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Human chorionic gonadotrophin (hCG) is released within hours of fertilization and has a profound ability to downregulate maternal cellular immunity against trophoblastic paternal antigens. It also promotes angiogenic activity of the extravillous trophoblast, and impairment of this function may lead to inadequate placentation and an increased risk of preeclampsia. There is increasing evidence that hCG alters the activity of dendritic cells via an upregulation of indoleamine 2,3-dioxygenase activity. This reduces T-cell activation and cytokine production, as well as encouraging Treg cell recruitment to the fetal-maternal interface. These changes are critical in promoting maternal tolerance. hCG is also able to increase the proliferation of uterine natural killer cells, while reducing the activity of cytotoxic peripheral blood natural killer cells. There are rare reports of autoantibodies directed against hCG or the luteinizing hormone/hCG receptor in women with recurrent miscarriage. These autoantibodies are more frequent in women with thyroid autoimmunity. This may explain the association between thyroid autoimmunity and impaired fertility. Downregulating these anti-hCG and anti-luteinizing hormone/hCG receptor autoantibodies may be helpful in some women with early miscarriage or recurrent failed in vitro fertilization.

Both organ-specific and systemic autoimmunity are associated with an increased prevalence of recurrent miscarriage (RM). The precise mechanism for this is unclear, as cross-reactivity between trophoblastic and maternal host autoantigens has not been demonstrated. In the antiphospholipid antibody syndrome, prothrombotic mechanisms are evident, along with direct inhibitory actions against trophoblastic activity. In many types of both systemic and organ-specific immunity, however, a disturbed T-helper cell profile is seen. This is also evident in women with RM. In both cases, reduced numbers of T regulatory cells have been reported. These are required to regulate excessive activity of the Th1 and the proinflammatory Th17 subsets that, when operating through excessive natural killer cell activity, may have antipregnancy effects. Checking for underlying autoimmunity is therefore a critical analysis in women with RM and future therapies will probably be aimed at correcting the deficiency of regulatory T cells or correcting excessive Th1 and Th17 function.

Problem: To investigate changes in the ratio of T-cell subpopulations expressing intracellular T helper1 (Th1) and T helper 2 (Th2) cytokines in women with a history of recurrent failed implantation under going in-vitro fertilization (IVF)-embryo transfer., Method of Study: Twenty-eight peripheral blood samples were obtained at two time points, from 14 women undergoing IVF treatment; eight women with a history of recurrent failed implantation, who did not get pregnant in the index IVF cycle and six who had one or more previous successful IVF pregnancy and who became pregnant in the index IVF cycle. The proportion of lymphocytes expressing interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), and interleukin 4 (IL-4) and the Th1:Th2 ratios of IFN-gamma:IL-4, and TNF-alpha:IL-4 in T helper cells was measured by flow cytometry, in samples obtained before commencing IVF treatment and in samples obtained after ovarian stimulation (on the day of oocyte retrieval)., Results: In samples collected during oocyte retrieval, women with a history of recurrent failed implantation had a higher IFN-gamma:IL-4 and TNF-alpha:IL-4 ratio than the control group, (18.6+/-9.3 versus 6.47+/-1.68, P=0.009) and (39.1+/-15.7 versus 11.53+/-3.76, P=0.001) respectively. In women with a history of recurrent failed implantation the ratio of IFN-gamma:IL-4 and TNF-alpha:IL-4 at oocyte retrieval was higher than pre-treatment ratios (18.6+/-9.3 versus 12.01+/-9.8, P=0.018) and 39.10+/-15.7 versus 18.66+/-11.42, P=0.010) respectively, showing a Th1 bias. In women with a successful IVF the converse was true; the ratio at oocyte retrieval was significantly lower than pre-treatment ratios (6.47+/-1.68 versus 9.37+/-6.8, P=0.035) and 11.53+/-3.76 versus 18.60+/-12.9, P=0.027) respectively, representing a Th2 bias., Conclusion: Women with a history of unexplained recurrent failed IVF treatment have a Th1 bias and this polarization is more enhanced following hormonal manipulations during IVF treatment. Comparing pre-treatment ratios of IFN-gamma:IL-4 and TNF-alpha:IL-4 to ratios obtained at oocyte retrieval may be clinically useful. Women with recurrent failed IVF have increasing ratios.