Inheritance patterns of HLA and T cell receptor (TCR alpha and TCR beta) genes which are unknown to play important roles in a variety of immune processes have been analyzed in human families. The extent of the TCR repertoire was investigated by analysis of cDNA and genomic libraries prepared from DNA samples derived from the members of families well characterized for HLA. The present studies have revealed both extensions and limitations of TCR V alpha and V beta repertoires. The known repertoire has been extended by identification of new V alpha and V beta families, new members of defined families and allelic polymorphism in V genes segments. On the other hand, certain V genes have been characterized as pseudogenes which limits TCR repertoires. Six V beta genes were found to be encoded on chromosome 9 outside of the TCR beta gene complex which is encoded on chromosome 7. These genes, designated orphons, have sequences 93-97% identical to V beta genes within the genes complex, show no obvious defects that would preclude expression, but are not detected as rearranged transcripts with C beta. Two frequently occurring insertion/deletion related polymorphisms (IDRP) were found in the TCR beta gene complex; one involves a stretch of about 30kb in the V region and another spans about 20kb near the C region. Three TCR V beta genes have been localized to the V region IDRP; one gene is a previously uncharacterized member of a V beta family, the second gene is a precise duplication of a v beta gene also present in deleted TCR beta haplotypes and the third gene is a pseudogene. Three different V beta genes were found to have unexpressed or null alleles. Holes in the TCR repertoire caused by these unexpressed TCR alleles appear to contribute to susceptibility to a number of clinical subsets of JRA. Allelic variation in genes encoded within the HLA Class II region may contribute to susceptibility to Reiter's Syndrome. TAP genes are thought to function as transporters of peptides for presentation by Class I molecules and may contribute to susceptibility to disease by influencing the selection of peptides. The frequency of the TAP2A allele was increased in the patient group as compared to control groups and all patients were TAP2A+. Certain HLA-DQ alleles were over-represented in the patient group as well. Detailed knowledge of the extent and diversity of the germline TCR repertoire will greatly facilitate our ability to understand the role of TCR genes in immune responses in normal and disease states.
