasthenia Gravis. In B. Dupont (ed.): Histocompatibility Testing 1980, pp. 662–667, Springer, New York, 1980
Dawkins, R. L., Owen, E. T., Cheah, P. S., Christiansen, F. T., Calin, A., and Gofton, P. J.: Prevalence of ankylosing spondylitis and radiological abnormalities of the sacroliac joints in HLA-B27 positive individuals. J Rheumatol 8: 1025–1026, 1981
Dawkins, R. L., Christiansen, F. T., Kay, P. H., Garlepp, M., McCluskey, J., Hollingsworth, P. N., and Zilko, P. J.: Disease associations with complotypes, supratypes and haplotypes. Immunol Rev 70: 5–22, 1983
Dawkins, R. L., Kay, P. H., Martin, E., and Christiansen, F. T.: The genomic structure of ancestral haplotypes revealed by pulsed field gel electrophoresis (PFGE). Immunology of HLA. In B. Dupont (ed.): Histocompatibility Testing 1987, pp. 893–895, Springer, New York, 1989a
Dawkins, R. L., Leaver, A., Cameron, P. U., Martin, E., Kay, P. H., and Christiansen, F. T.: Some disease-associated ancestral haplotypes carry a polymorphism of TNF. Hum Immunol 26: 91–97, 1989b
Dawkins, R. L., Degli-Esposti, M. A., Abraham, L. J., Zhang, W. J., and Christiansen, F. T.: Conservation and polymorphism of the MHC in relation to immune responses and autoimmune disease. In J. Klein and D. Klein (eds.): Molecular Evolution of the MHC pp. 391–402, Springer, New York, 1991
Delamere, J. P., Jobson, S., Mackintosh, L. P., Wells, L., and Walton, K. W.: Penicillamine-induced myasthenia in rheumatoid arthritis: its clinical and genetic features. Ann Rheum Dis 42: 500–504, 1983
Dupont, B., Pollack, M. S., Levine, L. S., O'Neill, G. J., Hawkins, B. R., and New, M. I.: Congenital adrenal hyperplasia. In B. Dupont (ed.): Histocompatibility Testing 1980, pp. 693–706, Springer, New York; 1980
Feinberg, A. P., and Vogelstein, B.: A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Analytical Biochem 132: 6–10, 1983
French, M. A. H., and Dawkins, R. L.: Central MHC genes, IgA deficiency and autoimmune disease. Immunol Today 11: 271–274, 1990
Garlepp, M. J., Kay, P. H., and Dawkins, R. L.: The diagnostic significance of autoantibodies to the acetylcholine receptor. J Neuroimmunol 3: 337–350, 1982
Garlepp, M. J., Christiansen, F. T., Chiewslip, P., and Dawkins, R. L.: Myasthenia gravis disease report. In B. Tait and M. Simons (eds.): Proceedings of the Second Asia and Oceania Histocompatibility Conference, pp. 343–347, Immunopublishing, Melbourne, 1983
Garlepp, M. J., and Dawkins, R. L.: Graves' disease and myasthenia gravis. In C. A. Gorman, R. R. Waller, and J. A. Dyer (eds.): The Eye and Orbit in Thyroid Disease, pp. 121–127, RavenPress, New York, 1984b
Garlepp, M. J., Wilton, A. N., Dawkins, R. L., White, P. C.: Rearrangement of 21-hydroxylase genes in disease associated MHC supratypes. Immunogenetics 23: 100–105, 1986
Ghiara, P., Boraschi, D., Nencioni, L., Ghezzi, P., and Tagliabue, A.: Enhancement of in vivo immune response by tumor necrosis factor. J Immunol 139: 3676–3679, 1987
Gin, W., Dawkins, R.L., Albert, E. D., Hawkins, B. R., Muller, C., Tsuji, K., Jeannet, M., and Schalke, B.: Myasthenia Gravis: Joint report. In B. Dupont (ed.): Immunobiology of HLA, pp. 895–899, Springer New York, 1989
Hawkins, B. R., Ip, M. S. M., Lam, K. S. L., Ma, J. T. C., Chan-Lui, W. Y., and Yeung, R. T. T.: HLA antigens and acetylcholine receptor antibody in the subclassification of myasthenia gravis in Hong Kong Chinese. J Neurol Neurosurg Psychiatry 49: 316–319, 1986
hawkins, B. R., Yu, Y. L., Wong, V., Woo, E., Ip, M. S. M., and Dawkins, R. L.: Possible evidence for a variant of myasthenia gravis based on HLA and acetylcholine receptor antibody in Chinese patients. Q J Med (New Series) 70, 263: 235–241, 1989
Juji, T., Satake, M., Honda, Y., and Doi, Y.: HLA antigens in Japanese patients with narcolepsy. Tissue Antigens 24: 316–319, 1984
Keller, E., Andreas-Zietz, A., McNicholas, A., Grooms, A., Scholz, S., and Albert, E. D.: Characterization of DR blank alleles by restriction fragment length polymorphism (RFLP). Tissue Antigens 29: 154–159, 1987
Kelly, H., McCann, V. J., Kay, P. H., and Dawkins, R. L.: Susceptibility to IDDM is marked by MHC supratypes rather than individual alleles. Immunogenetics 22: 643–651, 1985
Kramer, J., Gyodi, E., and Fust, G.: Usefulness of densitometry in typing of human complement C4. Immunogenetics 29: 121–123, 1989
Lindstrom, J. M., Seybold, M. E., Lennon, V. A., Whittingham, S., and Duane, D. D.: Antibody to acetylcholine receptor in myasthenia gravis.Neurology 26: 1054–1059, 1976
Martin, E., Gin, W., Kay, P. H., Christiansen, F. T., and Dawkins, R. L.: Complotypes and class III gene arrangements can be assigned from supratype specific restriction fragment length polymorphism. 10th International Histocompatibility Workshop Newsletter, 13–14, 1987
Moller, E., Hammarstrom, L., Smith, E., and Matell, G.: HLA-A8 and LD-8a in patients with myasthenia gravis. Tissue Antigens 7: 39–44, 1976
Patrick, J. and Lindstrom, J. M.: Autoimmune response to acetylcholine receptor. Science 180: 871–872, 1973
Pennica, D., Nedwin, G. E., Hayflick, J. S., Seeburg, P. H., Derynck, R. Kohr, W.J., Aggarwal, B. B., and Goedel, D. V. W.: Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 312: 724–729, 1984
Reed, K. C. and Mann, D. A.: Rapid transfer of DNA from agarose gels to Nylon membranes. Nucleic Acid Res 13: 7207–7221, 1985
Safwenberg, J., Hammarstrom, L., Lindblom, J. B., Matell, G., Moller, E., Osterman, P. O., and Smith, C. I. E.: HLA-A,-B,-C and-D antigens in male patients with myasthenia gravis. Tissue Antigens 12: 136–142, 1978
Sambrook, J., Fritsch, E. F., Maniatis, T.: Molecular cloning: A Laboratory Manual: Cold Spring Harbor Laboratory. Cold Spring Harbor, 1989
Schlosstein, L., Terasaki, P. I., Bluestone, M. D., and Pearson, C. M.: High association of an HL-A antigen, W27 with ankylosing spondylitis. New Eng J Med 288: 704–706, 1973
Schneider, P. M., Carroll, M. C., Alper, C. A., Rittner, C., Whitehead, A. S., and Colten, H. R.: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. J Clin Invest 78: 650–657, 1986
Segall, M. and bach, F. H.: HLA and Disease: The perils of simplification. New Eng J Med 322: 1879–1881, 1990
Speiser, P. W., New, M. I., and White, P. c.: Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14, DR1. New Eng J Med 319: 19–23, 1988
Spies, T., Bresnahan, M., and Strominger, J. L.: Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B. Proc Natl Acad Sci USA 86: 8955–8958, 1989
Svejgaard, A., Platz, P. and Ryder, L. P.: HLA and disease 1982 —A survey. Immunol Rev 70: 193–218, 1983
Tiwari, J. L. and Terasaki, P. I.: HLA antigens associated with diseases. In J. L. Tiwari and P. I. Terasaki (eds.): HLA and Disease Associations. pp. 42–48, Springer, New York, 1985
Tokunaga, K., Saueracker, G., Kay, P. H., Christiansen, F. T., and Anand, R.: Extensive deletions and insertions in different MHC supratypes detected by pulsed field gel electrophoresis. J Exp Med 168: 933–940, 1988
Westcott, M. Z., Awdeh, Z. L., Yunis, E. J., and Alper, C. A.: Molecular analysis distinguishes two HLA-DR3-bearing major histocompatibility complex extended haplotypes. Immunogenetics 26: 370–374, 1987
White, P. C., New, M. I., and Dupont, B.: Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA 83: 5111–5115, 1986
White, P. C., Vitek, A., Dupont, B., and New, M. I.: Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85: 4436–4440, 1988
Zhang, W. J., Kay, P. H., Cobain, T. J., and Dawkins, R. L.: C4 allotyping on plasma or serum: application to routine laboratories. Human Immunol 21: 165–171, 1988
Zhang, W. J., Degli-Esposti, M. A., Cobain, T. J., Cameron, P. U., Christiansen, F. T., and Dawkins, R. L.: Differences in gene copy number carried by different MHC ancestral haplotypes; quantitation after physical separationof haplotypes by pulsed field gel electrophoresis. J Exp Med 171: 2101–2114, 1990
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Degli-Esposti, M.A., Andreas, A., Christiansen, F.T. et al. An approach to the localization of the susceptibility genes for generalized myasthenia gravis by mapping recombinant ancestral haplotypes. Immunogenetics 35, 355–364 (1992). https://doi.org/10.1007/BF00179791
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00179791