Fetal cells can also engraft in the mother during pregnancy and can be identiied decades later. Fetal lymphocytes, CD34+ mesenchymal stem cells, and endothelial colony-forming cells all reside in maternal blood, bone marrow, or uterine vascula ture (Nguyen, 2006; Piper, 2007; Sipos, 2013). Termed micro chimerism, such residual stem cells have been implicated in the disparate female:male ratio of autoimmune disorders (Greer, 2011; Stevens, 2006). As discussed in Chapter 59 (p. 1139), they are associated with the pathogenesis of lymphocytic thy roiditis, scleroderma, and systemic lupus erythematosus.
Survival of the semi allogenic fetal graft requires complex interactions between fetal trophoblasts and maternal decidual immune cells. The fetal-maternal interface is not immunologically inert. Rather, it is an active hub of interactions that allows implantation and appropriate placental development and ensures immuno tolerance of the fetus. Despite this, a functional immune system must be maintained to protect the mother.
Immunogenicity of the Trophoblasts
Trophoblastic cells are the only fetus-derived cells in direct contact with maternal tissues and blood. Fetal syncytiotrophoblast synthesizes and secretes numerous factors that regulate the immune responses of maternal cells both at the implantation site and systemically.
Human leukocyte antigens (HLAs) are the human analogue of the major histocompatibility complex (MHC) (Hunt, 1992). There are 17 HLA class I genes, including three classic genes, HLA-A, -B, and -C, that encode the major class I (class Ia) transplantation antigens. Three other class I genes, designated HLA-E, -F, and -G, encode class Ib HLA antigens. MHC class I and II antigens are absent from villous trophoblasts, which appear to be immunologically inert at all gestational stages (Weetman, 1999). Invasive extravillous cytotrophoblasts do express MHC class I molecules. Thus, the ability of these cells to bypass transplantation rejection is the focus of considerable study.
Mofett-King (2002) reasoned that normal implantation depends on controlled trophoblastic invasion of maternal decidua and spiral arteries. Such invasion must proceed far enough to provide for normal fetal growth and development, but a mechanism must regulate invasion depth. She suggests that dNK cells combined with unique expression of three speciic HLA class I genes in extravillous cytotrophoblasts act in concert to permit and subsequently limit trophoblast invasion.
Class I antigens in extravillous cytotrophoblasts are accounted for by the expression of classic HLA-C and nonclassic class Ib molecules of HLA-E and HLA-G. HLA-G antigen is expressed only in humans, with expression restricted to extravillous cytotrophoblasts contiguous with maternal tissues. Embryos used for in vitro fertilization do not implant if they do not express a soluble HLA-G isoform (Fuzzi, 2002). hus, HLA-G may be immunologically permissive of the maternalfetal antigen mismatch (LeBouteiller, 1999). HLA-G has a proposed role in protecting extravillous trophoblasts from immune rejection via modulation of dNK functions (Apps, 2011; Rajagopalan, 2012). Last, Goldman-Wohl and associates (2000) have provided evidence for abnormal HA-G expression in extravillous trophoblasts from women with preeclampsia.