Expression Of Human Leucocyte Antigen G And E In Human Placenta And Their Relationship With Intrahepatic Cholestasis Of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a disease predominantly of the third trimester of pregnancy, characterized primarily by pruritus and biochemical disturbances in liver enzymes. It has been associated with poor fetal outcomes, including increased incidence of meconium-stained amniotic fluid, spontaneous preterm delivery, antepartum fetal death, fetal anoxia and stillbirth. The etiology and pathogenesis of the disease is poorly understood, and treatment modalities are controversial. Recent studies have suggested that the disturbance of maternal immune system function may contribute to the pathogenesis of the disease.The acceptance of the fetoplacental unit by the maternal uterine surface requires an element of immunogical tolerance and various mechanisms are believed to be involved in this process. Human leucocyte antigen(HLA)-G and HLA-E are nonclassical human leucocyte antigen class I molecules that are selectively expressed on trophoblasts at the fetal-maternal interface where they may play a major role in maternal-fetal immune tolerance.They protect fetal trophoblasts against natural killer cell or cytotoxic T cell mediated lysis in deciduas through direct interaction withinhibitory receptors. Furthermore, HLA-G and HLA-E can modulate the cytokine releasing of decidual and peripheral blood mononuclear cell.This results in a shift in the balance of cytokine profiles away from THl-type reactivity to a TH2-type reactivity and contributes to the maintenance of the fetal semi-allograft during pregnancy.The approprite expression of HLA-G and HLA-E in the trophoblasts is essential to successful pregnancy.We use ISH and IHC methods in this study to investigate the expression pattern of HLA-G and HLA-E mRNA and protein in normal human first trimester placenta > third trimester placenta and placenta of ICP patient. Meanwhile, a 14bp insertion/deletion polymorphism in exon 8 of HLA-G gene has also been analysed by PCP-SSP method.The results: (1) In first trimester placenta ,the mRNA of HLA-G and HLA-E were found in all kinds of trophoblast, including syncytiotrophoblast, villous and extravillous cytotrophiblast(EVCT). The expression of HLA-E protein was in consistant with its mRNA expression.whereas HLA-G protein expression was only found on EVCT by monoclone antibody 4H84.In third trimester placenta,the mRNA and protein expression of HLA-G and HLA-E were detected on EVCT and amnion epithelium cells;(2) No significant difference of HLA-G > E mRNA expression on EVCT of placenta were found between normal control group, ICP group with dexamethasone(DEX) treatment and ICP group without DEX treatment.However, the protein expression of HLA-G and HLA-E on placental EVCT of ICP group without DEX treatment was significantly lower than those of normal control group and ICP group with DEX treatment;(3)There were no significant difference between the control group and the ICP group concerning the allele and genotype of the 14bpinsertion/deletion polymorphism in exon 8 of HLA-G gene. The number of +14bp allele in combined mother-child genotype of both group was also not significantly different.Combined with other studies.we get the following deduction: (1) The anti-HLA-G monoclone antibody 4H84 stains exclusively EVCT and amnion epithelium cells; (2) The decreased EVCT expression of HLA-G > E protein may cause the disturbance of the maternal-fetal immune tolerance of ICP patient and play a role in the pathogenesis of ICP. The DEX can upregulate the EVCT expression of HLA-G ^ E protein and this may be one of the mechanisms in its treatment of ICP;(3) There is probably no evident association between susceptibility to ICP and the 14 bp insertion/deletion polymorphism of HLA-G gene.However, more genotyping studies of HLA-G gene are needed to be done with its relationship to ICP.