RESUMEN
The T cell receptor (TcR) is a heterodimer composed of an alpha,beta- or a gamma,delta-chain. The receptor is expressed on the cell surface in association with the CD3 complex, which in turn is composed of at least four chains (gamma, delta, epsilon, and zeta). In this review, we will summarize the recent findings on the genomic organization of the four T cell receptor genes, and the polymorphisms detected in the variable regions of these genes.
Asunto(s)
Genes MHC Clase II/genética , Polimorfismo de Longitud del Fragmento de Restricción , Receptores de Antígenos de Linfocitos T/genética , Sondas de ADN , Humanos , Receptores de Antígenos de Linfocitos T alfa-beta , Mapeo RestrictivoRESUMEN
We performed a multiple-affected-sib study to determine if T-cell receptor alpha-chain alleles affect susceptibility to insulin-dependent diabetes mellitus. Restriction fragment length polymorphisms were used to follow the segregation of allelic T-cell receptor alpha complexes within the families. The segregation of T-cell receptor alpha alleles in 29 multiplex families revealed no significant tendency for affected sibs to share T-cell receptor alpha-chain alleles more often than would be expected by chance alone (p greater than 0.2). In contrast, the same type of analysis for HLA alleles easily detected the well-known linkage of insulin-dependent diabetes mellitus susceptibility to the HLA complex (p = 0.003). We suggest that the importance of HLA alleles in insulin-dependent diabetes mellitus susceptibility and the lack of importance of T-cell receptor alpha alleles result from the different strategies by which HLA and T-cell receptor molecules achieve antigen-binding diversity: multiple loci and allelic diversity in the case of HLA; combinatorial, junctional, and N-region diversity in the case of the T-cell receptor. In this paper we also describe three new restriction fragment length polymorphisms of the T-cell receptor alpha complex and a new method for testing the significance of linkage in multiple-affected-sib studies.
Asunto(s)
Alelos , Diabetes Mellitus Tipo 1/genética , Receptores de Antígenos de Linfocitos T/genética , Femenino , Antígenos HLA/análisis , Antígenos HLA-DR/análisis , Humanos , Masculino , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allele-specific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, Dw10, Dw13, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and Dw10, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR less than 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination of certain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQ alpha). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/[DQ3.2, Dw4] or DR3/[DQ3.2, Dw10] had a relative risk of 38.0 and an absolute risk of 1 in 15.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplotipos , Alelos , Anticuerpos Monoclonales , Antígenos HLA-D/genética , Antígeno HLA-DR4 , Cadenas HLA-DRB1 , Humanos , Sondas de Oligonucleótidos , Factores de Riesgo , Linfocitos T/inmunologíaRESUMEN
Because of conflicting previous reports showing the presence or absence of Gm-HLA interaction in insulin-dependent diabetes mellitus (IDDM), we report results for a group of Wisconsin families having 2 or more siblings with IDDM. Although this study is very similar to one by Field et al., who found HLA-Gm interaction in IDDM, we find no evidence for such an interactive effect p = 0.33). We discuss published data on HLA-Gm interaction in IDDM, and conclude that overall there is little reason to postulate such an interaction.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Tipo 1/inmunología , Antígenos HLA/inmunología , Alotipos de Inmunoglobulina Gm , Enfermedades Autoinmunes/genética , Diabetes Mellitus Tipo 1/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA/genética , Haplotipos , Humanos , Alotipos de Inmunoglobulina Gm/genética , MasculinoRESUMEN
In this study, we report the RFLP of the human T cell receptor (TCR) alpha chain variable gene segments. Using DNA samples from 20 individuals and three restriction endonucleases (BamHI, EcoRI and HindIII), the degree of RFLP of a number of different V gene segments was defined. Half of the V alpha subfamilies (6/12) were characterized by a predominant hybridization pattern, with only a few individuals displaying a second pattern. However, one particular V gene family, V alpha 6, has at least five allelic forms that segregated consistently in familial studies. The V alpha polymorphisms revealed in this study, together with those exhibited by V beta gene subfamilies, should prove useful in studying possible associations between TCR gene usage and disorders of the immune system.