Aberrant expression of class II MHC determinants, or enhanced expression of MHC class I on syncytiotrophoblast occurring in response to IFN-γ (180) could mediate pregnancy loss by enhancing cytotoxic T-cell attack (181). This theory appears unlikely, because the expression of classical MHC antigens does not seem to be induced on aborted tissues from women experiencing one or more pregnancy losses (181). Finally, MHC class II genotypes appear to affect susceptibility to a variety of diseases, including diabetes and other autoimmune diseases. A similar link between MHC class II typing and adverse pregnancy outcome was reported for recurrent pregnancy loss (182,183).
Regulation of Decidual Immune Cells The characteristics of the interactions between decidual immune effector cells and the implanting fetus may be determined by factors other than those already mentioned. Local regulation of the cells that populate the human decidua will further modify the effects of selection, maintenance, and homing, as well as the distinctive characteristics of antigen presentation at the maternal–fetal interface. As might be predicted, these regulatory effects are often targets for investigative efforts, because they may offer more direct insight into potential therapies for immune-mediated disorders of pregnancy maintenance. Three such regulatory mechanisms will be discussed here: (i) alterations in T-helper cell phenotypes, (ii) reproductive hormones and immunosuppression, and (iii) tryptophan metabolism.
As discussed in Chapter 6, antigen-stimulated immune responses involving CD4+ T cells can be divided into two major classes: T helper 1 (TH1) responses and T helper 2 (TH2) responses. This subclassification may be overly simple, but it has been useful in broadly defining types of immune responses based on the characteristics of the CD4+ cells present, as well as their associated cytokines. The production of these responses rests on the environment in which relatively undifferentiated CD4+ TH0 cells become differentiated. Thus, TH0 cells exposed to IFN-γ become TH1-type cells, and those exposed to IL-4 become TH2-type cells (184). TH1 responses are associated with inﬂammation and primarily involve IFN-γ and IL-12, as well as IL-2, and tumor necrosis factor-β (TNF-β). TH2 cells responses are associated with antibody production and the cytokines IL-10, IL-4, IL-5, and IL-6 (184–186). Although TNF-α can be secreted by both TH1 and TH2 cells, it is most often a characteristic of TH1 response (187,188).
A reciprocal regulating relationship exists between TH1 and TH2 cells and cytokines, with one response supporting its own persistence while averting conversion to the other (189–191).
One additional T-helper cell subset, TH17 cells, has been recently distinguished, although many of their proinﬂammatory effects were previously attributed to TH1 cells (192). TH17 cells preferentially produce IL-17 family cytokines (including IL-17A and IL-17F), which upregulate stromal IL-8 and IL-6 and cause local neutrophilic inﬂammation. These cells are important in sustaining the inﬂammatory response and are closely associated with several autoimmune diseases (193).
Extending these immune regulatory phenomena to pregnancy, the type of CD4+ cellular response to the implanting fetus is controlled not only by the types of cells (e.g., T-helper cells) in the decidua, but also by the cytokine environment at the maternal–fetal interface.