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Chronic histiocytic intervillositis (CHI) is a pregnancy disorder characterized by infiltration of maternal macrophages into the intervillous space of the human placenta, often with accompanying perivillous fibrin deposition. CHI is associated strongly with foetal growth restriction and increased risk of miscarriage and stillbirth. Although rare, affecting 6 in every 10 000 pregnancies beyond 12 weeks' gestation, the rate of recurrence is high at 25%-100%. To date, diagnosis of CHI can only be made post-delivery upon examination of the placenta due to a lack of diagnostic biomarkers, and criteria vary across publications. No treatment options have shown proven efficacy, and CHI remains a serious obstetric conundrum. Although its underlying aetiology is unclear, due to the presence of maternal macrophages and the reported increased incidence in women with autoimmune disease, CHI is hypothesized to be an inappropriate immune response to the semi-allogeneic foetus. Given this lack of understanding, treatment approaches remain experimental with limited rationale. However, there is recent evidence that immunosuppression and antithrombotic therapies may be effective in preventing recurrence of associated adverse pregnancy outcomes. With similarities noted between the pathological features of CHI and acute rejection of solid organ transplants, further investigation of this hypothesis may provide a basis for tackling CHI and other immune-related placental conditions. This review will explore parallels between CHI and allograft rejection and identify areas requiring further confirmation and exploitation of this comparison., (© 2020 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Antiphospholipid syndrome is defined by the presence of thrombosis and/or obstetrical adverse events (≥3 recurrent early miscarriage or fetal death or a prematurity<34 weeks of gestation) associated with persistent antiphospholipid antibodies. The pregnancy outcome has been improved by the conventional treatment (aspirin 100mg/day with low molecular weight heparin [LMWH] from 30 to 75% of uncomplicated pregnancies. In PROMISSE study, 19% of pregnancies had at least one obstetrical adverse event despite treatment (maternal, fetal or neonatal complications) in relation with APS. In the European registry of babies born from APS mothers, maternal and foetal adverse events were observed in 13% of cases, with prematurity in 14% despite treatment. The presence of lupus erythematosus, a history of thrombosis, presence of lupus anticoagulant and APL triple positivity are considered as factors associated with unfavorable obstetrical outcome. Hydroxychloroquine (HCQ) has anti-inflammatory and anti-thrombotic properties. Studies in vitro have shown that HCQ is able to restore the placental expression of Annexin V, which has an anticoagulant effect and to prevent the placental injury induced by APL. HCQ used for lupus erythematosus decrease the thrombotic risk and its value for thrombotic APS has been raised in an open labelled French study. In European retrospective study, the addition of HCQ to conventional treatment improved refractory obstetrical APS. Its use during the pregnancy of patients with lupus erythematosus, the evidence of good safety during the pregnancy and follow-up of children born to mothers exposed to HCQ demonstrate an overall good safety profile for mothers and the fetus. This clinical trial is designed to assess the interest of the addition of hydroxychloroquine to conventional treatment in APS during the pregnancy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The chronic inflammatory lesions of the placenta often run in the shadows of the better-known acute inflammatory processes of the placenta, such as acute chorioamnionitis and acute funisitis. A heterogeneous population of T-cell lymphocytes, plasma cells, and macrophages is the primary player in chronic villitis, chronic chorioamnionitis, chronic deciduitis, and chronic intervillositis, and eosinophils are an added component of eosinophilic/T-cell chorionic vasculitis. The histologic appearance, sites of occurrence in the placenta, and pathogeneses of these entities are reviewed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS and affects women of childbearing age. Most patients with NMO have circulating Abs, termed NMO-IgG, against the astrocytic water channel protein aquaporin-4. In the CNS, NMO-IgG causes complement-mediated astrocyte damage, inflammatory cell infiltration, and myelin loss. In this study, we show that aquaporin-4 is expressed in the syncytiotrophoblast of human and mouse placenta. Placental aquaporin-4 expression is high during mid-gestation and progressively decreases with advancing pregnancy. Intraperitoneally injected NMO-IgG binds mouse placental aquaporin-4, activates coinjected human complement, and causes inflammatory cell infiltration into the placenta and placental necrosis. There was no damage to maternal organs that express aquaporin-4, including the brain, spinal cord, kidneys, and skeletal muscle. In control experiments, no placentitis was found in mice injected with NMO-IgG without complement, non-NMO-IgG with human complement, or in aquaporin-4 null mice injected with NMO-IgG and human complement. The infiltrating cells were primarily neutrophils with a few scattered eosinophils and macrophages. NMO-IgG and human complement-induced placentitis caused fetal death, but some fetuses were born normal when lower amounts of NMO-IgG and human complement were injected. Sivelestat, a neutrophil elastase inhibitor, and aquaporumab, a nonpathogenic IgG that competes with NMO-IgG for aquaporin-4 binding, significantly reduced NMO-IgG and human complement induced placentitis and fetal death. Our data suggest that NMO-IgG can cause miscarriage, thus challenging the concept that NMO affects only the CNS. These findings have implications for the management of NMO during pregnancy.

Women are at higher risk of Plasmodium falciparum infection when pregnant. The decreasing risk of malaria with subsequent pregnancies is attributed to parity-dependent acquisition of antibodies against placental parasites expressing variant surface antigens, VAR2CSA, that mediate placental sequestration through adhesion to chondroitin sulfate A (CSA). However, modulation of immunity during pregnancy may also contribute to increase the risk of malaria. We compared antibody responses among 30 Mozambican primigravidae and 60 multigravidae at delivery, 40 men, and 40 children. IgG levels were measured against the surface antigens of erythrocytes infected with P. falciparum isolated from 12 pregnant women (4 placental and 8 peripheral blood isolates) and 26 nonpregnant hosts. We also measured IgG levels against merozoite recombinant antigens and total IgG. Placental P. falciparum infection was associated with increased levels of total IgG as well as IgG levels against merozoite antigens and parasite isolates from pregnant and nonpregnant hosts. We therefore stratified comparisons of antibody levels by placental infection. Compared to multigravidae, uninfected primigravidae had lower total IgG as well as lower levels of IgGs against peripheral blood isolates from both pregnant and nonpregnant hosts. These differences were not explained by use of bed nets, season at delivery, neighborhood of residence, or age. Compared to men, infected primigravidae had higher levels of IgGs against isolates from pregnant women and CSA-binding lines but not against other isolates, supporting the concept of a pregnancy-specific development of immunity to these parasite variants. Results of this study show that parity and placental infection can modulate immune responses during pregnancy against malaria parasites.

The Toll receptor was originally identified as a regulator of embryogenesis in Drosophila. Toll-like receptors (TLRs) in mammals recognize infectious agents and other danger signals. Activation of TLRs on trophoblast influences immune cell recruitment, cytokine secretion, and decidual responses to invading pathogens during pregnancy. Importantly, biological effects of TLR signal transduction at multiple maternal-fetal interfaces may contribute to several pregnancy pathologies associated with placental dysfunction, including pre-eclampsia, intrauterine growth restriction, and preterm labor. We herein discuss mechanisms by which TLRs regulate the maternal immune response during normal and abnormal gestation, and we highlight recent data that assign a role to TLRs in the pathophysiology of selected pregnancy-associated complications.

Problem: polymorphic changes in the IL-10 gene promoter have been identified that lead to altered IL-10 production. We hypothesized that because of these genotypic changes, the IL-10 promoter might be expressed in a cell type-specific manner and may respond differentially to inflammatory triggers., Method of Study: we created reporter gene promoter constructs containing GCC, ACC, and ATA haplotypes using DNA from patients harboring polymorphic changes at -1082 (G→A), -819 (C→T), and -592 (C→A) sites in the IL-10 promoter. These individual luciferase reporter constructs were transiently transfected into either primary term trophoblasts or THP1 monocytic cells. DNA-binding studies were performed to implicate the role of the Sp1 transcription factor in response to differential promoter activity., Results: our results suggest that the GCC promoter construct was activated in trophoblast cells in response to lipopolysaccharide (LPS), as demonstrated by reporter gene expression, but not in monocytic cells. The ACC construct showed weaker activation in both cell types. Importantly, while the ATA promoter was constitutively activated in both cell types, its expression was selectively repressed in response to LPS, but only in trophoblasts. DNA-nuclear protein binding assays with nuclear extracts from LPS treated or untreated cells suggested a functional relevance for Sp1 binding differences at the -592 position., Conclusions: these results demonstrate cell type-specific effects of the genotypic changes in the IL-10 gene promoter. These responses may be further modulated by bacterial infections or other inflammatory conditions to suppress IL-10 production in human trophoblasts.

Villitis of unknown etiology (VUE) is an important pattern of placental injury occurring predominantly in term placentas. Although overlapping with infectious villitis, its clinical and histologic characteristics are distinct. It is a common lesion, affecting 5% to 15% of all placentas. When low-grade lesions affecting less than 10 villi per focus are excluded, VUE is an important cause of intrauterine growth restriction and recurrent reproductive loss. Involvement of large fetal vessels in the placenta (obliterative fetal vasculopathy) in cases of VUE is a strong risk factor for neonatal encephalopathy and cerebral palsy. Although the etiology of the eliciting antigen is unknown, many other characteristics of the immune response have been clarified. VUE is caused by maternal T lymphocytes, predominantly CD8-positive, that inappropriately gain access to the villous stroma. Fetal antigen-presenting cells (Hofbauer cells) expand and are induced to express class II major histocompatibility complex molecules. Maternal monocyte-macrophages in the perivillous space likely amplify the immune response. Although much speculation exists that VUE represents a host-versus-graft reaction analogous to transplant rejection, other eliciting antigens have not been excluded. Irrespective of target antigen or antigens, the pathophysiologic implications of having activated maternal lymphocytes within vascularized fetal tissues are not trivial.

Immune inflammation is a typical pathophysiological process caused by exogenous and endogenous factors. Fibrinoid necrosis and cell infiltrations are the morphological features of tissue lesion caused by immune inflammation. Tissue lesion in immune inflammation may be connected with immune complex (IC) formation or T-cell aggression. Lesion caused by antigen-antibody complexes develops as a result of direct IC formation in the tissue or their inflow from microcirculation. Potential sources of IC in the placenta are maternal blood flow, the formation of IC between maternal antibodies (AB) and embryonic antigens, and IC formation in fetal blood vessels. After sedimentation in the placenta, circulating IC can cross syncytiotrophoblast tissue with the participation of specific receptors to immunoglobulin Fc-fragment. The process of antifetal AB formation may start in the maternal organism, as a result of which it forms AB to embryonic and placental antigens, including paternal Rh, ABO, and HLA, and some trophoblast antigens. IC are able to initiate inflammatory process through interaction with the compliment system, through the activation of macrophages excreting cytokines (TNF-alpha and IL-1), and through influencing basophiles and thrombocytes (the liberation of vasoactive amines). Gestosis is associated with system inflammatory response with endothelial dysfunction as the main element. As the clinical features of gestosis do not develop before 20 weeks of pregnancy, its clinical manifestation is preceded by increased fetal blood-brain barrier permeability, elevation of the level of neurospecific proteins of fetal origin in maternal circulation, and the formation of specific IC causing acute endotheliosis.

We report the cases of two patients who had a favorable outcome with aspirin and corticosteroid therapy during pregnancy for chronic villitis of unknown etiology complicated by labor asphyxia and further intrauterine fetal demise in one gravida 3 patient and for chronic intervillositis of unknown etiology diagnosed after three perinatal deaths in another patient (gravida 4). Chronic villitis of unknown etiology (CVUE) is detected in 7 to 33% of placentas, mainly after intrauterine growth retardation (IUGR), unexplained prematurity, preeclampsia, perinatal asphyxia and intrauterine fetal death (IUFD). The less frequent chronic intervillositis of unknown etiology (CIUE) (0.6 to 0.9/1.000) has been implicated in recurrent severe pregnancy complications, such as spontaneous abortions, IUGR and IUFD. Histopathology and immunohistology are in favor of an immune response against the foreign fetal allograft. The favorable results obtained with corticosteroids and aspirin remain to be confirmed by larger series.

Objective: To evaluate the placental histopathology findings in women with systemic lupus erythematosus or antiphospholipid syndrome delivered preterm., Methods: We performed a case-control study comparing clinical outcomes and placental histopathology of 18 consecutive singleton pregnancies with systemic lupus erythematosus (n = 9) or antiphospholipid syndrome (n = 9) delivered between 24 and 37 weeks, and 54 controls matched for gestational age and type of preterm delivery (spontaneous or indicated). Placental examinations were performed by a single pathologist, and placental lesions were grouped into four categories: uteroplacental vascular pathology and related villous lesions; coagulation-related damage; chronic inflammation; and acute inflammatory lesions. Statistical analysis included the Mantel-Haenzsel or Fisher's exact test, and logistic regression, with a value of p < 0.05 or an odds ratio (OR) with 95% confidence intervals (Cl) not inclusive of unity considered significant., Results: Lupus anticoagulant was positive in ten out of 18 cases and medium or high positive IgG anticardiolipin antibodies in seven out of 18. Antenatal treatment included corticosteroids (n = 9), low-dose aspirin (n = 15) and heparin (n = 8). Rates of necrotizing enterocolitis (33% vs. 0%, p < 0.001) and of perinatal mortality (33% vs. 9%, p = 0.02) were significantly different between cases and controls, and rates of birth weight < 10th centile approached statistical significance. Uteroplacental vascular lesions (OR 3.7, 95% CI 1.1, 11.7) and coagulation-related damage (OR 16.8, 95% CI 3.9, 72.6) were significantly more common among cases than controls, and rates of chronic inflammatory lesions approached significance., Conclusions: Cases of systemic lupus erythematosus and antiphospholipid syndrome delivered preterm are associated with a significant increase in placental vascular and coagulation-related lesions, which are reflected clinically by higher rates of perinatal mortality, necrotizing enterocolitis, and small-for-gestational age neonates.

Problem: The survival of the fetoplacental unit might partly depend on down-regulation of rejection reactions. Pathological maternal cellular immune response mechanisms could therefore be of pathogenic importance in pregnancies complicated by placental disorders., Method: A flow-cytometric analysis of T-cell subsets and B-cell, as well as serological tests for anticardiolipin antibodies (aCL), antinuclear antibodies (ANA), and rheumatoid factor (RF) were done on 90 women with complicated pregnancies. The results were compared with that of nonpregnant women (n = 5), and normal pregnant women (n = 5) in the third trimester., Results: Two women, suffering from severe preeclampsia and eclampsia respectively, had aCL on 12 and 13 units, respectively. ANA occurred in 11 patients with moderate and severe preeclampsia and intrauterine growth retardation. All women had negative RF tests. Within the CD4 T-helper subpopulations, the proportion of suppressor/inducer T-cell population (CD4+CD45RA+) significantly increased, while the memory and helper/inducer T-cells (CD4+CD45RO+ and CD4+CD29+) significantly decreased during normal pregnancy compared to nonpregnant controls. This deviation of CD4 subpopulations was not found, or was less pronounced, in complicated pregnancies. The proportion of cytotoxic T cells (CD8+S6F1+) was significantly reduced during normal pregnancy. This reduction was less pronounced in complicated pregnancies., Conclusion: Systemic immunological deviations toward suppression or decreased activity of the immunological response as seen in normal pregnancies, was not observed in preeclampsia, intrauterine growth retardation, intrauterine fetal death, and abruptio placentae. This lack of suppression or increased T-cell activity may have a primary pathogenic role in some women with a complicated pregnancy, or it may be secondary to the placental disorders.