As mentioned previously, the human endometrium and decidua are replete with immune and inﬂammatory cells capable of cytokine secretion (194–196). Cytokines may affect reproductive events either directly or indirectly, depending on the specific cytokines secreted, their concentrations, and the differentiation stage of potential reproductive target tissues. It is well documented that TH1-type cytokines can be harmful to an implanting embryo (197,198). Further, most agree that some patients with recurrent pregnancy loss exhibit a dysregulation of their T-helper cellular immune response to antigens at the site of implantation, with typical shifts toward TH1 inﬂammatory responses (199,200). Depending on the individual series, 60% to 80% of nonpregnant women with a history of otherwise unexplained recurrent spontaneous abortion have been found to have evidence of abnormal in vitro TH1 cellular immune responses. Fewer than 3% of women with normal reproductive histories demonstrate these responses (199,201). Rather, most women with normal pregnancies have a TH2 immune response to trophoblast antigens (199). It has only been recently that the TH17 concept has been applied to pregnancy (202). In humans, a single study demonstrates an increase in the number of TH17 cells in the decidua and peripheral blood of women with otherwise unexplained recurrent pregnancy loss (203). Mechanistically, a dysregulation of TH17 cell control by Treg cells may lead to adverse pregnancy outcomes (204).
Methods for the documentation of cytokine dysregulation among recurrent pregnancy loss patients also varies among investigators; some groups have confirmed this abnormality within the endometrium or among immune cells isolated from the decidua of these patients (205– 208). Others use peripheral blood lymphocytes (PBLs) from women with a history of recurrent pregnancy loss and stimulate them in vitro with trophoblast antigens (199,209). One study documented aberrant cytokine secretion when PBLs from recurrent pregnancy loss patients were stimulated in vitro by HLA-G bearing cells, whereas another study demonstrated that decidual and peripheral immune cells exhibit a shift toward the TH2 phenotype when exposed to HLA-G (210,211). Whether peripheral cytokine levels reﬂect T-helper cell dysregulation at the maternal–fetal interface and whether this dysregulation affects peripheral as well as local immune response during pregnancy remains controversial (212,213). Finally, as with all immune theories, there seems to be significant redundancy in the necessity for particular cytokines and soluble immunoregulatory factors at the site of implantation. To date, animal models with directed gene deletions have shown few of these factors to be absolutely essential to pregnancy maintenance (e.g., leukemia inhibitory factor [LIF]) (214,215).