Maternal Response to Paternal Trophoblast Antigens
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PROBLEM: What is the function of the immunoglobulin (Ig) G antibody bound to trophoblast in normal pregnancy, and what is the antigen? METHOD: IgG was acid eluted from term human placental microvesicles and reacted with the antigen, R80K, left on the vesicles. The eluted antibody was used to detect the antigen on monocytes, lymphocytes, and lymphoblastoid cell lines. The eluted antibody is highly polymorphic, but monoclonal antibodies (mAbs) were made against conserved regions of the molecule. These also reacted with the murine equivalent of the human R80K and were used in inhibition studies of natural killer (NK) cell killing and the mouse abortion models, CBA x DBA2 F1 resorption in CBA females, the endotoxin-induced resorption model, and a sonic stress-induced murine resorption model. RESULTS: All 600 syncytiotrophoblast microvesicle preparations of human term placenta had IgG antibody bound, elutable at pH 3.0. The eluted antibody reacted with about 15% of unrelated human placentae. In horses mares make detectable antibody early in pregnancy, at about the time of implantation. The IgG antibody was bound to an 80-kDa protein (R80K) also detected on B lymphocytes and monocytes. In HLA homozygous lymphoblastoid B cell lines, which reacted with one or more eluted antibodies, had a pattern of cytotoxicity independent of HLA Class I; and as a single 80-kDa peptide chain, R80K did not resemble HLA molecules. Genetic studies in horses show that of the two paternal allotypes of R80K detectable by placental alloantibodies, only one, usually the grandpaternal one, is present in all the placentae of a sibship. Two of 26 eluted human antibodies had affinity for K562 and inhibited killing by human peripheral blood NK cells. One mAb, BA11, against a conserved site on R80K inhibited killing of K562, and also reacted with the murine R80K homologue. BA11 inhibited murine NK cell killing and virtually completely inhibited three NK cell-dependent mouse resorption models. CONCLUSION: R80K protein is a target molecule for NK cell activity expressed on all placentae. It has a polymorphic alloantigenic determinant completely covered with maternal antibody in all successful term pregnancies. In murine NK cell-dependent models of abortion, a mAb against a monomorphic determinant present in human and murine R80K prevents abortion very effectively. It seems that the R80K molecule must be covered with antibody to prevent NK attacks on trophoblast.
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