T cell receptor β chain genotyping in Australian relapsing-remitting multiple sclerosis patients

Abstract

This study focused on susceptibility to MS within the b-chain of the T-cell antigen receptor (TCRB locus, 7q35) in a cohort of 122 RR-MS patients compared with 96 normal individuals using biallelic polymorphisms across the bv8s1(Vb8.1) to bv11s1 (Vb11) TCRB subregion. The markers bv6s5, bv8s1, bv10s1, bv15s1 and bv3s1 were studied for allele and genotype frequencies; haplotypes were assigned with combinations of two of these markers and stratification for HLA-DR15 was also performed. Linkage disequilibrium was found between alleles of the bv8s1, bv10s1/bv15s1 and bv3s1 loci in both patients and controls. An increase among RR-MS patients in the allele frequency of bv8s1*2 (P=0.03) and the haplotype bv8s1*2/bv3s1*1 (P=0.006) was noted and both were found to be statistically significant. In the DR15-positive group, the association between TCRB and MS was seen with the bv8s1*2 allele (P_uc=0.05) and the bv8s1*2/bv10s1 haplotypes (P_uc=0.048), while the haplotype associations seen among DR15-negative RR-MS patients included the bv3s1*1 allele (bv10s1*1/bv3s1*1, P_uc=0.022; bv8s1*2/bv3s1*1, P_uc=0.048). These results support the involvement of the TCRB region in MS susceptibility and encourage further study of the variable gene segments in this region.

Keywords

multiple sclerosis TCRB region susceptibility haplotype HLA

Get full access to this article

View all access options for this article.

References

Sadovnick AD , Ebers GC , Dyment DA , Risch NJ , The Canadian Collaborative Study Group . (1996) Evidence for genetic basis of multiple sclerosis . Lancet 347: 1728-1730 .

Chataway J et al. (1998) The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systemic genome screen . Brain 121: 1869-1887 .

Compston DAS et al. (1995) Genes and susceptibility to multiple sclerosis . Acta Neurol Scand 161(suppl.): 43-51 .

Dyment DA , Sadovnick AD , Ebers GC. (1997) Genetics of multiple sclerosis . Hum Mol Genet 6: 1693-1698 .

Stewart GJ. (1997) Multiple sclerosis, multiple genes . Med J Aust 166: 573-574 .

Sawcer S et al. (1996) A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22 . Nature Genet 13: 464-468 .

Haines JL , The Multiple Sclerosis Genetics Group . (1996) A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex . Nature Genet 13: 469-471 .

Ebers GC et al. (1996) A full genome search in multiple sclerosis . Nature Genet 13: 472-476 .

Seboun E et al. (1989) A susceptibility locus for multiple sclerosis is linked to the T cell receptor b chain complex . Cell 57: 1095-1100 .

10.

Beall SS et al. (1989) The germline repertoire of T cell receptor b-chain genes in patients with chronic progressive multiple sclerosis . J Neuroimmunol 21: 59-66 .

11.

Charmley P et al. (1991) Further localization of a multiple sclerosis susceptibility gene on chromosome 7q using a new T cell receptor beta-chain DNA polymorphism . J Neuroimmunol 32: 231-240 .

12.

Beall SS et al. (1993) Susceptibility for multiple sclerosis is determined, in part, by inheritance of a 175-kb region of the TcR Vb chain locus and HLA class II genes . J Neuroimmunol 45: 53-60 .

13.

Martñez-Naves E , Victoria-Gutiérrez M , Uría DF , López-Larrea C. (1993) The germline repertoire of T cell receptor b-chain genes in multiple sclerosis patients from Spain . J Neuroimmunol 47: 9-14 .

14.

Epplen C et al. (1997) Genetic predisposition to multiple sclerosis as revealed by immunoprinting . Ann Neurol 41: 341-352 .

15.

Hockertz MK , Paty DW , Beall SS. (1998) Susceptibility to relapsing-progressive multiple sclerosis is associated with inheritance of genes linked to the variable region of the TcR beta locus: use of affected family-based controls . Amer J Hum Genet 62: 373-385 .

16.

Hillert J , Leng C , Olerup O. (1991) No association with germline T cell receptor b-chain gene alleles or haplotypes in Swedish patients with multiple sclerosis . J Neuroimmunol 31: 141-147 .

17.

Fugger L et al. (1990) The germline repertoire of T-cell receptor b chain genes in patients with relapsing/remitting multiple sclerosis or optic neuritis . Immunogenet 31: 278-280 .

18.

Vandevyver C et al. (1994) HLA and T-cell receptor polymorphisms in Belgian multiple sclerosis patients: No evidence for disease association with the T-cell receptor . J Neuroimmunol 52: 25-32 .

19.

Wei S , Charmley P , Birchfield R , Concannon P. (1995) Human T-cell receptor Vb gene polymorphism and multiple sclerosis . Am J Hum Genet 56: 963-969 .

20.

Droogan AG et al. (1996) T-cell receptor alpha, beta, gamma, and delta chain gene microsatellites show no association with multiple sclerosis . Neurology 47: 1049-1053 .

21.

Kuokkanen S et al. (1997) Genomewide scan of multiple sclerosis in Finnish multiplex families . Am J Hum Genet 61: 1379-1387 .

22.

Jaeger EE et al. (1998) Characterization of chimpanzee TCRV gene polymorphism: how old are human TCRV alleles? Immunogenet 47: 115-123 .

23.

Gruen JR , Weissman SM. (1997) Evolving views of the major histocompatibiliy complex . Blood 90: 4252-4265 .

24.

Charmley P , Concannon P , Gatti RA. (1990) T-cell receptor b-chain DNA polymorphism frequencies in healthy HLA-DR homozygotes . Tissue Antigens 35: 157-164 .

25.

Jardetzky TS et al. (1994) Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen . Nature 368: 711-718 .

26.

Halle J-P et al. (1997) A conserved tissue-specific structure at a human T-cell receptor b-chain core promoter . Mol Cell Biol 1997; 17: 4220-4229 .

27.

Donahue JP et al. (1994) Genetic analysis of low Vb3 expression in humans . J Exp Med 179: 1701-1706 .

28.

Posnett DN et al. (1994) Level of human TCRBV3S1 (Vb3) expression correlates with allelic polymorphism in the spacer region of the recombination signal sequence . JExp Med 179: 1707-1711 .

29.

Rowan L , Koop BK , Hood L. (1996) The complete 685- Kilobase DNA sequence of the human b T cell receptor locus . Science 272: 1755-1762 .

30.

Vessey SJR , Bell JI , Jakobsen BK. (1996) A functionally significant allelic polymorphism in a T cell receptor Vb gene segment . Eur J Immunol 26: 1660-1663 .

31.

Vukusic B et al. (1995) Both MHC and background gene heterozygosity alter T cell receptor repertoire selection in an antigen-specific response . Mol Immunol 32: 1355-1367 .

32.

Poser CM et al. (1983) New diagnostic criteria for multiple sclerosis: Guidelines for research protocols . Ann Neurol 13: 227-231 .

33.

Bennetts BH et al. (1995) TAP2 polymorphisms in Australian multiple sclerosis patients . J Neuroimmunol 59: 113-121 .

34.

Svejgaard A et al. (1979) The HLA System . Monogr Hum Genet 7: 29-30 .

35.

Lynch SG et al. (1991) Discordance of T-cell receptor b-chain genes in familial multiple sclerosis . Ann Neurol 30: 402-410 .

36.

Briant L et al. (1993) Multiple sclerosis susceptibility: Population and twin study of polymorphisms in the T-cell receptor b and t genes region . Autoimmunity 15: 67-73 .

37.

Murphy B , Krensky AM. (1999) HLA derived peptides as novel immunomodulatory therapeutics . J Am Soc Nephrol 10: 1346-1355 .

38.

Becker KG et al. (1998) Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune disease . Proc Natl Acad Sci (USA) 95: 9979-9984 .