Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting.</p> <p>Methods</p> <p>We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the <it>CTLA-4 </it>+49G > A polymorphism and cancer risk.</p> <p>Results</p> <p>Compared with the common <it>CTLA-4 </it>+49G > A GG genotype, the carriers of variant genotypes (<it>CTLA-4 </it>+49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, <it>P </it>< 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the <it>CTLA-4 </it>+49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, <it>P </it>< 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, <it>P </it>= 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, <it>P </it>< 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, <it>P </it>= 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, <it>P </it>< 0.00001) and 1.29 (95% CI = 1.17-1.41, <it>P </it>< 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with <it>CTLA-4 </it>+49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, <it>P </it>= 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, <it>P </it>< 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, <it>P </it>< 0.00001).</p> <p>Conclusion</p> <p>Our meta-analysis suggests that the <it>CTLA-4 </it>+49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.</p

Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals.

The CD28 locus is associated with susceptibility to a variety of autoimmune and immune-mediated inflammatory diseases including primary sclerosing cholangitis (PSC). Previously, we linked the CD28 pathway in PSC disease pathology and found that vitamin D could maintain CD28 expression. Here, we assessed whether the PSC-associated CD28 risk variant A (rs7426056) affects CD28 expression and T cell function in healthy individuals (n = 14 AA, n = 14 AG, n = 14 GG). Homozygotes for the PSC disease risk allele (AA) showed significantly lower CD28 mRNA expression ex-vivo than either GG or AG (p < 0.001) in total peripheral blood mononuclear cells. However, the CD28 risk variant alone was not sufficient to explain CD28 protein loss on CD4 T cells. All genotypes responded equally to vitamin D as indicated by induction of a regulatory phenotype and an increased anti-inflammatory/pro-inflammatory cytokine ratio. A genotypic effect on response to TNFα stimuli was detected, which was inhibited by vitamin D. Together our results show: (a) an altered gene expression in carriers of the susceptible CD28 variant, (b) no differences in protein levels on CD4 T cells, an

Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase‐deficient mouse model of human hyper‐IgD syndrome (HIDS)

Objective We sought to determine the activation status and proliferative capacities of splenic lymphocyte populations from a mevalonate kinase‐deficient mouse model of hyper‐IgD syndrome (HIDS). We previously reported that murine mevalonate kinase gene ablation was embryonic lethal for homozygous mutants while heterozygotes (Mvk+/−) demonstrated several phenotypic features of human HIDS including increased serum levels of IgD, IgA, and TNFα, temperature dysregulation, hematological abnormalities, and splenomegaly. Methods and results Flow cytometric analysis of cell surface activation markers on T and B lymphocytes, and macrophage populations, demonstrated aberrant expression of B7 glycoproteins in all splenic cell types studied. Differences in expression levels between Mvk+/− and Mvk+/+ littermate controls were observed in both the basal state (unstimulated) and after Concanavalin A (Con‐A) stimulation in vitro of whole splenocyte cultures. In Mvk+/− CD4 and CD8 T cells, alterations in expression of CD25, CD80, CD152, and CD28 were observed. Mvk+/− splenic macrophages expressed altered levels of CD80, CD86, CD40, and CD11c while Mvk+/− B lymphocytes had differential expression of CD40, CD80, and CD86. Mvk+/− splenocyte subpopulations also exhibited altered proliferative capacities in response to in vitro stimulation. Conclusion We postulate that imbalances in the expression of cell surface proteins necessary for activation, proliferation, and regulation of the intensity and duration of an immune response may result in defective T cell activation, proliferation, and effector functions in our model and potentially in human HIDS

In vitro exploration of a myeloid-derived suppressor cell line as vehicle for cancer gene therapy

Recent research indicates that cell-mediated gene therapy can be an interesting method to obtain intratumoral expression of therapeutic proteins. This paper explores the possibility of using transfected myeloid-derived suppressor cells (MDSCs), derived from a murine cell line, as cellular vehicles for transporting plasmid DNA (pDNA) encoding interleukin-12 (IL-12) to tumors. Transfecting these cells via electroporation caused massive cell death. This was not due to electroporation-induced cell damage, but was mainly the result of the intracellular presence of plasmids. In contrast, pDNA transfection using Lipofectamine 2000 (LF2000) did not result in a significant loss of viability. Differences in delivery mechanism may explain the distinctive effects on cell viability. Indeed, electroporation is expected to cause a rapid and massive influx of pDNA resulting in cytosolic pDNA levels that most likely surpass the activation threshold of the intracellular DNA sensors leading to cell death. In contrast, a more sustained intracellular release of the pDNA is expected with LF2000. After lipofection with LF2000, 56% of the MDSCs were transfected and transgene expression lasted for at least 24 h. Moreover, biologically relevant amounts of IL-12 were produced by the MDSCs after lipofection with an IL-12 encoding pDNA. In addition, IL-12 transfection caused a significant upregulation of CD80 and considerably reduced the immunosuppressive capacity of the MDSCs. IL-12-transfected MDSCs were still able to migrate to tumor cells, albeit that lipofection of the MDSCs seemed to slightly decrease their migration capacity