Sweden CTLA-4 is an important negative regulator of the immune system. The regulation of the CTLA-4 gene (Ctla-4) transcription is poorly understood. A single nucleotide polymorphism (SNP) at −318 in the Ctla-4 promoter region is associated with certain autoimmune diseases. Since the −318 SNP occurs in a potential regulatory region, it is conceivable that the CЈ T transition may affect the expression of In the present study, we show that the −318T allele is associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49 CTLA-4 plays an important role in the immune system as a T cell inhibitory factor. This inhibitory signal not only determines whether T cells become activated, but also affects the clonal representation in an immune response. CTLA-4 regulates cell cycle progression rather than directly the induction of apoptosis. 1 CTLA-4 Ig and anti-CTLA-4 have been applied for the treatment of both autoimmune diseases and cancers.Little is known about the regulatory mechanism for CTLA-4 expression. Polymorphisms in the Ctla-4 are associated with several autoimmune diseases, and polymorphisms at certain locations of the Ctla-4 might conceivably affect its expression. We have described a higher prevalence of thymine at position −318 of the Ctla-4 promoter (−318T) in patients with Wegener's granulomatosis. 2 Recently, Ligers and colleagues reported that individuals carrying −318T exhibited significantly increased expression both of cell-surface CTLA-4 in activated cells and of Ctla-4 mRNA in non-stimulated cells, 3 suggesting a potential role for the CЈ T transition in the regulation of expression. In the present study, we examined the effect of CЈ T switch at −318 on the Ctla-4 promoter activity. Our results demonstrated that the −318T allele was associated with a significantly higher promoter activity than the −318C allele. Results and discussionTo determine whether the CЈ T transition at position −318 transcriptionally regulates the Ctla-4 gene expression, we made two Ctla-4 promoter reporter constructs which contained C and T alleles, respectively. As shown in Figure 1, the −318T allele was associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49). This result was also confirmed in the THP-1 cell line transfected with these two reporter constructs, and stimulated with IFN-␥ (5 mg/ml) and PMA (10 ng/ml).Our allele-specific transcription data indicate that the −318T allele is associated with higher transcriptional activity than the −318C allele. The -318T allele could be considered as protective against autoimmune reactions. Our results could explain the increased expression of CTLA-4 3 and the observed associations of the −318T allele to some diseases. 4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respective...

The cytotoxic T lymphocyte associated protein 4 (CTLA-4) gene

Background Sepsis, a severe systemic inflammatory response resulting from an infection, often culminates in high mortality rates. Cytokines, specifically IL-10, and pathogenic microbial load, play a pivotal role in its pathogenesis. IL-10's integral role in immune regulation potentially impacts the clearance of pathogenic microorganisms and the disease's severity. However, the correlation between IL-10 levels, pulmonary pathogenic microbial load in sepsis, and their subsequent impact on patient prognosis remain unclear. Therefore, this study aims to elucidate the association between IL-10 levels, lung pathogenic microbial load, and their impact on the prognosis of sepsis. Methods We gathered clinical data from 79 patients with sepsis, including age, gender, BMI, history of chronic diseases, laboratory test results, cytokine levels, and mNGS analysis results. Univariate analysis and multivariate linear regression were utilized to examine the relationship between each variable and the pathogenicic microbial load in bronchoalveolar lavage fluid, as determined by mNGS. To further study the prognosis, patients were categorized based on the quantity of pathogenic microbes, and survival analysis was conducted using the Kaplan-Meier method. Results The study identified a significant positive correlation between cytokine IL-10 levels and the quantity of pathogenic microbes (β: 0.018,95%CI: 0.014 ~ 0.021,P value < 0.001). Multivariate linear regression analysis further confirmed this positive correlation (β:0.01,95%CI: 0.01 ~ 0.02,P value < 0.001), which held stable after adjusting for all potential confounders. Furthermore, Kaplan-Meier survival analysis revealed a significant increase in the 28-day mortality rate for sepsis patients when the count of pathogenic microbes reached or exceeded three. Conclusion Our study discloses the correlation between IL-10 levels and pathogenic microbial load, and their substantial predictive value for the short-term survival of sepsis patients. These findings highlight the critical importance of meticulous monitoring and managing of IL-10 levels and pathogenic microbial load in clinical practice. Timely intervention measures are particularly imperative for sepsis patients exhibiting both high IL-10 levels and pathogenic microbial load. These results provide fresh insights and understanding that can potentially enhance the clinical treatment and prognosis of sepsis.