Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestational-age infants.
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Female↗
Biomedical subjects
C A Labarrere
Publications and source records attributed to C A Labarrere.
Primary chronic abortion, preeclampsia, idiopathic intrauterine growth retardation, hydatidiform mole, and choriocarcinoma: a unifying concept.
Different degrees of maternal hyporesponse, as far as blocking activity is concerned, are proposed for primary chronic abortion, preeclampsia, and idiopathic intrauterine growth retardation. On the other hand, a maternal hyperresponse to fetal antigens with a higher production of blocking antibodies may be related to an unusual proliferation of the trophoblast in cases of hydatidiform mole and choriocarcinoma.
Abortion, Habitual↗
Intrauterine growth retardation of unknown etiology: II. Serum complement and circulating immune complexes in maternal sera and their relationship with parity and chronic villitis.
Significantly lower CH50 levels were found in women with small for gestational age (SGA) infants. The lowest values corresponded to nulliparous with placental chronic villitis (124.0 +/- 10.6). Three out of five mothers with circulating immune complexes from SGA group were nulliparous, having placental chronic villitis. An immunological derangement in women with SGA infants is proposed for the development of placental lesions, mainly in nulliparous mothers with a lower previous exposure to fetal antigens.
Antigen-Antibody Complex↗
Placental lesions in maternal autoimmune diseases.
We have investigated the presence and clinical implications of maternal vascular lesions and chronic villitis of unknown etiology (CVUE) in 18 placentas of 15 mothers with several autoimmune diseases (AD), including, for the first time, idiopathic thrombocytopenic purpura, autoimmune thyroid diseases, and multiple sclerosis. The group with AD had significantly more maternal vascular lesions and CVUE than the control group. We did not find lesions that could be attributed to any of the diseases in particular. The histopathologic picture was similar in these diseases, although there appears to be a spectrum in severity. Placental vascular damage with deposits of IgM, C3, and C1q was more prominent in systemic lupus erythematosus and in a patient with systemic sclerosis. In both of these diseases but not in the other conditions, these lesions were related to poor fetal outcome. Although the precise role of each of these autoimmune diseases in pregnancy and fetal outcome remains to be established, there appears to be at least one link between them represented by the presence of severe acute atherosis and heavy granular vascular deposits of IgM, C3, and C1q associated in some with poor fetal outcome. The role of CVUE remains speculative.
Adult↗
Parathyroid activity and bone formation.
Patients of both sexes with primary hyperparathyroidism showed increments in the total subperiosteal diameter and the medullary cavity diameter of the second metacarpal bone. When two groups of females of similar age were compared, those with hyperparathyroidism had significantly greater total metacarpal area and medullary area than that of hypoparathyroid patients. An increased subperiosteal apposition has therefore been found in primary hyperparathyroidism. This might be due to a direct stimulation of PTH on bone formation at the subperiosteal surface or to a nonspecific compensatory response to endosteal resorption.
Adolescent↗
Acute atherosis. A histopathological hallmark of immune aggression?
Acute atherosis is a maternal vascular lesion observed regularly in cases of pre-eclampsia and idiopathic intrauterine growth retardation. This vasculopathy is characterized by fibrinoid necrosis of the vessel wall, an accumulation of lipid-laden macrophages, and a mononuclear perivascular infiltrate. Similar vascular lesions are seen in the decidual vessels of patients with autoimmune diseases, and in renal, cardiac and hepatic homograft rejection. Immunohistochemical studies often reveal extensive vascular deposition of IgM and complement in acute atherosis-like lesions. Granular deposition of immunoglobulins and complement within the vessel walls and mononuclear perivascular infiltrate may be a histopathological hallmark of a maternal immunological aggression against fetal tissues.
Acute Disease↗
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↗
Anchoring villi in human placental basal plate: lymphocytes, macrophages and coagulation.
We have studied basal plates in 25 normal placentae, ten placentae from primary aborters and six placentae from secondary aborters for leukocyte markers and coagulation components. Anchoring villi contained class II MHC antigen-reactive (HLA-DR, DP and DQ) macrophages and T-lymphocytes of the helper (CD4) phenotype. Antibodies to coagulation components revealed the presence of tissue factor, factor IX and fibrin in and around anchoring villi. Immune cells and coagulation components in anchoring villi were more frequently identified in secondary aborters. These findings provide morphological support for an idea that there is a linkage between the presence of immune cells and coagulation in anchoring villi of the basal plate. Helper T-lymphocytes can activate macrophages which release cytokines that activate coagulation through the extrinsic pathway. We envision this as an expression of maternal allogeneic recognition of extraembryonic tissues in the basal plate.
Abortion, Spontaneous↗
Concordant expression of tissue factor and class II MHC antigens in human placental endothelium.
Villitis of unestablished etiology is a placental lesion frequently associated with high risk pregnancies: it is also found in placentae from normal term pregnancies. The etiology of the lesion is unknown. Vasculitis and thrombosis have been described in villitis areas of placentae from normal and high risk pregnancies. We asked if fetal stem vessel endothelium in villitis lesions expresses MHC class II antigens, and if this is associated with a thrombogenic activity of these vessels. We found that endothelium of fetal stem vessels in villitis areas was usually MHC class II (HLA-DR, DP and DQ) reactive. Reactivity of fetal stem vessel endothelium for MHC class II antigens was associated with the presence of tissue factor reactivity and the absence of thrombomodulin reactivity. These changes on endothelial plasma membranes can promote intravascular coagulation, ischemic necrosis, vasculitis and other histological changes characteristic of villitis.
Chorionic Villi↗
A nodule of adrenocortical tissue within a human placenta: light microscopic and immunocytochemical findings.
A case of adrenocortical tissue within a human placenta is described, this being the second example of such a phenomenon. Immunocytochemistry showed that the adrenal tissue reacted positively for DHEA-S but negatively for 17-OH progesterone and cortisol. This suggests that the heterotopic adrenal tissue resembled metabolically the fetal zone of the adrenal cortex.
Adrenal Cortex↗
Allogeneic recognition and rejection reactions in the placenta.
One of the major questions in medicine is how human extraembryonic tissues escape rejection by maternal immune responses, because these tissues are allogeneic and should stimulate allogeneic recognition and rejection reactions. Evidence for maternal allogeneic recognition of extraembryonic tissues in chorionic villi, basal plate, and spiral arteries is presented. Extraembryonic membranes seem always to stimulate maternal allogeneic recognition and rejection reactions, and abnormal pregnancies appear to be associated with a simple quantitative increase of the same placental immunopathological lesions found in normal pregnancies.
Autoantigens↗
Fetal stem vessel endothelial changes in placentae from normal and abnormal pregnancies.
Areas of immunocytochemically defined immunopathology are common in placentae from secondary recurrent spontaneous aborters. Endothelial cells of affected villi were found to be negative for the thrombomodulin natural anticoagulant pathway, and these cells were reactive with monoclonal antibodies to tissue factor and fibrin. Endothelial cells of normal villi adjacent to affected villi also were negative for thrombomodulin and positive for tissue factor and fibrin, but endothelium of normal villi distant to affected villi were thrombomodulin-positive, tissue factor-negative, and did not contain deposits of fibrin. These findings indicate that a loss of endothelial anticoagulant activity precedes the onset of immunopathology. This observation, coupled with the findings that fetal stem vessels normally lack the heparan sulfate proteoglycan-antithrombin III natural anticoagulant pathway and that normal cord blood contains a heparin-like anticoagulant, suggest that a failure of endothelial anticoagulation may be a primary event in the development of placental immunopathology.
Abortion, Habitual↗
Microvascular perturbations in human allografts: analogies in preeclamptic placentae.
The thromboresistance of endothelium is maintained as long as natural anticoagulant pathways are functionally present on endothelial plasma membranes. The principal anticoagulant pathways in human hearts and kidneys are thrombomodulin (TM) and heparan sulfate proteoglycan-antithrombin III (HSPG-ATIII). The downregulation of TM or the loss of ATIII is associated with fibrin deposition. This sequence of events occurs when stable allografts of hearts or kidneys become unstable or rejected. Human placentae do not contain the HSPG-ATIII natural anticoagulant pathway, but the TM system is uniformly represented on endothelium of normal chorionic villi. However, many villi in placentae from preeclamptic pregnancies contain thrombomodulin-negative endothelium, and these vessels contain fibrin thrombi. These thrombi compromise blood flow through the placental microcirculation and are associated with ischemic changes either with or without the presence of cellular infiltrates.
Adult↗
The complement system in human reproduction.
Regulation of the complement system in reproduction is unique inasmuch as reproductive tissues represent the only condition where allogeneic interactions occur naturally. Both allogeneic extraembryonic membranes and semen that contact and interact with maternal cells and tissues must avert complement-mediated damage to ensure reproductive success. Several regulators of complement activation exist. Membrane cofactor protein (MCP) and decay accelerating factor (DAF) inactivate C3 and C5 convertases on cell surfaces. In addition, CD59 inhibits the membrane attack complex (MAC) of the complement cascade. Strong expression of these membrane glycoproteins by trophoblast and amniotic epithelium has been observed. MCP, DAF, and CD59 likely safeguard extraembryonic tissues from complement damage originating from maternal and fetal blood or amniotic fluid. Different reproductive tract fluids vary in complement levels. With the exception of ovarian follicular fluid, these levels are generally much less than those in blood. Endometrial and cervical content of C3 appear to be regulated by hormones. These observations suggest that the effects of complement activation may vary in reproductive tissues. MCP is absent from the surfaces of oocytes. Sperm express MCP and DAF in discrete areas that would not be associated with the known complement-regulatory functions of these proteins. Seminal plasma contains MCP and the MAC inhibitor SP-40,40 but not DAF.SP-40,40 may exemplify how complement-regulatory proteins perform alternative functions as it interacts with molecules other than complement components. We have reviewed aspects of the complement system that relate to allogeneic interactions in reproduction and that suggest fruitful areas for further research.
Antigens, CD↗
Vascular events in placentae and organ allografts.
This investigation explores the transplantation analogy of placentae with allografted human organs. Biopsies of cardiac and renal allografts and placentae were studied immunocytochemically with antibodies to components of the immunological, coagulational, anticoagulational, and fibrinolytic systems. Cellular rejection of cardiac and renal allografts was identified by infiltrating lymphocytes and macrophages. This was accompanied by vascular damage characterized by loss of endothelial anticoagulant pathways, vascular deposits of fibrin, and depletion of arterial tissue plasminogen activator (tPA). Failing allografts, including placentae from abnormal pregnancies, demonstrated coagulation/fibrinolytic changes consistent with vascular rejection, regardless of the presence of cellular infiltrates. An IgM autoantibody to allogeneic endothelium was associated with vascular protection. Its presence in cardiac and renal transplant biopsies was associated with an absence of fibrin deposits, and its absence was associated with vascular damage. Atherosclerosis commonly was identified in allograft biopsies (including placentae from abnormal pregnancies). These changes were shown in serial biopsies of transplanted hearts to be preceded by or associated with diminished IgM autoantibody, impaired endothelial anticoagulant pathways, vascular fibrin deposits, and depleted arterial reactivity for tPA. These results indicate the transplantation analogy of pregnancy should be viewed more specifically as vascular smooth muscle cell and endothelial responses to as yet unidentified microenvironmental stimuli.
Arteriosclerosis↗
Natural anticoagulant pathways in normal and transplanted human hearts.
We have studied two natural anticoagulant pathways in normal and in transplanted human hearts. The first is the thrombomodulin pathway. Our immunocytochemical results show thrombomodulin localized to endothelium in heart biopsy specimens before transplantation. This reactivity persists in the absence of cellular rejection, but the infiltration of immune cells is associated with a lack of endothelial thrombomodulin. The second pathway is composed of antithrombin III (ATIII) bound to heparan sulfate proteoglycan (HSPG) molecules on endothelial cells. These ATIII-HSPG complexes bind and inactivate thrombin at the endothelial surface. Our immunocytochemical results show ATIII localized to endothelium in heart biopsy specimens before transplantation. This reactivity is present in the absence of vascular rejection as defined by either angiography or microscopy. The absence of thrombomodulin and ATIII is always associated with fibrin deposition within the microcirculation. Thrombomodulin and ATIII pathways appear to be independent, for cellular rejection often is associated with thrombomodulin-negative ATIII-positive endothelium, and vascular rejection often is associated with thrombomodulin-positive ATIII-negative endothelium. Cytokines from activated macrophages down-regulate endothelial thrombomodulin without generally affecting the ATIII-HSPG pathway. Immunosuppressive therapy depletes cytokine-producing cells that affect thrombomodulin, but there presently is no therapy to protect endothelium in vascular rejection. It is possible that heparin could interact with endothelium and bind ATIII to maintain a state of thromboresistance.
Antithrombin III↗
Major histocompatibility antigens in transplanted human hearts before perfusion.
The expression of major histocompatibility class I and II antigens is described in human normal donor hearts before perfusion with recipients' blood. Class I and II major histocompatibility antigens were found on interstitial but not on myocardial cells. Endothelial cells accounted for most of the generic class I reactions (that is, W6/32 and beta 2 microglobulin), and endothelial cells accounted for most of the HLA-DR and -DP reactivity. HLA-DQ antigens were not found in this series of normal donor hearts. The earliest time we were able to identify HLA-DQ antigens during the follow-up biopsies from these patients was 1 week after the allograft had been in place. Macrophages accounted for little of the class II reactivity. Variations in the HLA-DQ antigen expression on endothelial cells may be useful in the follow-up of transplanted hearts, considering that these antigens have been found to be more susceptible to the effects of interferon-gamma than either HLA-DR or -DP.
Adult↗
Immunoglobulin M antibodies in transplanted human hearts.
We have studied 56 human hearts before and after transplantation for the presence of immunoglobulin M. None of the 56 time-zero biopsy specimens studied contained immunocytochemically detectable immunoglobulin M, but they all had immunoglobulin M deposits on vascular endothelial cells after transplantation. The vascular location of immunoglobulin M was confirmed in double-antibody experiments with antibodies to von Willebrand factor and immunoglobulin M. None of the immunoglobulin M antibody reactivity was shown to colocalize with complement. Biopsy specimens from 29 of the 56 patients contained abundant deposits of immunoglobulin M. These patients were clinically stable, and only one of them has died. Biopsy specimens from 27 of the 56 patients had scant deposits of immunoglobulin M. These patients were clinically unstable; eight of them have died, and one has undergone retransplantation. In addition, biopsy specimens from stable allografts contained fewer fibrin deposits than biopsy specimens from unstable grafts, suggesting a protective role for non-complement fixing immunoglobulin M. The observation that immunoglobulin deposits were found soon after transplantation prompts us to consider them to be natural antibodies. Efforts to identify the antigen for immunoglobulin M natural antibodies in heart transplant recipients are currently under study.
Coronary Vessels↗