Abstract
This report demonstrates a T-cell receptor (Tcr) restriction fragment length polymorphism, defined by a Tcrb-V6.1 gene probe and Bgl II restriction enzyme, to be absolutely correlated with allelic variation in the coding sequence of a Tcrb-V6.1 gene. A pair of non-conservative amino acid substitutions distinguish the Tcrb-V6.1 allelic variants. An association of this Tcrb-V6.1 gene allelic variant with one form of juvenile rheumatoid arthritis (JRA) was established in a cohort of 126 patients. The association was observed in patients possessing the HLA-DQA1*0101 gene. Among HLA-DQA*0101 individuals, 19 of 26 patients (73.1%) carried one particular Tcrb-V6.1 gene allele as opposed to 11 of 33 controls (33%; p<0.005). Haplotypes carrying this HLA gene have previously been shown to confer increased risk for progression of arthritis in JRA. This demonstration of a disease-associated Tcrb-V gene allelic variant has not, to our knowledge, been previously reported and supports the contribution of polymorphism in the Tcr variable region genomic repertoire to human autoimmune disease.
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Acha-Orbea, H., Mitchell, D. J., Timmermann, L., Wraith, D. C., Tausch, G. S., Waldor, M. K., Zamvil, S. S., McDevitt, H. O., and Steinman, L.: Limited heterogeneity of T-cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54: 263–273, 1988
Banerjee, S., Haggi, T. M., Luthra, H. S., Stuart, J. M., and David, C. S.: Possible role of V beta T-cell receptor genes in susceptibility to collagen-induced arthritis in mice. J Exp Med 167: 832–839, 1988
Barth, R., Kim, B., Lan, N., Hunkapiller, T., Sobriele, N., Winoto, A., Gershenfeld, M., Oliada, C., Hansburg, D., Weissman, I., and Hood, L.: The murine T-cell receptor employs a limited repertoire of expressed Vβ gene segments. Nature 316: 517–522, 1985
Cassidy, J. T., Levinson, J. E., Bass, J. C., Baum, J., Brewer, E. J., Fink, C. W., Hanson, V., Jacobs, J. C., Masi, A. T., Schaller, J. G., Fries, J. E., McShane, D., and Young, D.: A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 29: 274–281, 1986
Charmley, P., Concannon, P., and Gatti, R. A.: Lack of linkage disequilibrium between Tcr-beta variable and constant genes: implications for disease associations. FASEB J s (Suppl 4): A661, 1988
Charmley, P., Chao, A., Concannon, P., Hood, L., and Gatti, R. A.: Haplotyping the human T-cell receptor β-chain gene complex by use of restriction fragment length polymorphisms. Proc Natl Acad Sci USA 87: 4823–4827, 1990
Chothia, C., Boswell, D. R., and Leslie, A. M.: The outline structure of the T-cell αβ receptor. EMBO J 7: 3745–3755, 1988
Davis, M. M. and Bjorkman, P. J.: T-cell antigen receptor genes and T-cell recognition. Nature 334: 395–402, 1988
Demaine, A. G., Ratanchiya, S., Pope, R., Ewins, D., Dillward, B. A., and McGregor, A. M.: Thyroglobulin antibodies in Graves' disease are associated with T-cell receptor beta chain and major histocompatibility complex loci. Clin Exp Immunol 77: 21–27, 1989
Feinberg, A. P. and Vogelstein, B.: A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Analyt Biochem 132: 6-18, 1983
Frank, M. B., McArthur, R., Marley, J. B., and Fujisaku, A.: Anti-Ro (SSA) autoantibodies are associated with T-cell receptor β genes in systemic lupus erythematosus patients. J Clin Invest 85: 33–39, 1990
Ghatak, S., Sainis, K., Owen, F. L., and Datta, S. K.: T-cell receptor beta-and I-A beta chain genes of normal SWR mice are linked with the development of lupus nephritis in NZB × SWR crosses. Proc Natl Acad Sci USA 84: 6850–6853, 1987
Gulwani-Akolkar, B., Gregersen, P. K., Akolkar, P., Manji, R., Janson, C. H., Posnett, D., and Silver, J.: HLA genes influence the human T-cell receptor repertoire. FASEB J 5: A7718, 1991
Holmdahl, R., Karlsson, M., Andersson, M. E., Rask, L., and Andersson, L.: Localization of a critical restriction site on the I-Aβ chain that determines susceptibility to collageninduced arthritis in mice. Proc Natl Acad Sci USA 86: 9475–9479, 1989
Jones, N., Leiden, J., Dalynas, D., Fraser, J., Clabby, M., Kishimoto T., and Strominger, J. L.: Partial primary structure of the alpha and beta chains of human tumor T-cell receptors. Science 227: 311–314, 1984
Lai, E., Concannon, P., and Hood, L.: Conserved organization of the human and murine T-cell receptor beta-gene families. Nature 331: 543–548, 1989
Leiden, J. M. and Strominger, J. L.: Generation of diversity of the beta-chain of the human T-lymphocyte receptor for antigen. Proc Natl Acad Sci USA 83: 4456–4461, 1986
Li, Y., Szabo, P., Robinson, M. A., Dong, B., and Posnett, D. N.: Allelic variations in the human T-cell receptor Vβ6.7 gene products. J Exp Med 171: 221–230, 1990
Maksymowych, W. P., Gabriel, C. A., Luyrink, L., Van Kerckhove, C., Leiden, J., Choi, E., and Glass, D. N.: Polymorphic markers related to a single Tcrβ V6 gene segment. Immunogenetics 33: 281–285, 1991
Millward, B. A., Welsh, K. I., Leslie, R. D. G., Pyke, D. A., and Demaine, A. G.: T-cell receptor beta chain polymorphisms are associated with insulin-dependent miabetes mellitus. Exp Immunol 70: 152–157, 1987
Mittal, K. K., Mickey, M. Rr., Singal, E. R., and Terasaki, P.: Serotyping for homotransplantation. VIII. Regimen of microdroplet lymphocyte cytotoxicity test. Transplantation 6: 913–927, 1968
Myers, K. L., Stuart, J. M., Seyer, J. M., and Kang, A. H.: Identification of an immunosuppressive epitope of Type II collagen that confers protection against collagen-induced arthritis. J Exp Med 170: 1999–2010, 1989
Posnett, D. N.: Allelic variations of human Tcr V gene products. Immunol Today 11: 368–373, 1990
Pullen, A. M., Potts, W., Wakeland, E. K., Kappler, J., and Marrack, P.: Surprisingly uneven distribution of the T cell receptor Vβ repertoire in wild mice. J Exp Med 171: 49–62, 1990
Robinson, M. A.: Allelic sequence variations in the hypervariable region of a T-cell receptor beta chain: Correlation with restriction fragment length polymorphism in human families and populations. Proc Natl Acad Sci USA 86: 9422–9426, 1989
Seboun, E., Robinson, M. A., Doolittle, T. H., Ciulla, T. A., Kindth, T. J., and Hauser, S. L.: A susceptibility locus for multiple sclerosis is linked to the T-cell receptor B chain complex. Cell 57: 1095–1110, 1989
Tebib, J. G., Aloocer-Varely, J., Alarcon-Segovia, D., and Schur, P. H.: Association between a T-cell receptor restriction fragment length polymorphism and systemac lupus erythematosus. J Clin Invest 86: 1961–1967, 1990
Urban, J. L., Kumar, V., Kono, D. H., Gomez, C., Horwath, S. J., Clayton, J., Ando, D. G., Sercarz, E. E., and Hood, L.: Restricted use of T-cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell 54: 577–591, 1988
Van Kerckhove, C., Luyrink, L., Taylor, J., Melin-Aldana, H., Balakrishnan, K., Maksymowych, W., Elma, M., Lovell, D. J., Choi, E., and Glass, D. N.: HLA-DQA1*0101 influences disease outcome in EOPA-JRA. J Rheumatol, 18: 874–879, 1991
Yanagi, Y., Hirose, S., Nagasawa, R., Shirai, T., Mak, T. W., and Tada, T.: Does the deletion within T-cell receptor beta-chain gene of NZW mice contribute to autoimmunity in (NZB × NZW) F1 mice 2. Eur J Immunol 16: 1179–1182, 1986
Zhou, P., Anderson, G. D., Savanirayan, S., Inoko, M., and David, C. S.: Human HLA-DQb chain presents minor lymphocyte stimulating locus gene products and clonally deletes Tcr Vb6+, Vb8.1 + T cells in single transgenic mice. Hum Immunol 31: 47–56, 1991
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The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession numbers M67511 for V6.1A and M67512 for V6.1B.
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Maksymowych, W.P., Gabriel, C.A., Luyrink, L. et al. Polymorphism in a T-cell receptor variable gene is associated with susceptibility to a juvenile rheumatoid arthritis subset. Immunogenetics 35, 257–262 (1992). https://doi.org/10.1007/BF00166831
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DOI: https://doi.org/10.1007/BF00166831