Polymorphism in a T-cell receptor variable gene is associated with susceptibility to a juvenile rheumatoid arthritis subset

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 less than 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.

Reduced expression of a human V beta 6.1 T-cell receptor allele.

“…We have reported a bi-allelic polymorphism (V,96.1A, V,36.1B) and have noted that the Vp6.1B allele is associated with a subset of patients with one form of a childhood autoimmune disease, juvenile rheumatoid arthritis (JRA) (5,12). The present study shows that mRNA expression from the V,6.1B allele is reduced compared with V,86.1A.…”

“…Allelic polymorphisms in the germ-line TCR genes provide additional diversity in the population (2). Polymorphisms that result in amino acid substitutions have been described for several human Vp genes, including V01, V,6.1, and V,6.7 (3)(4)(5). A null allele resulting from a stop codon in the human V,20 gene has also been described (6,7).…”

Systematic study of human αβ T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes

“…Together with the other frequent coding polymorphisms of TCRB [5,6,8] and of TCRA loci (Table l), this suggests that the overall level of allelic variation might be very large.…”

“…There exists, however, one additional source of variation in these loci, namely allelic polymorphism. In man four Vg regions have been established as showing at least diallelic polymorphism, Vs1 [5], Vp6.7 [6], Vp2 [7] and Vf36.1 [8]. The identification of such variation has been hampered by the…”

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“…Thus, a recently identified allele of the TCR Vp6.1 gene (Vp6.1B) was shown to be associated with a subset of type I pauciarticularonset JRA, i.e., patients whose disease will evolve to become polyarticular and who have a reduced frequency of iridocyclitis. This association was found to be even stronger when patients were stratified by HLA haplotype, especially HLA-DQAl*OlOl (32). The Vp6.1A and Vp6.1B polymorphisms differ by 4 amino acids, including a cys-tyr mutation at position 92 in Vp6.1B.…”