REDUCED EXPRESSION OF A HUMAN-V-BETA-6.1 T-CELL RECEPTOR ALLELE

We have previously described an allelic polymorphism in the V(beta)6.1 T-cell receptor gene. The V(beta)6.1B allele is associated with disea se in a subgroup of patients with juvenile rheumatoid arthritis. Limit ed sequence data demonstrated nucleotide differences that resulted in two amino acid changes between the two alleles in positions predicted to be important in major histocompatibility complex/antigen recognitio n. The present study demonstrates substantially reduced expression of mRNA from the disease-associated allele (V(beta)6.1B) in peripheral bl ood and thymic tissue. The complete genomic sequence of both alleles r evealed two additional amino acid changes in the V(beta)6.1B gene as w ell as nucleotide differences in the promoter and intron. A cysteine-t o-arginine substitution at position 92 in the disease-associated allel e makes this a non-functional beta chain, since this conserved cystein e is involved with disulfide bonding to cysteine-23 to form an immunog lobulin-like domain structure, thus resulting in a potential hole in t he T-cell receptor repertoire.