Abstract
Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is considered as a negative regulator of T cell activation and its role in maintaining immune tolerance is well established. The present case-control study aimed to investigate the CTLA-4 +49 A/G, -1661 A/G, -318 C/T and -1722 T/C single nucleotide polymorphisms (SNPs) and predisposition to recurrent pregnancy loss (RPL) in Gaza Strip - Palestine. The study was performed on 200 women with a history of two or more pregnancy losses (case group) and 200 control women with at least two live births and without any previous history of abortion. PCR-based restriction fragment length polymorphism (RFLP-PCR) method was used for genotyping CTLA-4 polymorphisms. Study results revealed that there is no significant association between the allele/genotype frequencies of the four investigated CTLA-4 SNPs and RPL. This trend remained true under dominant, co-dominant and recessive models. The A\G genotype of -1661 A\G polymorphism was higher in patients (45%) as compared to controls (39.5%) but without statistical significance. The minor allele frequencies (MAFs) of the CTLA-4 gene polymorphisms in the patient/control group were as follows: +49A>G: 0.22/0.22, -318 C>T: 0.15/0.11, -1661 A>G: 0.30/0.26 and -1722 T>C: 0.08/0.08. The four investigated CTLA-4 polymorphisms do not contribute to the risk of RPL in the study population. Testing other CTLA-4 gene polymorphisms and the level of CTLA-4 expression in RPL patients is recommended.
Highlights
Recurrent pregnancy loss, the occurrence of 2 or more consecutive miscarriages, is one of the most common pregnancy complications with a prevalence of 1-2% among pregnant women in reproductive life [1].Despite years of effort to determine the factors involved in miscarriage, the cause remains unclear in around 50% of the cases this reflects the heterogeneous nature of this malady [2].Several mechanisms have been proposed to function actively in the protection of the semi-allogeneic fetus from maternal immune system
Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) has a suppressive effect on T cell activation and might be involved in establishing immune tolerance by blocking CD28dependent T cell activation through interactions with its ligand CD80/86 on antigen presenting cells in the decidua
Hardy-Weinberg equilibrium for investigated single nucleotide polymorphisms (SNPs) The distribution of the genotypes of -318C\T, -1661 A\G and -1722 T\C SNPs conformed with Hardy–Weinberg equilibrium as there was no significant difference between the expected and the observed genotypes
Summary
Several mechanisms have been proposed to function actively in the protection of the semi-allogeneic fetus from maternal immune system. The presence of regulatory T cells (Tregs) and the expression of immunomodulatory molecules at the fetal maternal interface have been identified as crucial factors for fetomaternal tolerance [3]. Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is constitutively expressed in Foxp3+ Tregs and induced in conventional T cells following activation [4]. CTLA-4 has a suppressive effect on T cell activation and might be involved in establishing immune tolerance by blocking CD28dependent T cell activation through interactions with its ligand CD80/86 on antigen presenting cells in the decidua. CTLA-4 dysregulation, has the potential to affect fetal tolerance through altered activation of T cells to fetal antigens
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