HLA-G and Recurrent Pregnancy Loss

Abstract

Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40–60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.

Maternal HLA class II alleles and haplotypes associated with altered risk of recurrent pregnancy loss: A case‐control study

“…[21][22][23][24] Moreover, the HLA alleles play an important role in the maternal immune system's tolerance to pregnancy, thus, gestational complications such as preterm delivery, recurrent miscarriage, preeclampsia, and gestational diabetes might occur in cases of HLA deregulation. 5,[21][22][23][24][25][26][27][28][29][30] Since RPL is linked with dysregulated immunity, the relationship between specific class I and class II alleles and corresponding multilocus haplotypes with increased susceptibility to, or protection from RPL were addressed in several ethnic groups, often with no clear consensus. An earlier study on Japanese women documented the positive link between HLA-DPB1*0402 and HLA-DPB1*04 alleles with an increased risk of RPL.…”

UP‐regulated levels of sHLA‐G in women with a history of RPL in mid‐gestation presumably to achieve ongoing pregnancy

“…25 This suggests studies are warranted associating maternal, fetal and paternal HLA-G genotypes (Trio testing) along with sHLA-G concentrations for linking it with the obstetrics outcomes. 17 Our theory could be proved more appropriate if the placental samples of iRPL group and male factor were examined. Nevertheless, this study can give us indication of the pathway stated above.…”

“…In mice its seen that priming uterus with semen promotes implantation and fetal growth in following pregnancies, even in partner‐specific manner and in humans exposure to semen at the time of embryo transfer significantly improved live birth rates during invitro fertilization 25 . This suggests studies are warranted associating maternal, fetal and paternal HLA‐G genotypes (Trio testing) along with sHLA‐G concentrations for linking it with the obstetrics outcomes 17 . Our theory could be proved more appropriate if the placental samples of iRPL group and male factor were examined.…”

“…The maternal immune system has to modulate appropriately in such a way to combat invading pathogens and at the same time suppressing maternal immune response against the embryo to avoid pregnancy‐related complications 2 and any kind of mishap can lead to autoimmune diseases like Antiphospholipid syndrome and systemic lupus erythematous where trophoblast apoptosis with heightened inflammatory responses is associated with abnormal spiral arteries, vascular endothelium dysfunction 3 and placental dysfunction 4 causing recurrent pregnancy loss 5,6 . To avoid this cells and molecules has to work in harmony, one such mechanism is the secretion of Natural antimicrobial peptides which are the key mediators of innate immunity especially in the human endometrium, 7 the microbiota and the HLA‐G expressed on the surface of extravillous trophoblastic cells 8–12 a non‐classical class I MHC molecule 13,14 responsible for tiling the maternal immune system towards tolerance for semiallogenic fetus thereby preventing its rejection 8,15–17 . The peptides have diverse range of anti‐microbial properties providing protection against many pathogens preventing pregnancy‐related complications 18 .…”

“…5,6 To avoid this cells and molecules has to work in harmony, one such mechanism is the secretion of Natural antimicrobial peptides which are the key mediators of innate immunity especially in the human endometrium, 7 the microbiota and the HLA-G expressed on the surface of extravillous trophoblastic cells [8][9][10][11][12] a non-classical class I MHC molecule 13,14 responsible for tiling the maternal immune system towards tolerance for semiallogenic fetus thereby preventing its rejection. 8,[15][16][17] The peptides have diverse range of anti-microbial properties providing protection against many pathogens preventing pregnancy-related complications. 18 The human endometrium expresses beta-defensins 1−4, Whey acidic protein (WAP) motif protein, and secretory leukocyte protease inhibitor (SLPI).…”