Chronic villitis in untreated neonatal alloimmune thrombocytopenia: An etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy

Althaus, Janyne; Weir, Edward G.; Askin, Fred; Kickler, Thomas S.; Blakemore, Karin J.

doi:10.1016/j.ajog.2005.06.043

Cited by 47 publications

(43 citation statements)

References 22 publications

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“…These results suggest that either more foreign antigens or the absence of shared selfantigens in the placenta play a role in susceptibility [30]. Finally, a poorly understood correlation between neonatal alloimmune thrombocytopenia with VUE has been reported, particularly in untreated mothers (36% overall, 83% in the absence of therapy) [31]. Maternal antiplatelet antibodies in this condition could bind platelets or cross-reacting antigens on or within villi leading to antibody-dependent cellular cytotoxicity or immune complex-mediated injury.…”

Section: Clinical Associationsmentioning

confidence: 89%

Villitis of unknown etiology: noninfectious chronic villitis in the placenta

2007

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Section: Clinical Associationsmentioning

confidence: 89%

Villitis of unknown etiology: noninfectious chronic villitis in the placenta

2007

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“…It is unknown whether this FcRn-independent IgG transport pathway plays a significant role in FNIT and whether this pathway can be up-regulated when inflammation and other pathologies occur in the placenta during FNIT. 39 It has been reported from several independent groups that additional IgG binding molecules are expressed in the placenta, including Fc␥RIIb, annexin II, and placental alkaline phosphatase, which may be involved in the transplacental transport of IgG. [42][43][44] Since the binding of IgG to FcRn at physiologic blood pH is minimal, 21,22 it remains to be determined whether other IgG binding proteins are involved in the transport of IgG from the maternal blood to the fetus.…”

Section: Discussionmentioning

confidence: 99%

“…39 To test this, we set breeding cages of ␤3 Ϫ/Ϫ FcRn Ϫ/Ϫ female mice (immunized twice with ␤3 ϩ/ϩ FcRn Ϫ/Ϫ platelets) with ␤3 ϩ/ϩ FcRn Ϫ/Ϫ males. Although anti-␤3 integrin IgG was detected in these females both during pregnancy and after delivery (Figure 2A), the platelet counts in the antigen-positive heterozygous pups (␤3 Ϫ/ϩ FcRn Ϫ/Ϫ ) were not significantly decreased (392 Ϯ 17 ϫ 10 9 /L versus 342 Ϯ 16 ϫ 10 9 /L; P ϭ .14; n ϭ 8-21; Figure 2B) and circulating anti-␤3 integrin IgG and platelet-associated IgG were undetectable in these pups ( Figure 2C).…”

Section: Fcrn Is Indispensable For Maternal Anti-␤3 Integrin Antibodimentioning

confidence: 99%

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

Chen

Lang

et al. 2010

Blood

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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...

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“…VUE is characterised by patchy villous infiltration by chronic inflammatory cells, mainly histiocytes and lymphocytes, especially in basal/maternal floor villi, in the absence of an identifiable infective cause. It is postulated that VUE represents an abnormal maternofetal immune reaction, with consequently increased risk of VUE recurrence [73,74,75,76,77]. VUE is approximately twice as common and more diffuse in multigravidity [78], and it has a higher than expected concordance in twin pregnancies [79].…”

Section: Other Placental Histological Lesions Associated With Fgrmentioning

confidence: 99%

Placental Pathology in Early-Onset and Late-Onset Fetal Growth Restriction

2014

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Several histopathological features are found more frequently in placentas from pregnancies complicated by fetal growth restriction (FGR), including villous infarction, maternal vascular changes and villous morphological alterations, although around one quarter of placentas associated with FGR lack any morphological abnormality on routine examination. Since similar changes may also affect clinically uncomplicated pregnancies, the positive predictive value of such findings for pathological FGR in an unselected case remains low. However, the pattern of placental pathologies varies with clinical subgroup. The combination of placental bed and parenchymal lesions in FGR with abnormal uterine artery Doppler velocimetry is essentially identical to preterm pre-eclampsia (PET), and there is an association between FGR with abnormal umbilical artery Doppler findings and lesions of fetal stem arteries and terminal villous hypovascularity. Conversely, placentas from pregnancies complicated by PET or FGR presenting at or near term have a significantly lower frequency of histological abnormalities compared to early-onset disease and absence of a distinctive biochemical profile. The histological placental findings in FGR are therefore varied, from morphologically unremarkable through to severe uteroplacental vasculopathy, with no single pathological feature associated with high sensitivity or specificity. Severe early-onset FGR, overlapping with severe early-onset PET, is mainly associated with features of impaired maternal uteroplacental perfusion secondary to defective extravillous trophoblast invasion, and its consequences. Late-onset FGR probably represents a more heterogeneous group with less characteristic histological changes. Future research using histopathological assessment of aggregated data from multiple studies into larger datasets with centralised pathology review will allow delineation of distinctive clinicopathological associations and further understanding of pathophysiology.

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Chronic villitis in untreated neonatal alloimmune thrombocytopenia: An etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy

Cited by 47 publications

References 22 publications

Villitis of unknown etiology: noninfectious chronic villitis in the placenta

Villitis of unknown etiology: noninfectious chronic villitis in the placenta

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

Placental Pathology in Early-Onset and Late-Onset Fetal Growth Restriction

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