Mechanism of Human Chorionic Gonadotrophinmediated Immunomodulation in Pregnancy

Amolak S Bansal; Shabana A Bora; Srdjan Saso; J Richard Smith; Mark R Johnson; Meen-Yau Thum

Disclosures

Expert Rev Clin Immunol. 2012;8(8):747-753. 

In This Article

hCG & Immune Function

Table 1 summarizes the action of hCG on the different cells involved in human pregnancy. There is now ample evidence that hCG is important in maintaining pregnancy by promoting a downregulation of harmful maternal immunity.[19] The immunosuppressive effects of hCG were first demonstrated over 30 years ago by Fuchs et al. in 1980. They demonstrated the ability of hCG in a murine model to stimulate lymphocytes that were able to depress polyclonal antibody production by various B-cell mitogens.[20] Subsequently with human lymphocytes, they showed physiologically relevant concentrations of hCG to depress the induction of an antibody response by tuberculin purified protein derivative, phytohemagglutinin, lipopolysaccharide and pokeweed mitogen.[21] The hCG receptor, which is shared with luteinizing hormone (LH), was subsequently demonstrated on T and B lymphocytes,[22] and T lymphocytes were shown to express mRNA for the hCG receptor.[23] Further work in women undergoing in vitro fertilization (IVF) treatment showed that those returning a positive hCG test at day 14 had a serum factor that was able to suppress T-cell CD3 z-chain expression.[24] Importantly, this was absent before confirmation of pregnancy.

Several reports have dissected the mechanism of action of hCG on immune function. This has been stimulated by the observation that female non-obese diabetic mice given recombinant hCG between weeks 3 and 15 had a significantly reduced incidence of diabetes.[25] This was associated with reduced T-cell proliferative responses against β-cell antigens. Furthermore, splenocytes stimulated with anti-CD3 antibody showed increased IL-10 and TGF-β production with suppressed IFN-γ.[25] Interestingly, the hCG treatment also increased the ratio of CD4+CD25+ Tregs compared with overall CD4+ T cells in the spleen and pancreatic lymph nodes.[25] In an earlier investigation, hCG administered to non-obese diabetic mice reduced activation of the diabetogenic CD4 and CD8 T cells via the upregulation of dendritic cell (DC) indoleamine 2,3-dioxygenase (IDO), which was reversed by 1-methyl-tryptophan that is known to inhibit IDO activity.[26] In human lipopolysaccharide and IFN-γ-stimulated DCs, hCG has been shown to stimulate IDO mRNA expression, which was accompanied by reduced levels of tryptophan and elevated levels of its kynurenine metabolites.[27] Importantly, human trophoblast cells have been shown to express mRNA for IDO and trophoblast-mediated downregulation of T-cell activity involves tryptophan depletion.[28] Recently, Segerer et al. have shown hCG to reduce DC-mediated activation of autologous T cells.[29] hCG also reduced DC proliferation and cytokine production,[27] as well as stimulating the recruitment of Tregs to the site of the fetal–maternal interface.[19]

It is now clear that the downregulation of T-cell function that may be harmful to the developing embryo is an important early event. In this regard, the peripheral blood mononuclear cells of women "who received hCG preconditioning prior to IVF" were found to have raised expression of anti-inflammatory IL-27 accompanied by reduced expression of the proinflammatory IL-17.[30] Furthermore, there was an increased level of circulating IL-10 levels and elevated numbers of peripheral blood Tregs. Serum levels of hCG have been shown to be inversely related with mRNA for IL-18 in pregnant women.[31] As IL-18 is proinflammatory, this suggests the importance of hormones such as hCG to reduce the activity of those factors that are harmful to the pregnancy.

Initial early work suggested that progesterone rather than hCG was able to stimulate NK-cell proliferation in in vitro endometrial cultures.[32] While progesterone is certainly important in encouraging Treg proliferation and activity,[33] the importance of hCG has gained increasing recognition. Thus, Carbone et al. have reported markedly reduced CD3/CD28-stimulated CD4 T-cell proliferation and IFN-γ secretion by the peripheral blood mononuclear cells of ten women in the follicular phase of their menstrual cycle when incubated with follicle-stimulating hormone (FSH), LH and hCG compared with FSH and LH alone.[34] This was accompanied by increased IL-10 production, confirming the importance of hCG in downregulating Th1 type immunity and increasing Treg cell activity. hCG, acting via the mannose binding protein receptor on the surface of the cytokine-secreting uterine NK cells, has been shown to increase their proliferation and as a consequence placentation.[35] The binding was mediated by the terminal mannose residues on the N-linked carbohydrate side chains on the hCG protein as excess mannose inhibited this interaction. In their review of T and NK cells in miscarriage, Nakashima et al. reported an increase in the numbers of IL-10-secreting regulatory NK cells formed from peripheral blood cells from healthy nonpregnant women stimulated with hCG and progesterone.[36] These cells were earlier reported to be increased in pregnant women compared with those who were not pregnant and reduced in women suffering miscarriage compared with women with normal pregnancy.[37] Thus, hCG has a significant role in maintaining pregnancy by encouraging the formation of those cells that promote tolerance to the haploidentical fetus and coordinate vascularization.

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