Tim-3, also known as hepatitis A virus cellular receptor 2 (HAVCR2), is a newly discovered surface molecule on T cells, with important immune regulatory functions. In humans, Tim-3 is located on chromosome 5q33.2. Tim-3 comprises 301 amino acids, including elementary structural domains such as the signal peptide domain, immunoglobulin V (IgV) structural domain, mucin-like structural domain, transmembrane zone, and cytomere domain of phosphorylation site. In the IgV structural domain, there are 2 antiparallel β fragments and a metal ion ligand binding site (MILIBS), which together function as the ligand-binding site of Tim-3 [12, 13].
In this study, rs10053538 and rs1055746 loci of Tim-3 were studied. Statistical data showed that in both healthy women and URSA patients, the frequencies of mutant-type homozygote TT on both loci were low. Hence, the data of mutant-type homozygote TT and mutant-type heterozygote GT were merged and re-analyzed by χ2 test. However, still, no significant statistical difference was found between the distribution frequencies of GT + TT genotype in either group (Table 1). The distribution frequencies of T allele on rs10053538/rs10515746 locus of each group were of no statistical difference either (see Table 2). All these data suggested that the polymorphisms of rs10053538/rs10515746 may not contribute to the URSA in Han Chinese women.
Tim-3 deficiency has been reported to precipitate the aggravation of diseases in which the Th1-type immune response prevails, increasing the magnitude of illness and mortality . Furthermore, the Th1/Th2-type cytokine balance leans toward a radical overbalance of Th1-type cytokine in URSA patients . Herein, it can be postulated that Tim-3/Tim-3 polymorphisms might be closely related to URSA.
Meanwhile, researchers found that the distribution frequencies of +4259 T/G in Tim-3 in patients with pancreatic cancer or renal cell carcinoma were statistically different from those of healthy people [15, 16]. The distribution frequencies of +4259 T/G in Tim-3 in rheumatoid arthritis patients have been shown to be statistically different compared with those of healthy people both in the Han Chinese and Hui Chinese . According to another report, in Korea, the distribution frequencies of +4259 T/G in Tim-3 in children with dermatitis or asthma were not statistically different from those of healthy children, but this was not so in Caucasian or Hispanic children .
Given these findings, it might be concluded that Tim-3/Tim-3 polymorphisms and their association with diseases not only pertain to the inclusion criteria of subjects but also to ethnic and regional differences.
Despite the current data don’t complying with the postulation, the polymorphisms of rs10053538/rs10515746 loci in Tim-3 and their relationship with URSA are still not that clear. This is because of several reasons. First, this study included as research subjects only Han Chinese women in Taizhou, a Han Chinese habitation. Second, not all patients in this study had a precise record of miscarriage history. The number of miscarriages was self-reported; therefore, there might have been errors in the precise number of miscarriages. Third, many studies have found that Tim-3 plays an important role in certain immune diseases. Therefore, the polymorphisms in Tim-3 and their association with URSA, such as the relationship between genotype and phenotype and their function in the molecular genetic mechanisms of URSA, warrant further investigation.