Selective loss of mouse embryos due to the expression of transgenic major histocompatibility class I molecules early in embryogenesis

Abstract

Among the numerous hypotheses proposed to explain the absence of fetal rejection by the mother in mammals, it has been suggested that regulation of expression of the polymorphic major histocompatibility complex (MHC) at the fetal‐maternal interface plays a major role. In addition to a lack of MHC gene expression in the placenta throughout gestation, the absence of polymorphic MHC molecules on the early embryo, as well as their low level of expression after midgestation, could contribute to this important biologic phenomenon. In order to test this hypothesis, we have produced transgenic mice able to express polymorphic MHC class I molecules early in embryogenesis. We have placed the MHC class Ia gene H‐2Kb under the control of a housekeeping gene promoter, the hydroxy‐methyl‐glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has been tested for functionality after transfection into mouse fibroblast L cells. The analysis of three founder transgenic mice and their progeny suggested that fetoplacental units that could express the H‐2Kb heavy chains are unable to survive in utero beyond midgestation. We have shown further that a much higher resorption rate, on days 11 to 13 of embryonic development, is observed among transgenic embryos developing from eggs microinjected at the one‐cell stage with the pHMG‐Kb construct than in control embryos. This lethality is not due to immune phenomena, since it is observed in histocompatible combinations between mother and fetus. These results are discussed in the context of what is currently known about the regulation of MHC expression at the fetal‐maternal interface and in various transgenic mouse models. Mol. Reprod. Dev. 50:35–44, 1998. © 1998 Wiley‐Liss, Inc.

Teratogenicity induced by targeting a placental immunoglobulin transporter

“…There is active research addressing the role of MHC-I in immune tolerance of the fetus during pregnancy (31). Along the lines of our findings, embryo resorption was observed on expression of transgenic MHC-I molecules early in embryogenesis (32). Therefore, it is possible that TPKTSVT similarity to MHC-I contributes to placental inflammation.…”

Peripheral deletion of mature alloreactive B cells induced by costimulation blockade

“…The fact that both immature and mature self-reactive B cells were eliminated suggests that deletion occurred at the immature stage, soon after B cells migrated out of the bone marrow and contacted self-antigen. In another report, the expression of K k antigen (also recognized by 3-83 B cells) by the fetus resulted in the profound deletion of the immature 3-83 transgenic B cells and a partial loss of the mature 3-83 B cells (27). When the K b antigen is expressed only in mouse trophoblast, it caused the deletion of bone marrow B cell subpopulation, including immature and transitional B cells, but not in the spleen (28).…”

Pathogen Protection

“…Further, animal studies have demonstrated that there is a pregnancy-specific, local partial deletion of those maternal B cells that are directed against paternal antigens within the uterine decidua of the maternal-fetal interface. Significantly more antibody-producing cells can be found in the lower genital tract of the pregnant woman (endocervix > ectocervix > vagina) to maintain mucosal pathogen surveillance (Aït-Azzouzene et al 1998). Decidual stromal cells are also immunologically unique and have recently been shown to respond to diverse bacterial and viral ligands that could cause placental inflammation (chorioamnionitis) and subsequent adverse outcomes such as preterm birth, neonatal sepsis, and cerebral palsy (Anders et al 2017).…”