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PubMedDate not supplied

Syncytiotrophoblast brush border proteins recognized by monoclonal antibody TRA-2-10 and rabbit anti-TLX sera.

Different subsets of placental trophoblast epithelium are directly exposed to the maternal immune system during pregnancy and consequently represent major elements in allogeneic interactions. It has been proposed that the trophoblast--lymphocyte cross-reactive (TLX) alloantigen system is involved in maternal allogeneic recognition during pregnancy. Monoclonal antibody TRA-2-10 putatively recognizes TLX antigens, but its reactivity with trophoblast and normal tissues has not been documented in detail. In this report, immunohistological investigations revealed that TRA-2-10 recognizes all subsets of trophoblast in addition to amniotic and seminal vesicle epithelia. Immunoblotting demonstrated reactivity with glycoproteins of 55,000 and 65,000 mol. mass under non-reducing conditions on various cell types. These proteins displayed tissue-specific size variations and individuals varied in the amounts expressed of the two species. On the basis of blocking and immunoprecipitation experiments, TRA-2-10 reactive antigens are recognized by rabbit anti-TLX sera and are potential TLX antigen candidates. However, TLX antigens are found in seminal plasma whilst TRA-2-10 reactive antigens are not. Both TLX and TRA-2-10 antigens appear related if not identical to membrane cofactor protein (MCP) by virtue of shared molecular characteristics and blocking of lymphocyte binding of monoclonals to MCP by polyclonal anti-TLX. Extra-embryonic membranes are thus richly endowed with a complement regulatory protein which could facilitate their roles in protection of the fetus by avoidance of harmful maternal immune response amplification.

Antibodies, Monoclonal↗
PubMed1989

Isolation and identification of trophoblast lymphocyte cross-reactive (TLX) antigens from human lymphocytes.

It has been proposed that allotypic trophoblast lymphocyte cross-reactive (TLX) antigens are involved in the maintenance of normal human reproduction. Despite such a potentially important role for TLX antigens, isolation of human TLX proteins has not yet been reported. As an initial step toward elucidation of the structure and function of TLX antigens, we have isolated TLX proteins from Lubrol-solubilized lymphocytes (termed "wTLX") by anti-trophoblast membrane-Sepharose immunoaffinity chromatography. Using Ouchterlony immunodiffusion and immunoelectrophoresis, we have identified an immunoreactive wTLX antigen which forms a single immunoprecipitation line against absorbed anti-trophoblast membrane. From 17.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analyses, a 35-kDa band was determined to be a major protein band in the immunoaffinity-isolated wTLX fraction, along with multiple minor wTLX bands. These results suggest the possible existence of antigenic polymorphism of TLX, with predominant expression of the 35-kDa wTLX antigen in lymphocytes. The strong staining of the TLX antigens with Coomassie Brilliant Blue and Amido Black indicates they are largely proteins. Co-isolation of beta 2-microglobulin in the immunoaffinity-isolated wTLX pool could imply that the wTLX antigens may be unique class I HLA-like antigens. This possibility has yet to be resolved.

Autoantigens↗
PubMed1986

Differential expression of trophoblast lymphocyte cross-reactive (TLX) antigens on T and B lymphocytes.

Heterologous sera raised to human trophoblast (TLX antisera) have been shown to recognize peripheral blood lymphocytes (PBL); in unrelated studies noncytotoxic Fc receptors blocking B lymphocyte antibodies have been found in the sera of women during normal pregnancies. This study aimed to determine whether (a) there was any relation between Fc receptor blocking and cytotoxic anti-TLX activity in ten TLX sera and (b) different reactivity patterns arose when ten TLX antisera were tested in the cytotoxicity assay against separated T and B lymphocytes. Independent factor analysis showed four antisera with T lymphocytotoxicity patterns giving a loading high on one mathematical factor and low on a second. Three sera shared the opposite pattern and three were intermediate. The groups were similar but more discrete than those obtained when PBL were used as targets. Patterns of B lymphocytoxicity were dissimilar from T and both differed from the erythrocyte antibody rosette inhibition activity. Activity did not correlate with the HLA-A, -B, or -DR types carried by the panel cells. These data indicate that TLX antisera contain antibodies directly cytotoxic to antigens differentially expressed on T and B lymphocytes and that noncytotoxic Fc receptor blocking antibodies are not associated with any TLX groupings.

Animals↗
PubMedDate not supplied

A role for TLX antigens in pregnancy.

Maternal responses to allotypic TLX antigens are proposed as necessary in the immunological maintenance of human pregnancy. The TLX antigens are strategically and strongly expressed in semen and on the extraembryonic tissues which form the anatomical materno-fetal interfaces. Recent findings suggest that CD 46 proteins (a membrane cofactor which protects self tissues from autologous complement damage) in association with the activated complement component, C 3b produce a novel antigenic epitope recognized by both rabbit and human anti-TLX antisera. Control of TLX immunity involves an idiotype-antiidiotype network. We now report the development of rabbit antiidiotypes specific for cross-reactive idiotypes on human anti-TLX IgG antibodies. These antiidiotypes appear to recognize different TLX allotypes and will be useful for gaining additional insight into the immunogenetics of human reproduction.

Animals↗
PubMed1987

HLA and TLX antigen expression on the human oocyte, zona pellucida and granulosa cells.

The expression of human leukocyte antigen (HLA) class I and class II molecules and one trophoblast-lymphocyte crossreactive (TLX) antigen by human oocytes and granulosa cells was investigated. Well-defined monoclonal antibodies directed against HLA class I and class II molecules as well as beta 2-microglobulin and a TLX molecule were used in a standard indirect immunofluorescence test and some immunogold techniques at the electron microscopic level. Single unfertilizable or multiply fertilized oocytes and granulosa cells obtained from an in-vitro fertilization programme as well as oocytes in primary, secondary and tertiary follicles of ovaries were studied. Neither HLA class I or class II molecules, nor beta 2-microglobulin, nor a TLX molecule were detected on cultured oocytes or oocytes in human ovarian follicles or in their zona pellucida. Granulosa cells taken from a culture medium and those in follicles at various stages of development expressed class I antigens, while granulosa cells from tertiary follicles also expressed HLA-DR antigens. These results confirm that the female human gamete belongs to that very small group of cells that lack major histocompatibility complex antigens. Since spermatozoa also lack HLA antigens, human germ cells are entirely different from other nucleated human cells with regard to the antigenic structures expressed on the cell surface. This would prevent recognition of these cells by the cellular immune system. Furthermore, HLA and TLX antigens are not involved in fertilization and early differentiation.

Antibodies, Monoclonal↗
PubMed1990

The human cell-surface glycoproteins HuLy-m5, membrane co-factor protein (MCP) of the complement system, and trophoblast leucocyte-common (TLX) antigen, are CD46.

The non-lineage restricted human CD46 antigen, with two glycoproteins of 56,000 molecular weight (MW) and 66,000 MW, was defined using a panel of monoclonal antibodies (mAb) that included the E4.3 mAb to the HuLy-m5 antigen. Here the E4.3 mAb is used to show that two other human cell-surface molecules, membrane co-factor protein (MCP) of the complement system and trophoblast leucocyte-common antigen (TLX), are the same as HuLy-m5; thus, these three independently identified molecules are equivalently CD46. A mouse mAb to TLX (H316) and a specific rabbit antiserum to purified MCP (RA-MCP) blocked the binding of FITC-labelled E4.3 to the surface of human peripheral blood leucocytes (PBL). In sequential immunoprecipitation studies, E4.3 cleared all molecules detected by H316 and the RA-MCP antiserum. Immunoprecipitation from Chinese hamster ovary cells expressing transfected MCP cDNA showed that E4.3 detects both the mature 66,000 higher MW form of MCP and its 48,000 MW pro-MCP precursor, which lacks O-linked carbohydrate and bears only simple high-mannose-type N-linked carbohydrate. The IgG fraction of a polyclonal antiserum to purified MCP blocked factor I-mediated cleavage of C3b, whereas the E4.3 mAb did not. These data establish that three independently identified antigen systems are indeed the same: HuLy-m5, which shares a cross-reactive epitope with some primate retroviral gp 70 molecules and can be physically associated with class I major histocompatibility complex (MHC) chains in the cell membrane; MCP, of interest as a member of the regulators of complement activation gene family thought to protect autologous cells from complement activation; and TLX, a polymorphic molecule of interest for its potential role at the foeto-maternal tissue interface during pregnancy. Thus, the human CD46 antigen amalgamates the HuLy-m5, MCP and TLX cell-membrane glycoproteins.

Antibodies, Monoclonal↗
PubMedDate not supplied

Regulation of immunity to extraembryonic antigens in human pregnancy.

Pregnancy results in the immunologic challenge of the female to a wide variety of allogeneic antigens. Particular attention has been given to antibodies directed to allotypic trophoblast antigens (TLX), for trophoblast form the true allograft interface between mother and fetus. Studies found that antibodies to paternal TLX allotypes are produced in women suffering from secondary recurrent abortions. These TLX antibodies are not directed to classical HLA private epitopes. In this report, treatment of lymphocytes with papain to remove HLA Class I did not decrease TLX antigen densities. These results suggest TLX antibodies are not directed to Class I epitopes, public or private. The allotypic nature of TLX antigens requires that a pregnant female must be able to regulate TLX immune responses to avoid rejection of the conceptus. One mechanism to specifically and systemically regulate TLX immunity is the idiotype anti-idiotype network. We provide preliminary evidence in this report for the presence of TLX idiotype network in a normal primigravida. Initially, no antipaternal TLX antibodies were detected in the serum of the primigravida, suggesting no TLX immunization had occurred. However, separation of Ab1 from Ab2 by absorption of primigravida serum with 2 degrees aborter Ab1 resulted in seroconversion. The primigravida's Ab1 was cytotoxic for paternal and 3rd-party lymphocytes in a non-HLA-restricted pattern. Primigravida's Ab2 was recovered from the Ab1 matrix by competitive elution by using platelets as source of TLX antigen. The Ab2 was found to inhibit cytotoxicity by 2 degrees aborter Ab1 as well as primigravida Ab1. This is evidence that the Ab2 recognizes a cross-reactive idiotype (CRI) on TLX antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Anti-Idiotypic↗
PubMed1987

Antigens of human trophoblast: trophoblast-lymphocyte cross-reactive antigens on platelets.

Human and rabbit antibodies to trophoblast-lymphocyte cross-reactive (TLX) antigens were employed in an enzyme-linked immunosorbent assay (ELISA) to identify and characterize the TLX alloantigen system on human platelets. Neither washing nor extraction in chaotrope or acid altered platelet TLX. The antigen was significantly changed by pronase and trypsin digestion, but Folch extraction yielded antigen in the hydrophilic interface, suggesting carbohydrate. Rabbit antibodies prepared to HLA-negative human syncytiotrophoblast TLX antigens were shown by platelet ELISA to have the same specificity and similar allotypy as anti-TLX antibodies from secondary (2 degrees) spontaneously aborting women. Patients with normal pregnancies before becoming 2 degrees aborters had both IgG and IgM antibodies to TLX. Anti-TLX in patients who never had a normal pregnancy were predominantly IgG. ELISA reactions performed with different concentrations of protein in the buffers detected anti-TLX activity in buffers containing high protein concentrations. This has been observed in studies of blocking antibodies in graft-versus-host disease and immune responses to tumor cells. Platelet TLX offers a new genetic and immunological approach to study similarities of the host-parasite relationships in pregnancy, transplantation, and cancer.

Abortion, Habitual↗
PubMed1988

Trophoblast antigens in human seminal plasma.

Secondary recurrent spontaneous (2 degrees) aborters manifest persistent IgG, which show differential cytotoxicity patterns with lymphocytes from many donors. These are non-HLA-directed antibodies, which react allotypically with both trophoblast and lymphocytes. The antigens they recognize are designated trophoblast-lymphocyte crossreactive (TLX) antigens. Xenogeneic anti-TLX sera were studied with the use of enzyme-linked-immunosorbent (ELISA) and immunochemical assays to determine the TLX status of seminal plasma. The results showed 1) allotypic TLX antigens are present in seminal plasma; 2) seminal plasma TLX antigens may be membrane associated; 3) by immunoblotting, the molecular weights of antigens reactive with TLX antisera are 15, 22, 28, 33 kD and a smear between 180 and 340 kd; 4) by isoelectric focusing, TLX antigens show pI 4.0, 5.35, 5.9, 6.5, 6.8, and 7.2. Allotypic seminal plasma TLX antigens may provide the antigenic stimuli for persistent maternal humoral immunity.

Abortion, Habitual↗
PubMed1986

Trophoblast antigens in normal and abnormal human pregnancy.

With all of this information about trophoblast antigens, it is necessary to have a working hypothesis of how these antigens might be dealt with by a normal woman's immunologic system. Two sets of observations have helped formulate such a working hypothesis. First is the finding that trophoblast is the only normal tissue recognized by antibodies to TA1 (and it is exceedingly difficult to demonstrate maternal anti-TA1 in normal pregnancies). Second is the serologic result that antibodies to TLX antigens within the TA2 group are lymphocytotoxic (and maternal anti-TLX can be demonstrated both in normal and abnormal pregnancies). We interpret this as meaning that TA1 is "foreign" (i.e., oncoextraembryonic) antigen and TA2 (TLX) is "self"-antigen, and that mothers have TA2 (TLX) reactive B-lymphocytes in their repertoire. Antigen-reactive B-lymphocytes can be activated to produce TA1-blocking antibodies by either allotypic TA2 (TLX) in seminal plasma or allogeneic trophoblast membrane antigens during the host-versus-graft reaction subsequent to blastocyst implantation. If allotypic or allogeneic stimulation fails to produce an adequate anti-TA2 (TLX) response, the oncoextra-embryonic TA1 antigens are recognized and rapidly rejected. If allotypic or allogeneic stimulation produces an aberrant anti-TA2 (TLX) response (e.g., a cytotoxic rather than a blocking antibody), the extra-embryonic membranes and placenta come under immune attack and eventually are rejected. This working hypothesis has led us to develop new immunologic approaches to the diagnosis and prevention of some types of pregnancy failures in both mice and human beings.

Abortion, Habitual↗
PubMed1989

Immunological studies of trophoblast antigens: no evidence for human leucocyte antigen (HLA) linkage.

Parental disparity for trophoblast-lymphocyte crossreactive (TLX) antigens may promote successful pregnancy. A TLX antigen system has been defined on peripheral blood lymphocytes by heteroantisera. More recently, we have reported additional activity against antigens on B lymphocytes alone termed trophoblast-B lymphocyte crossreactive (TBX) antigens. In the present study we have investigated ten TLX sera in order to determine if their target antigens are linked to the human leucocyte antigen (HLA) gene complex. The sera showed no selective activity when tested against target B lymphocytes from ten normal donors. Cytotoxic activity of TLX antisera against peripheral blood lymphocytes from six normal donors was not reduced when the class I HLA antigens of the target cells were blocked with a monoclonal antibody (PA 2.6). Similarly the cytotoxic activity of both TBX antisera against B lymphocytes from six normal donors was not decreased when class II HLA antigens were blocked by a monoclonal antibody (FMC 4). Within a family the cytotoxic activity of the TLX antisera was absorbed equally by lymphocytes from siblings who shared neither HLA haplotype. Antibody content in TLX and TBX antisera is not directed toward the classically defined HLA class I or class II antigens and is not linked to the HLA gene complex.

Animals↗
PubMedDate not supplied

Immune recognition at the maternal-fetal interface: overview.

Trophoblast antigens at the maternal-fetal interface that are capable of stimulating maternal immune responses have been studied. Candidates are blood group I and P, HLA, Fc gamma-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 of suppressor T cells. Receptors for IgG (Fc gamma-RI, Fc gamma-RII and Fc gamma-III) are present on trophoblast but allotypy is limited to the NA1-NA2 antigen system associated with Fc gamma-RIII on neutrophils. Maternal Fc-gamma R blocking antibodies have been linked to pregnancy success. The TLX alloantigen system was described by using xenogeneic antisera. Idiotype-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, beta 2 GPI and not phospholipid per se. We produced three Mab specific for beta 2 GPI, one of which fails to recognize beta 2 GPI bound to phospholipid [corrected].(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1989

Seminal vesicles: a source of trophoblast lymphocyte cross-reactive antigen.

Maternal recognition of allotypic trophoblast lymphocyte cross-reactive (TLX) antigens is proposed to be involved in immunologic acceptance of the allogeneic fetus. The presence of TLX antigens in seminal plasma suggests that sensitization can occur before fertilization and implantation. In this study, the origin of TLX antigens within the male reproductive tract was investigated. Analysis of split ejaculates and immunohistological examinations of male accessory gland tissues showed the luminal epithelium of seminal vesicles as the source of seminal plasma TLX antigens. This finding suggests that seminal vesicles may play a role in the immunology of human reproduction.

Animals↗
PubMed1991

Trophoblast immunity in human pregnancy defined by antiidiotype.

Successful reproduction in mammals requires the mother to immunologically accept genetically disparate tissues. Allotypic trophoblast antigens (TLX) are thought to be responsible for influencing maternal acceptance of the feto-placental graft, and faulty regulation of immunity to TLX antigens has been associated with recurrent pregnancy losses. In this report, rabbit antiidiotype (RAb2) was produced to a human TLX antibody (Ab1). This RAb2 detected TLX cross-reactive idiotypes (CRI) on antitrophoblast IgG from women with normal and abnormal pregnancies. These findings support an hypothesis that women respond immunologically to allotypic trophoblast antigens, and that idiotype-antiidiotype regulation of this response is characteristic of normal pregnancy.

Abortion, Spontaneous↗