Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy

Abstract

IntroductionFetal and neonatal immune thrombocytopenia (FNIT) is an alloimmune disorder that results from fetal platelet opsonization by maternal antibodies and subsequent platelet destruction. There are several platelet antigens that may have the potential to induce a maternal alloimmune response, particularly those polymorphisms within several extracellular domains of ␤3 integrin (eg, human platelet antigen-1a in whites and human platelet antigen-4b in Asians). [1][2][3] The incidence of FNIT has been estimated at 0.5-1.5 per 1000 live-born neonates, although the reported incidence varied in the different studies. [4][5][6][7] The major risk of this disease is intracranial hemorrhage, which is associated with death and neurologic sequelae in affected neonates. [8][9][10][11][12] In addition, FNIT may also cause miscarriage, as has been reported from several independent research groups. 7,13 The recurrence rate of FNIT among subsequent platelet antigen-positive siblings is almost 100%, with the degree of thrombocytopenia generally being either similar or more severe. 1,14 However, the immunopathogenic mechanisms of this disease are still largely unknown.Although several treatments, such as intravenous immunoglobulin G (IVIG), steroids, and fetal and neonatal platelet transfusions, have been used to manage FNIT, 1,8,[10][11][12]15 antenatal management of FNIT has not been standardized. 16 A safer and more effective therapy remains to be developed.The neonatal Fc receptor (FcRn) is a heterodimer consisting of a ␤2-microglobulin (␤2m) and a transmembrane ␣-chain that is homologous to the ␣-chain of major histocompatibility complex class I. 17,18 FcRn was first identified as the protein that mediated transfer of maternal, milk-borne immunoglobulin Gs (IgGs) across the neonatal rodent intestine. 19,20 It has been demonstrated that the binding of FcRn to IgG is strictly pH-dependent, 21,22 with binding occurring in slightly acidic environments (optimum pH 6.0) and no detectable binding at pH 7.4. Thus, FcRn binds to IgG in the neonatal gut lumen (low pH), transcytoses the bound IgG across intestinal epithelial cells, and releases it into the newborn blood circulation (pH 7.4). [21][22][23][24] Recent studies demonstrated that FcRn protected IgG from catabolic degradation. It is thought that during transcytosis, IgG is taken up into endosomes, which are acidified, allowing IgG to bind FcRn, whereas unbound IgG is degraded. 25,26 FcRn therefore plays an important role in extending IgG half-life in the blood circulation. 27 In several animal models of antibodymediated autoimmune diseases, 28-31 including autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]), therapeutic interventions that target FcRn have demonstrated to be effective in enhancing clearance of pathogenic antibodies. However, there are no reports available that indicate whether modulation of FcRn is a useful therapy for FNIT. FcRn was also reported to play an important role in the transplacental transport of IgG from the mother to the fe...

Prediction of the fetal status in noninvasive management of alloimmune thrombocytopenia

“…20,21 The striking result we obtained was the observation, for the first time, that maternal alloantibody concentration measured during managed pregnancy could be a prognostic factor. The areas under the curves of the maternal alloantibody concentration weighted by the weeks of gestation were predictive of IVIG (with or without steroids) therapy failure.…”

Alloantibodies against MHC Class I: A Novel Mechanism of Neonatal Pancytopenia Linked to Vaccination

“…In humans, a correlation between HPA1a Ab titers in the mother and severity of the thrombocytopenia at birth has been reported, despite several analytical variation factors (35)(36)(37). FcRn, the neonatal IgG receptor, has been shown to modulate FNAIT in a mouse model (38). Other genetically determined factors may also exist.…”

Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage

“…We used our established murine models of FNAIT (2,37,40) to investigate the mechanism of ICH in affected fetuses and neonates. To mimic exposure to β3 or GPIbα during conception, Itgb3 -/-and Gp1ba -/-both active and passive (postnatal antisera injections) murine models of FNAIT.…”

“…Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder in which maternal antibodies cross the placenta and destroy fetal/neonatal platelets (1)(2)(3). FNAIT occurs in approximately 0.5 to 1.5 per 1,000 live-born neonates, but this does not include miscarriages in utero, as has been reported (4,5).…”