MATERNAL RESPONSE TO PATERNAL TROPHOBLAST ANTIGENS

PROBLEM: What is the function of the immunoglobulin (Ig) G antibody bo und to trophoblast in normal pregnancy, and what is the antigen? METHO D: IgG was acid eluted from term human placental microvesicles and rea cted with the antigen, R80K, left on the vesicles. The eluted antibody was used to detect the antigen on monocytes, lymphocytes, and lymphob lastoid cell lines. The eluted antibody is highly polymorphic, but mon oclonal antibodies (mAbs) were made against conserved regions of the m olecule. These also reacted with the murine equivalent of the human R8 0K and were used in inhibition studies of natural killer (NK) cell kil ling and the mouse abortion models, CBA x DBA2 F1 resorption in CBA fe males, the endotoxin-induced resorption model, and a sonic stress-indu ced murine resorption model. RESULTS: All 600 syncytiotrophoblast micr ovesicle preparations of human term placenta had IgG antibody bound, e lutable at pH 3.0. The eluted antibody reacted with about 15% of unrel ated human placentae. In horses mares make detectable antibody early i n pregnancy, at about the time of implantation. The IgG antibody was b ound to an 80-kDa protein (R80K) also detected on B lymphocytes and mo nocytes. In HLA homozygous lymphoblastoid B cell lines, which reacted with one or more eluted antibodies, had a pattern of cytotoxicity inde pendent 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 th e two paternal allotypes of R80K detectable by placental alloantibodie s, only one, usually the grandpaternal one, is present in all the plac entae of a sibship. Two of 26 eluted human antibodies had affinity for K562 and inhibited killing by human peripheral blood NK cells. One mA b, BA11, against a conserved site on R80K inhibited killing of K562, a nd also reacted with the murine R80K homologue. BA11 inhibited murine NK cell killing and virtually completely inhibited three NK cell-depen dent mouse resorption models. CONCLUSION: R80K protein is a target mol ecule for NK cell activity expressed on all placentae. It has a polymo rphic alloantigenic determinant completely covered with maternal antib ody in all successful term pregnancies. In murine NK cell-dependent mo dels of abortion, a mAb against a monomorphic determinant present in h uman and murine R80K prevents abortion very effectively. It seems that the R80K molecule must be covered with antibody to prevent NK attacks on trophoblast.