These immunologic characteristics were thoroughly described and investigated for the immune effector cells populating the peripheral immune system. The peripheral immune system consists of the spleen and peripheral blood, and it is generally responsible for protection against blood-borne pathogens. Pathogens that enter the host via the extensive surface areas of the lacrimal ducts, respiratory system, gastrointestinal tract, mammary ducts, and genitourinary tract encounter a very distinct and important immune environment—that of the mucosal immune system. Although the mucosal immune system may be primarily responsible for the initial protection against most exogenous pathogens, an understanding of its immune characteristics lags far behind that of the peripheral immune system. Insight into the specific characteristics of immunity within the reproductive tract is even further limited.
Many of the immune theories surrounding the causes of isolated and recurrent spontaneous pregnancy losses have stemmed from attempts to define immunologic rules as they apply specifically to the mucosal reproductive tract. Four main questions summarize much of the theoretical thinking surrounding pregnancy maintenance and reproductive immunology: 1.
Which immune cells populate the reproductive tract, particularly at implantation sites?
2.
How do these cells arrive at this mucosal immune site and are they educated in the same way as those populating the periphery?
3.
How do the characteristics of antigen presentation differ at the maternal–fetal interface?
4.
What regulatory mechanisms specifically affect reproductive tract immune cells?
Resident Cells Immune cells populating the reproductive tract exhibit many characteristics that distinguish them from their peripheral counterparts. In particular, the human endometrium is populated by T cells, macrophage, and NK-like cells, but very few B cells are present. The relative proportions of these resident cells vary with the menstrual cycle and change dramatically during early pregnancy. In fact, surrounding the time of implantation, one particular cell type comprises between 70% to 80% of the total endometrial lymphocyte populations (128,129). This cell type is called a variety of names, including decidual granular lymphocytes (DGLs), large granular lymphocytes (LGLs), and decidual NK cells. This heterogeneity of names reﬂects the fact that this particular cell type differs from similar cells isolated from the periphery, although most believe it to be an NK cell variant. While the majority of peripheral NK cells have low cell surface expression of CD56 (CD56dim) and express high levels of CD16, the immunoglobulin receptor responsible for NK-mediated, antibody-dependent cellular cytotoxicity, those in the uterine decidua and at the placental implantation site, are largely CD56bright and CD16dim or CD16− (130). If these unusual endometrial cells are considered NK cells, the implantation site represents the largest accumulation of NK cells in any state of human health or disease. The true function of these cells remains unclear, but their remarkable abundance at the maternal–fetal interface compels further study. These decidual NK cells display fairly poor cytotoxic function but are robust cytokine secretors (131,132). The balance of activating and inhibitory receptors expressed on their cell surfaces determines their ultimate killing versus secretion patterns (133,134). Increases in killer-type activating receptors in comparison to inhibitory receptors were found among patients with a history of recurrent pregnancy loss (135,136). Other immune cells have been described in the periphery as having the characteristics of both NK cells and T cells. These NKT cells demonstrated a role in pregnancy loss in animal models (137). They are present in the decidua in humans and may play an important immunoregulatory role at this site (138).