AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY 28:127-131 © 1992 MUNKSGAARD
Immune Recognition at the Maternal-Fetal Interface: Overview JOHN A. MCINTYRE Center for Reproduction and Transplantation Immunology, Methodist Hospital ofIndiana, Indianapolis, Indiana ABSTRACT: Trophoblast antigens at the maternalfetal interface that are capable of stimulating maternat immune responses have been studied.. Candidates are blood group I and P, HA, Fca-receptors, TLX, and phospholipids. Antigens I and P on trophoblast have been implicated in pregnancy loss but incompatible i,p mothers are rare. HLA-G is expressed on cytotrophoblast; however, no evidence for HLA-G allotypy or maternal responses to these molecules exists, although HLA-G has been implicated in recruitment ofsuppressor T cells. Receptors for IgG (Fcl1·RI, Fcl1-RII and Fcl1-III) are present on trophoblast but allotypy is limited to the NA1·NA2 antigen system associated with Fcl1-RIII on neutrophils. Maternal Fc-oyR blocking antibodies have been linked to pregnancy success. The TLX alloantigen system was described by using xenogeneic antisera. ldiotype-antiidiotype regulated maternal responses to TLX are proposed as necessary for successful pregnancy. Several putative TLX monoclonal antibodies (Mab) recognize a regulator of complement activation called MCP (membrane cofactor protein, or CD46). Mab to MCP do not exhibit allotypy. Syncytial and cytotrophoblastic membranes are rich sources of MCP. Preliminary data suggest that a conformational site induced by C3b (iC3) binding to MCP may be responsible for TLX allotypy. Certain pregnancy loss patients produce antiphospholipid antibodies (aPA). Some investigators believe that aPA recognize a plasma protein cofactor, 132GPI and not phospholipid per se, We produced three Mab specific for 132GPI, one of which fails to recognize 132GPIbound to phospholipid. By using these Mab in immunocytochemical studies of normal term placentae, 132GPIwas observed on syncytial and cytotrophoblast as well as on fetal stem vessel endothelia. These Mab indicate that the 132GPI present in placentae is phospholipid bound. (Am J Reprod Immunol. 1992; 28:127-131.) Key words: Pregnancy, trophoblast, HA antigens, Fcl1Receptors, membrane cofactor protein, 132-Glycoprotein I INTRODUCTION
In efforts to explain the transplantation analogies of human pregnancy, researchers have focused their attention upon the extra-embryonic tissues, and in particular the trophoblast. Because of its location, the trophoblast is strategically important, ensuring a zone of anatomical contact and physiological exchange between maternal and fetal tissues. 1 Extra-embryonic membranes express alloantigens and thus should stimulate allogeSubmitted for publication June 29, 1992; accepted July 6, 1992. Address reprint requests to John A. McIntyre, Ph.D., MRC Path., Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis, IN 46202.
neic recognition and rejection reactions.v" The lack of maternal rejection reactions in normal pregnancies, however, suggests that pregnant women can regulate effectively a potentially harmful response against the conceptus." Indeed, the reported low frequency of maternal humoral and cellular immune responses to paternallyinherited fetal antigens begs the question of what regulates the immunobiology of normal pregnancy'S? It is proposed that certain pregnancies succumb to immunological problems," yet many pregnancies succeed. Knowledge of which trophoblast antigens elicit maternal humoral and cellular responses may hold promise for solving questions concerning pregnancy immunology. Answers to these questions may also lead to novel forms of treatment for mothers with histories of repeated pregnancy losses, and perhaps have impact on clinical transplantation and certain types of cancer therapy. CANDIDATE ANTIGENS FOR MATERNAL IMMUNE RECOGNITION
Blood Group Antigens In the case of ABO and Rh antigens for which the pathophysiology of maternal immunizations is well established, immunocytochemical studies have indicated their absence from human trophoblast.v'" Blood groups alloantigens termed I and i which are carried on backbone carbohydrate structures vary ontogenetically between fetus and adult. It is possible that these carbohydrate molecules present on trophoblast may serve as alloantigens.'! Materno-fetal incompatibility in the P blood group system also shown to be expressed on trophoblast has been associated with spontaneous abortion in early pregnancy.'" Approximately 50% of pregnancies in women with circulating anti-P or anti-p" antibodies end in miscarriage, and it has been proposed that these antibodies exert cytotoxic effects on placental tro~hoblast and fetal tissues which express the P antigen. 1 ,14 Histocompatibility Antigens (HLA) HLA genes encode molecules with extensive polymorphism and wide tissue distribution that have fundamental roles in transplantation immunclogy.P Because pregnancy is in many ways similar to a successful allograft, much work has focused on the role of transplantation antigens in feto-maternal interactions. The applications of immunocytochemical techniques employing monoclonal antibodies (Mab) and molecular probes specific for MHC gene products have shown that no normal trophoblastic tissue constitutively expresses classical HLA antigens at the materno-fetal interface.l" The presence on human trophoblast of a novel class I MHC-molecule, HLA-G, has been reported!" and precise chromosomal mapping has been done. 18 ,19 The marked difference in expression of cell associated HLA-G
Immune Recognition at the Maternal-Fetal Interface: Overview JOHN A. MCINTYRE Center for Reproduction and Transplantation Immunology, Methodist Hospital ofIndiana, Indianapolis, Indiana ABSTRACT: Trophoblast antigens at the maternalfetal interface that are capable of stimulating maternat immune responses have been studied.. Candidates are blood group I and P, HA, Fca-receptors, TLX, and phospholipids. Antigens I and P on trophoblast have been implicated in pregnancy loss but incompatible i,p mothers are rare. HLA-G is expressed on cytotrophoblast; however, no evidence for HLA-G allotypy or maternal responses to these molecules exists, although HLA-G has been implicated in recruitment ofsuppressor T cells. Receptors for IgG (Fcl1·RI, Fcl1-RII and Fcl1-III) are present on trophoblast but allotypy is limited to the NA1·NA2 antigen system associated with Fcl1-RIII on neutrophils. Maternal Fc-oyR blocking antibodies have been linked to pregnancy success. The TLX alloantigen system was described by using xenogeneic antisera. ldiotype-antiidiotype regulated maternal responses to TLX are proposed as necessary for successful pregnancy. Several putative TLX monoclonal antibodies (Mab) recognize a regulator of complement activation called MCP (membrane cofactor protein, or CD46). Mab to MCP do not exhibit allotypy. Syncytial and cytotrophoblastic membranes are rich sources of MCP. Preliminary data suggest that a conformational site induced by C3b (iC3) binding to MCP may be responsible for TLX allotypy. Certain pregnancy loss patients produce antiphospholipid antibodies (aPA). Some investigators believe that aPA recognize a plasma protein cofactor, 132GPI and not phospholipid per se, We produced three Mab specific for 132GPI, one of which fails to recognize 132GPIbound to phospholipid. By using these Mab in immunocytochemical studies of normal term placentae, 132GPIwas observed on syncytial and cytotrophoblast as well as on fetal stem vessel endothelia. These Mab indicate that the 132GPI present in placentae is phospholipid bound. (Am J Reprod Immunol. 1992; 28:127-131.) Key words: Pregnancy, trophoblast, HA antigens, Fcl1Receptors, membrane cofactor protein, 132-Glycoprotein I INTRODUCTION
In efforts to explain the transplantation analogies of human pregnancy, researchers have focused their attention upon the extra-embryonic tissues, and in particular the trophoblast. Because of its location, the trophoblast is strategically important, ensuring a zone of anatomical contact and physiological exchange between maternal and fetal tissues. 1 Extra-embryonic membranes express alloantigens and thus should stimulate allogeSubmitted for publication June 29, 1992; accepted July 6, 1992. Address reprint requests to John A. McIntyre, Ph.D., MRC Path., Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis, IN 46202.
neic recognition and rejection reactions.v" The lack of maternal rejection reactions in normal pregnancies, however, suggests that pregnant women can regulate effectively a potentially harmful response against the conceptus." Indeed, the reported low frequency of maternal humoral and cellular immune responses to paternallyinherited fetal antigens begs the question of what regulates the immunobiology of normal pregnancy'S? It is proposed that certain pregnancies succumb to immunological problems," yet many pregnancies succeed. Knowledge of which trophoblast antigens elicit maternal humoral and cellular responses may hold promise for solving questions concerning pregnancy immunology. Answers to these questions may also lead to novel forms of treatment for mothers with histories of repeated pregnancy losses, and perhaps have impact on clinical transplantation and certain types of cancer therapy. CANDIDATE ANTIGENS FOR MATERNAL IMMUNE RECOGNITION
Blood Group Antigens In the case of ABO and Rh antigens for which the pathophysiology of maternal immunizations is well established, immunocytochemical studies have indicated their absence from human trophoblast.v'" Blood groups alloantigens termed I and i which are carried on backbone carbohydrate structures vary ontogenetically between fetus and adult. It is possible that these carbohydrate molecules present on trophoblast may serve as alloantigens.'! Materno-fetal incompatibility in the P blood group system also shown to be expressed on trophoblast has been associated with spontaneous abortion in early pregnancy.'" Approximately 50% of pregnancies in women with circulating anti-P or anti-p" antibodies end in miscarriage, and it has been proposed that these antibodies exert cytotoxic effects on placental tro~hoblast and fetal tissues which express the P antigen. 1 ,14 Histocompatibility Antigens (HLA) HLA genes encode molecules with extensive polymorphism and wide tissue distribution that have fundamental roles in transplantation immunclogy.P Because pregnancy is in many ways similar to a successful allograft, much work has focused on the role of transplantation antigens in feto-maternal interactions. The applications of immunocytochemical techniques employing monoclonal antibodies (Mab) and molecular probes specific for MHC gene products have shown that no normal trophoblastic tissue constitutively expresses classical HLA antigens at the materno-fetal interface.l" The presence on human trophoblast of a novel class I MHC-molecule, HLA-G, has been reported!" and precise chromosomal mapping has been done. 18 ,19 The marked difference in expression of cell associated HLA-G
