Malaria is not responsible for the selection of TCR beta-subunit variable gene haplotypes in The Gambia.

Previous work has shown that a single haplotype of the T-cell antigen receptor beta-subunit (TCRB) locus is predominant in African populations. This is likely to be due to selection pressure for gene(s) that protect children against disease. This study has tested the hypothesis that malaria is the responsible selection pressure, due to its impact on child mortality. The haplotypes of BV8S3, BV2S1, BV15S1, and BV3S1 were determined in children suffering from severe malaria and unaffected adult controls. No significant difference between cases and controls was shown for any of the haplotypes studied. In addition, an insertion/deletion (INDEL) haplotype in the 5' region of the TCRB locus was investigated. Again no differences between the two groups were detected. Therefore, the evidence suggests that malaria is not responsible for haplotype selection in The Gambia

Different pathways of human T-cell activation revealed by PHA-P and PHA-M.

Antigen-specific T-cell activation is mediated via the CD3-Ti (antigen receptor) complex, and monoclonal antibodies to both CD3 and Ti cause a rapid rise in intracellular Ca2+. This calcium mobilization is not inhibited by monoclonal antibodies to CD2. The rise in calcium mobilization induced by purified PHA (PHA-P) does not occur in a cell line which lacks CD2 expression, and can be blocked in other T cells by anti-CD2 antibodies. A combination of monoclonal antibodies to different epitopes of CD2 causes calcium mobilization and mitogenesis. Reagent grade PHA (PHA-M) induces calcium moblization in cells that lack CD2, and its effects in other T cells cannot be blocked by anti-CD2 antibodies. The effects of PHA-P and PHA-M are thus mediated predominantly through different activation pathways

Early rheumatoid arthritis is associated with a deficit in the CD4<em>⁺</em>CD25^high regulatory T cell population in peripheral blood

Objective. Our aim was to test the hypothesis that there is a deficit in the CD4 + CD25 high regulatory T-cell population in early rheumatoid arthritis (RA), either in size or functional activity. Methods. Peripheral blood mononuclear cells were examined from subjects with early active RA who had received no previous disease-modifying therapy (n = 43), from individuals with self-limiting reactive arthritis (n = 14), from subjects with stable, well-controlled RA (n = 82) and from healthy controls ( n = 72). The frequencies of CD4 + CD25 high T-cells were quantified using flow cytometry, and function was assessed by the ability to suppress proliferation of CD4 + CD25 - T-cells. Paired blood and synovial fluid was analysed from a small number of RA and reactive arthritis patients. Results. There was a smaller proportion of CD4+CD25high T-cells in the peripheral blood of early active RA patients (mean 4.25%) than in patients with reactive arthritis or in controls (mean 5.90 and 5.30%, respectively, P = 0.001 in each case). Frequencies in stable, well-controlled RA (mean 4.63%) were not significantly different from early active RA or controls. There were no differences in suppressor function between groups. Higher frequencies of CD4+CD25high T-cells were found in synovial fluid than blood in both RA and reactive arthritis. Conclusions. These data demonstrate a smaller CD4+CD25high regulatory T-cell population in peripheral blood of individuals with early active RA prior to disease-modifying treatment. This may be a contributory factor in the susceptibility to RA and suggests novel approaches to therapy. \ua9 2006 Oxford University Press

Unique TCR beta-subunit variable gene haplotypes in Africans.

This study investigated polymorphisms of genes in two regions of the T-cell antigen receptor beta-subunit (TCRB) locus, including BV9S2P, and BV6S7 in a 5' linkage group, and BV8S3, BV24S1, BV25S1, BV18S1, BV2S1, BV15S1 and BV3S1 in a 3' linkage group. These loci have been genotyped in individuals from five regions in Africa, including The Gambia, Nigeria, Cameroon, Tanzania, and Zambia, and in individuals from northern Britain, northern India, and Papua New Guinea (PNG). In the 3' linkage group, 11 unique haplotypes were identified in the combined African populations; two equally frequent haplotypes represent the majority of African chromosomes. One haplotype was found in all four regions studied. This is the most frequent haplotype in the northern British, northern Indian and PNG populations. Although present, it is infrequent in the African populations. A North-South gradient in the frequency of a common African haplotype was observed. The distribution did not represent that of a known disease. Evidence suggests that malaria is not responsible for selection of these haplotypes. Overall, this study highlights large differences in the genetic constitution of the TCRB locus between Africans and other populations