Ultrastructural localization of glycoprotein IIIa (GPIIIa, β3 integrin) on placental syncytiotrophoblast microvilli: implications for platelet alloimmunization during pregnancy

Kumpel, Belinda M.; Sibley, K.; Jackson, David J.; White, Gregory; Soothill, Peter

doi:10.1111/j.1537-2995.2008.01832.x

Cited by 60 publications

(47 citation statements)

References 51 publications

(37 reference statements)

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“…In terms of prophylactic and therapeutic potential, stable binding to HPA-1a on trophoblasts may be an advantageous property. It has been speculated that HPA-1a on aVb3 expressed on trophoblast cells could initiate an alloimmune response in the mother (42,43). One could envision that stable binding of 26.4 to aVb3 derived from placenta could prevent alloimmunization by blocking activation of Ag-specific B cells and by accelerated removal of cells and material expressing this Ag from the maternal circulation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Eksteen

Tiller

Averina

et al. 2015

The Journal of Immunology

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Human platelet Ag (HPA)-1a, located on integrin β3, is the main target for alloantibodies responsible for fetal and neonatal alloimmune thrombocytopenia (FNAIT) in the white population. There are ongoing efforts to develop an Ab prophylaxis and therapy to prevent or treat FNAIT. In this study, an mAb specific for HPA-1a, named 26.4, was derived from an immortalized B cell from an alloimmunized woman who had an infant affected by FNAIT. It is the only HPA-1a–specific human mAb with naturally paired H and L chains. Specific binding of mAb 26.4, both native and recombinant forms, to platelets and to purified integrins αIIbβ3 (from platelets) and αVβ3 (from trophoblasts) from HPA-1a+ donors was demonstrated by flow cytometry and surface plasmon resonance technology, respectively. No binding to HPA-1a− platelets or integrins was detected. Moreover, the Ab binds with higher affinity to integrin αVβ3 compared with a second HPA-1a–specific human mAb, B2G1. Further in vitro experimentation demonstrated that mAb 26.4 can opsonize HPA-1a+ platelets for enhanced phagocytosis by monocytes, inhibit binding of maternal polyclonal anti–HPA-1a Abs, and weakly inhibit aggregation of HPA-1a–heterozygous platelets, the latter with no predicted clinical relevance. Thus, mAb 26.4 is highly specific for HPA-1a and could potentially be explored for use as a prophylactic or therapeutic reagent for FNAIT intervention and as a phenotyping reagent to identify women at risk for immunization.

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Section: Discussionmentioning

confidence: 99%

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Eksteen

Tiller

Averina

et al. 2015

The Journal of Immunology

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“…Maternal immunization against fetal platelet GPIbα may also occur during human pregnancy when fetal GPIbα antigen-positive platelets leak into the maternal circulation via fetomaternal hemorrhage (58,59). Since (a) β3 integrin (GPIIIa) is expressed on human placental syncytiotrophoblast microvilli that are in direct contact with maternal blood and may induce the immune response against HPA-1a on β3 integrin in primiparous mothers (60,61) and (b) GPIbα has been reported to be expressed on human endothelial cells under certain conditions (62-64), we cannot exclude the possibility that GPIbα, like β3 integrin, may also be expressed on placental syncytiotrophoblasts and endothelial cells, thus contributing to maternal anti-GPIbα antibody generation during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies

et al. 2011

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Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbβ3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbα-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbα and β3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIbα-mediated FNIT, which was far more frequent than in anti-β3-mediated FNIT. Dams with anti-GPIbα antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIbα (but not anti-β3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIbα-mediated FNIT. Thus, the maternal immune response to fetal GPIbα causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIbα-mediated FNIT, but also point to possible therapeutic interventions.

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“…Recent studies suggest that β 3 integrin is expressed on human placental syncytiotrophoblast cells as early as the first trimester of pregnancy [190, 191]. Thus, the maternal immune system may mount an immune response against “platelet” antigens on placental syncytiotrophoblasts or on fetal platelets that “leak” into the maternal circulation through fetomaternal hemorrhage during pregnancy [112, 190, 191].…”

Section: Pathogenesis Of Immune-mediated Thrombocytopeniamentioning

confidence: 99%

Crosstalk between Platelets and the Immune System: Old Systems with New Discoveries

et al. 2012

Advances in Hematology

121

102

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Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-β and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions.

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Ultrastructural localization of glycoprotein IIIa (GPIIIa, β3 integrin) on placental syncytiotrophoblast microvilli: implications for platelet alloimmunization during pregnancy

Cited by 60 publications

References 51 publications

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies

Crosstalk between Platelets and the Immune System: Old Systems with New Discoveries

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