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Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance

  • Chong Jai Kim
    Affiliations
    Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI
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  • Roberto Romero
    Correspondence
    Corresponding author: Roberto Romero, MD, DMedSc.
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI

    Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
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  • Piya Chaemsaithong
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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  • Jung-Sun Kim
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI

    Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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      Chronic inflammatory lesions of the placenta are characterized by the infiltration of the organ by lymphocytes, plasma cells, and/or macrophages and may result from infections (viral, bacterial, parasitic) or be of immune origin (maternal anti-fetal rejection). The 3 major lesions are villitis (when the inflammatory process affects the villous tree), chronic chorioamnionitis (which affects the chorioamniotic membranes), and chronic deciduitis (which involves the decidua basalis). Maternal cellular infiltration is a common feature of the lesions. Villitis of unknown etiology (VUE) is a destructive villous inflammatory lesion that is characterized by the infiltration of maternal T cells (CD8+ cytotoxic T cells) into chorionic villi. Migration of maternal T cells into the villi is driven by the production of T-cell chemokines in the affected villi. Activation of macrophages in the villi has been implicated in the destruction of the villous architecture. VUE has been reported in association with preterm and term fetal growth restriction, preeclampsia, fetal death, and preterm labor. Infants whose placentas have VUE are at risk for death and abnormal neurodevelopmental outcome at the age of 2 years. Chronic chorioamnionitis is the most common lesion in late spontaneous preterm birth and is characterized by the infiltration of maternal CD8+ T cells into the chorioamniotic membranes. These cytotoxic T cells can induce trophoblast apoptosis and damage the fetal membranes. The lesion frequently is accompanied by VUE. Chronic deciduitis consists of the presence of lymphocytes or plasma cells in the basal plate of the placenta. This lesion is more common in pregnancies that result from egg donation and has been reported in a subset of patients with premature labor. Chronic placental inflammatory lesions can be due to maternal anti-fetal rejection, a process associated with the development of a novel form of fetal systemic inflammatory response. The syndrome is characterized by an elevation of the fetal plasma T-cell chemokine. The evidence that maternal anti-fetal rejection underlies the pathogenesis of many chronic inflammatory lesions of the placenta is reviewed. This article includes figures and histologic examples of all chronic inflammatory lesions of the placenta.

      Key words

      The term chronic inflammation refers to a pathologic process that is characterized by the infiltration of lymphocytes, plasma cells, and histiocytes (ie, tissue macrophages).

      Murphy HS. Inflammation. In: Strayer DS, Rubin E, editors. Rubin’s Pathology. 6th ed. China: Lippincott Williams & Wilkins; 2012:47-82.

      Chronic placental inflammatory lesions can be present in the villous tree, extraplacental chorioamniotic membranes, chorionic plate, and basal plate of the placenta (Figure 1). Identification of the causes of chronic inflammatory lesions of the placenta is an important challenge.

      Benirschke K, Burton GJ, Baergen RN, editors. Infectious diseases. In: Pathology of the human placenta. 6th ed. Berlin: Springer; 2012:557-656.

      Fox H, Sebire NJ. Infections and inflammatory lesions of the placenta. In: Pathology of the placenta. 3rd ed. China: Elsevier; 2007:303-54.

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      Infection
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      Chronic inflammatory lesions of the placenta.
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      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
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      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
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      Distinct patterns of C4d immunoreactivity in placentas with villitis of unknown etiology, cytomegaloviral placentitis, and infarct.
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      Chronic chorioamnionitis is the most common placental lesion in late preterm birth.
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      Positive C4d immunostaining of placental villous syncytiotrophoblasts supports host-versus-graft rejection in villitis of unknown etiology.
      Figure thumbnail gr1
      Figure 1The human placenta
      Modified from Benirschke K, Burton GJ, Baergen RN, editors. Infectious diseases. In: Pathology of the human placenta. 6th ed. Berlin: Springer; 2012:557-656.
      Chronic inflammatory lesions can affect different parts of the placenta. Chronic villitis refers to the inflammation involving the villous tree. Chronic chorioamnionitis involves either the extraplacental chorioamniotic membranes or chorionic plate. Chronic deciduitis affects the basal plate.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.
      The placenta and fetus are semiallografts; a maternal (host) immune response against paternal antigens (expressed in the placenta or fetus) can be considered analogous to allograft rejection.
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      We will review the evidence in support of the concept that many cases of idiopathic chronic placental inflammation reflect maternal anti-fetal rejection, in which the main effector is the infiltration of maternal CD8+ T cells (cytotoxic lymphocytes) into fetal tissues (Figure 2).
      • Kim M.J.
      • Romero R.
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      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      • Kim J.S.
      • Romero R.
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      Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology.
      This state is associated with the presence of fetal human leukocyte antigen (HLA)-specific antibodies in the maternal serum,
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Maternal HLA panel-reactive antibodies in early gestation positively correlate with chronic chorioamnionitis: evidence in support of the chronic nature of maternal anti-fetal rejection.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery.
      C4d deposition in the umbilical vein,
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d.
      • Lee K.A.
      • Kim Y.W.
      • Shim J.Y.
      • et al.
      Distinct patterns of C4d immunoreactivity in placentas with villitis of unknown etiology, cytomegaloviral placentitis, and infarct.
      and the syncytiotrophoblast.
      • Rudzinski E.
      • Gilroy M.
      • Newbill C.
      • Morgan T.
      Positive C4d immunostaining of placental villous syncytiotrophoblasts supports host-versus-graft rejection in villitis of unknown etiology.
      The presence of fetal HLA-specific antibodies in maternal serum was first determined by the performance of HLA genotyping with the use of fetal genomic DNA and then the assessment of whether the maternal HLA antibodies were directed against fetal antigens with the use of a Luminex assay (Life Technologies, Rockville, MD).
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Maternal HLA panel-reactive antibodies in early gestation positively correlate with chronic chorioamnionitis: evidence in support of the chronic nature of maternal anti-fetal rejection.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery.
      Furthermore, the concentrations of T-cell chemokine CXCL10 are elevated in different fetal compartments, such as the amniotic fluid and fetal plasma.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      • Lee J.
      • Romero R.
      • Chaiworapongsa T.
      • et al.
      Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response.
      These phenomena resemble those that are observed in allograft rejection in solid organ transplantation.
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      Expression of chemokines and chemokine receptors during human renal transplant rejection.
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      Figure thumbnail gr2
      Figure 2Microscopic findings of chronic nonspecific villitis of unknown etiology
      A, Normal chorionic villi showing the villous core with fetal vessels and stroma. The intervillous space contains maternal red blood cells. The rest of the image shows cross-sections of the villous tree of the placenta; each chorionic villus is lined with syncytiotrophoblast. Inside the villi, fetal capillaries are observed. B, Destructive inflammation of the chorionic villus (asterisk). The inflammatory process is diagnosed by the presence of an infiltration of mononuclear cells. Obliteration of the villous capillaries is also seen in comparison to unaffected villi adjacent to the distorted villus (asterisk). Unaffected villi (black arrow). C, Destructive inflammation of the chorionic villi (asterisk) Immunoperoxidase staining for CD8+ T cells. Cells stained in brown express CD8 on their surface and are therefore cytotoxic lymphocytes. These cells are of maternal origin, and are derived from the intervillous space. Original magnification (A-C), 200×.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Chronic nonspecific villitis

      Definition and cellular composition

      Villitis of unknown etiology (VUE) is a destructive inflammatory lesion characterized by the infiltration of maternal T cells into the chorionic villi (fetal tissue).
      • Redline R.W.
      • Patterson P.
      Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells.
      • Myerson D.
      • Parkin R.K.
      • Benirschke K.
      • Tschetter C.N.
      • Hyde S.R.
      The pathogenesis of villitis of unknown etiology: analysis with a new conjoint immunohistochemistry-in situ hybridization procedure to identify specific maternal and fetal cells.
      The frequency of VUE varies among studies, and its prevalence ranges from 2-33.8%.
      • Boog G.
      Chronic villitis of unknown etiology.
      • Knox W.F.
      • Fox H.
      Villitis of unknown aetiology: its incidence and significance in placentae from a British population.
      • Redline R.W.
      • Abramowsky C.R.
      Clinical and pathologic aspects of recurrent placental villitis.
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      • Feeley L.
      • Mooney E.E.
      Villitis of unknown aetiology: correlation of recurrence with clinical outcome.
      • Tamblyn J.A.
      • Lissauer D.M.
      • Powell R.
      • Cox P.
      • Kilby M.D.
      The immunological basis of villitis of unknown etiology: review.
      The wide range is thought to represent variations in the study population, sampling methods, and diagnostic criteria. The frequency of detection of VUE increases when the number of paraffin blocks from a given placenta increases to 4.
      • Knox W.F.
      • Fox H.
      Villitis of unknown aetiology: its incidence and significance in placentae from a British population.
      The main maternal T-cell subset infiltrating the chorionic villi is CD8+ cytotoxic T cells.
      • Kim J.S.
      • Romero R.
      • Kim M.R.
      • et al.
      Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology.
      The maternal origin of these T cells was demonstrated by Redline and Patterson
      • Redline R.W.
      • Patterson P.
      Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells.
      who used in situ hybridization analysis with X and Y chromosome-specific probes, along with CD3 (a pan-T lymphocyte marker) and CD45 (a leukocyte marker) immunostaining of placental tissues that were obtained from 4 male neonates. T lymphocytes infiltrating the villous tree were consistently of maternal origin (as shown by the lack of Y chromosome signals).
      • Redline R.W.
      • Patterson P.
      Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells.
      Another important cell type in VUE is the macrophage, which is of fetal origin, as demonstrated by the use of chromogenic in situ hybridization with a Y chromosome-specific probe.
      • Kim J.S.
      • Romero R.
      • Kim M.R.
      • et al.
      Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology.
      Placental macrophages, also known as Hofbauer cells, have an activated phenotype in VUE, as shown by expression of CD14.
      • Kim J.S.
      • Romero R.
      • Kim M.R.
      • et al.
      Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology.
      Increased CD14 immunoreactivity in VUE cases indicates that there is proinflammatory activation of placental macrophages. Therefore, VUE is a unique inflammatory process that involves T cells and macrophages originating from two different hosts (T cells from the mother and macrophages from the fetus).
      • Kim J.S.
      • Romero R.
      • Kim M.R.
      • et al.
      Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology.
      • Tang Z.
      • Abrahams V.M.
      • Mor G.
      • Guller S.
      Placental Hofbauer cells and complications of pregnancy.
      A key feature of VUE is fetal tissue damage by maternal cytotoxic T cells that resembles allograft rejection. The relative numbers of regulatory T cells (CD4+, CD25+, FoxP3+) are also higher in placentas with VUE, compared with those placentas without this lesion.
      • Katzman P.J.
      • Murphy S.P.
      • Oble D.A.
      Immunohistochemical analysis reveals an influx of regulatory T cells and focal trophoblastic STAT-1 phosphorylation in chronic villitis of unknown etiology.
      This is an interesting observation, given that regulatory T cells are implicated in the generation of a tolerogenic state in pregnancy.
      • Erlebacher A.
      Mechanisms of T cell tolerance towards the allogeneic fetus.
      • Aluvihare V.R.
      • Kallikourdis M.
      • Betz A.G.
      Regulatory T cells mediate maternal tolerance to the fetus.
      • Somerset D.A.
      • Zheng Y.
      • Kilby M.D.
      • Sansom D.M.
      • Drayson M.T.
      Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.
      • Piccinni M.P.
      T cell tolerance towards the fetal allograft.
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      • Teles A.
      • Zenclussen A.C.
      Regulatory T cells and their role in pregnancy.
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      • Zenclussen A.C.
      Regulatory T cells: regulators of life.
      The destruction of the villous architecture by the inflammatory process appears to be related to apoptosis, which is more extensive in areas of the placenta with VUE, as demonstrated with the use of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).
      • Ito Y.
      • Matsuoka K.
      • Uesato T.
      • et al.
      Increased expression of perforin, granzyme B, and C5b-9 in villitis of unknown etiology.
      Two mechanisms have been proposed to result in apoptosis: (1) the release of perforin and granzyme B by activated CD8+ T cells, which can induce caspase-dependent cell death in target cells, and (2) complement activation that leads to pore formation. Immunohistochemistry studies show expression of perforin and granzyme B and C5b-9 (membrane attack complex of the complement system) deposition in VUE.
      • Ito Y.
      • Matsuoka K.
      • Uesato T.
      • et al.
      Increased expression of perforin, granzyme B, and C5b-9 in villitis of unknown etiology.

      Grading

      Histopathologic grading of VUE is based on the number of chorionic villi affected and whether the distribution of villous inflammation is patchy or diffuse. Redline
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      has proposed a grading system using the number of villi that is affected per focus. In low-grade lesions, <10 villi are affected, and the lesions can either be focal (only 1 slide involved) or multifocal (>1 slide involved). High-grade lesions are defined as those with >10 villi affected per focus and are divided into patchy and diffuse subgroups.
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      The lesion is defined as diffuse when >5% of all distal villi are affected (Figure 3). Other grading systems have also been proposed.
      • Knox W.F.
      • Fox H.
      Villitis of unknown aetiology: its incidence and significance in placentae from a British population.
      • Russell P.
      Inflammatory lesions of the human placenta; III, The histopathology of villitis of unknown aetiology.
      The higher the grade, the greater the risk of adverse pregnancy outcomes.
      • Redline R.W.
      • O’Riordan M.A.
      Placental lesions associated with cerebral palsy and neurologic impairment following term birth.
      • Redline R.W.
      Severe fetal placental vascular lesions in term infants with neurologic impairment.
      Figure thumbnail gr3
      Figure 3The severity of villitis is assessed by a grading system
      A, Well-preserved chorionic villi in a normal placenta. B, A low-grade lesion shows involvement of chorionic villi; <10 villi are affected (indicated within the circle). C and D, High-grade lesions show patchy involvement. The villi within the oval are affected; those outside the oval are unaffected. Most of the villi are involved in 3D, which represents diffuse involvement. Original magnification (A-D), 100×.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Pattern of involvement

      Redline and O’Riordan
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      • Redline R.W.
      • O’Riordan M.A.
      Placental lesions associated with cerebral palsy and neurologic impairment following term birth.
      proposed that the patterns of VUE involvement be classified as distal, proximal, and basal (Figure 4). The distal type is the most common (approximately 50% of cases) and involves the distal villi (terminal and mature intermediate villi). The proximal type occurs in 30% of cases and involves the proximal stem villi (sometimes the chorionic plate along with the distal villi).
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      This type can be associated with obliterative vasculopathy and fetal vascular thromboocclusive disease, which results in hyalinized avascular villi.
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      The basal villitis type involves anchoring villi to the basal plate; this type is frequently associated with chronic deciduitis.
      • Redline R.W.
      Villitis of unknown etiology: noninfectious chronic villitis in the placenta.
      Figure thumbnail gr4
      Figure 4Histologic findings of villitis of unknown etiology
      A, The illustration shows the placental villous tree. Inflammation of the villous tree is the hallmark of villitis: i indicates a stem villus; ii indicates terminal and mature intermediate villi; iii indicates an anchoring villus. B, The infiltration of lymphocytes at the stem villi represents proximal villitis (asterisk). C, Distal villitis involving terminal and mature intermediate villi is the most common pattern of villitis of unknown etiology (asterisks). D, Basal villitis involves an anchoring villus (asterisk). Original magnification (B-D), 100×.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Pathogenesis

      What drives maternal T cells in the intervillous space to infiltrate the chorionic villi? Gene expression profiling of placentas affected by VUE demonstrates overexpression of genes involved in the immune response. For example, there is overexpression of major T-cell chemokines and their receptor (ie, CXCR3). The T-cell chemokines CXCL9, CXCL10, and CXCL11 are overexpressed in Hofbauer cells (placental macrophages of fetal origin), stromal cells, and endothelial cells.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      Therefore, a chemotactic gradient could be established between villi and the intervillous space, where maternal lymphocytes circulate. Importantly, maternal CD8+ T cells within the villi express the receptor for the T-cell chemokine CXCR3+, which indicates that they are able to receive the chemotactic signal.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      Based on this evidence, we propose that activated Hofbauer cells attract maternal T cells into the villous compartment through the production of chemokines. Another potential mechanism facilitating maternal T-cell infiltration into the chorionic villi includes the increased expression of intercellular adhesion molecule-1 in both the syncytiotrophoblast and maternal immunocytes.
      • Xiao J.
      • Garcia-Lloret M.
      • Winkler-Lowen B.
      • Miller R.
      • Simpson K.
      • Guilbert L.J.
      ICAM-1-mediated adhesion of peripheral blood monocytes to the maternal surface of placental syncytiotrophoblasts: implications for placental villitis.
      • Juliano P.B.
      • Blotta M.H.
      • Altemani A.M.
      ICAM-1 is overexpressed by villous trophoblasts in placentitis.
      • Labarrere C.A.
      • Bammerlin E.
      • Hardin J.W.
      • Dicarlo H.L.
      Intercellular adhesion molecule-1 expression in massive chronic intervillositis: implications for the invasion of maternal cells into fetal tissues.
      • Egal E.S.
      • Mariano F.V.
      • Blotta M.H.
      • et al.
      ICAM-1 expression on immune cells in chronic villitis.
      It is also possible that small breaks in the syncytiotrophoblast contribute to the disease process.
      • Nelson D.M.
      Apoptotic changes occur in syncytiotrophoblast of human placental villi where fibrin type fibrinoid is deposited at discontinuities in the villous trophoblast.
      In support of an immunologic origin of this lesion, we reported that, using transcriptomic analysis, placentas with VUE have an enrichment of genes that are involved in antigen presentation, such as class II major histocompatibility antigens (HLA-DM, -DO, -DP, -DQ, -DR)
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      and overexpression of class I molecules (HLA-B, -C, -G).
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      VUE is characterized by the proliferation of Hofbauer cells within the villi (demonstrated by nuclear immunoreactivity for Ki-67, a protein associated with cell proliferation). In summary, the gene expression profile of VUE resembles that observed in transplant rejection and graft-vs-host disease.
      • Akalin E.
      • Hendrix R.C.
      • Polavarapu R.G.
      • et al.
      Gene expression analysis in human renal allograft biopsy samples using high-density oligoarray technology.
      • Gimino V.J.
      • Lande J.D.
      • Berryman T.R.
      • King R.A.
      • Hertz M.I.
      Gene expression profiling of bronchoalveolar lavage cells in acute lung rejection.
      • Ichiba T.
      • Teshima T.
      • Kuick R.
      • et al.
      Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays.
      • Flechner S.M.
      • Kurian S.M.
      • Head S.R.
      • et al.
      Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes.
      • Sugerman P.B.
      • Faber S.B.
      • Willis L.M.
      • et al.
      Kinetics of gene expression in murine cutaneous graft-versus-host disease.
      • Deng M.C.
      • Eisen H.J.
      • Mehra M.R.
      • et al.
      Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling.
      The immunologic changes in VUE are not restricted to the villi, since maternal and fetal plasma concentrations of CXCL9, -10, and -11 are also significantly higher in cases with VUE than in control subjects.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      Moreover, VUE is histologic evidence of maternal cell trafficking into the fetus, which could lead to the development and establishment of fetal-maternal microchimerism.
      • Jeanty C.
      • Derderian S.C.
      • Mackenzie T.C.
      Maternal-fetal cellular trafficking: clinical implications and consequences.
      It remains to be determined whether maternal T cells are grafted into the visceral organs of the fetus. The precise nature of the fetal antigens that induce the maternal immune response has not been established. However, we have evidence that maternal sensitization to fetal-specific HLA antigens occurs in patients with VUE.
      Placentation provides a unique anatomic context for allograft rejection. The fetus (the placental villi are of fetal origin) differs from typical allografts, such as the kidney and the liver, in that it is a distinct immunologically competent host (Figure 5).
      Figure thumbnail gr5
      Figure 5The unique immunologic nature of villitis of unknown etiology
      A and B, Circulating maternal T cells entering the intervillous space can infiltrate the villus. C, After maternal T-cell infiltration, Hofbauer cells (fetal placental macrophages) are activated. This would be considered semiallograft rejection because maternal T cells (recipient of the semiallograft) infiltrate the placenta (semiallograft).
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Clinical significance

      VUE generally is considered to be a lesion of term pregnancies and is often subclinical in nature (normal pregnancy outcome).
      • Romero R.
      • Korzeniewski S.J.
      • Chaiwaropongsa T.
      • et al.
      Histologic features of placentas delivered by low-risk women with singleton term gestations.
      However, extensive involvement of the placenta by VUE has been associated with preterm and term fetal growth restriction,
      • Altshuler G.
      • Russell P.
      The human placental villitides: a review of chronic intrauterine infection.
      • Becroft D.M.
      • Thompson J.M.
      • Mitchell E.A.
      Placental villitis of unknown origin: epidemiologic associations.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Redline R.W.
      • Abramowsky C.R.
      Clinical and pathologic aspects of recurrent placental villitis.
      • Russell P.
      Inflammatory lesions of the human placenta; III, The histopathology of villitis of unknown aetiology.
      • Labarrere C.
      • Althabe O.
      • Telenta M.
      Chronic villitis of unknown aetiology in placentae of idiopathic small for gestational age infants.
      • Labarrere C.
      • Althabe O.
      Chronic villitis of unknown etiology and maternal arterial lesions in preeclamptic pregnancies.
      • Althabe O.
      • Labarrere C.
      Chronic villitis of unknown aetiology and intrauterine growth-retarded infants of normal and low ponderal index.
      • Salafia C.M.
      • Vintzileos A.M.
      • Silberman L.
      • Bantham K.F.
      • Vogel C.A.
      Placental pathology of idiopathic intrauterine growth retardation at term.
      • Redline R.W.
      • Patterson P.
      Patterns of placental injury: correlations with gestational age, placental weight, and clinical diagnoses.
      • Salafia C.M.
      • Minior V.K.
      • Pezzullo J.C.
      • Popek E.J.
      • Rosenkrantz T.S.
      • Vintzileos A.M.
      Intrauterine growth restriction in infants of less than thirty-two weeks’ gestation: associated placental pathologic features.
      • Derricott H.
      • Jones R.L.
      • Heazell A.E.
      Investigating the association of villitis of unknown etiology with stillbirth and fetal growth restriction: a systematic review.
      spontaneous preterm delivery,
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Redline R.W.
      • Patterson P.
      Patterns of placental injury: correlations with gestational age, placental weight, and clinical diagnoses.
      • Salafia C.M.
      • Vogel C.A.
      • Vintzileos A.M.
      • Bantham K.F.
      • Pezzullo J.
      • Silberman L.
      Placental pathologic findings in preterm birth.
      small-for-gestational-age fetuses associated with preeclampsia
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Labarrere C.
      • Althabe O.
      Chronic villitis of unknown etiology and maternal arterial lesions in preeclamptic pregnancies.
      • Veerbeek J.H.
      • Nikkels P.G.
      • Torrance H.L.
      • et al.
      Placental pathology in early intrauterine growth restriction associated with maternal hypertension.
      • Benzon S.
      • Zekic Tomas S.
      • Benzon Z.
      • Vulic M.
      • Kuzmic Prusac I.
      Involvement of T lymphocytes in the placentae with villitis of unknown etiology from pregnancies complicated with preeclampsia.
      and fetal death.
      • Becroft D.M.
      • Thompson J.M.
      • Mitchell E.A.
      Placental villitis of unknown origin: epidemiologic associations.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Knox W.F.
      • Fox H.
      Villitis of unknown aetiology: its incidence and significance in placentae from a British population.
      • Russell P.
      Inflammatory lesions of the human placenta; III, The histopathology of villitis of unknown aetiology.
      • Redline R.W.
      • Zaragoza M.
      • Hassold T.
      Prevalence of developmental and inflammatory lesions in nonmolar first-trimester spontaneous abortions.
      The frequency of VUE in the “great obstetrical syndromes”
      • Romero R.
      Prenatal medicine: the child is the father of the man, 1996.
      • Di Renzo G.C.
      The great obstetrical syndromes.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
      is displayed in Figure 6. This lesion is also associated with the occurrence of chronic chorioamnionitis (Figure 6, B).
      Figure thumbnail gr6
      Figure 6Villitis of unknown etiology in the great obstetrical syndromes and its relationship with chronic chorioamnionitis
      Modified from Kim CJ, Romero R, Kusanovic JP, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Mod Pathol 2010;23:1000-11.
      A, The frequency of villitis of unknown etiology in women who delivered at term not in labor or who had preterm labor with intact membranes, preterm prelabor rupture of the membranes, preeclampsia at term, preterm preeclampsia, and small-for-gestational-age fetuses; B, The frequency of villitis of unknown etiology is higher in the placenta of patients who had preterm labor with intact membranes and in patients with preterm prelabor rupture of the membranes who had chronic chorioamnionitis than in those who did not.
      PROM, prelabor rupture of the membranes; VUE, villitis of unknown etiology.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.
      In a cohort study of 180 neonates with a birthweight of <10th percentile who were delivered at <34 weeks of gestation with abnormal umbilical artery Doppler velocimetry, the presence of villitis was an independent risk factor for infant death (odds ratio, 5.7; 95% confidence interval, 1.16–28.1), and VUE was a predictor of necrotizing enterocolitis. Moreover, infants from pregnancies with placental villitis were at risk for abnormal developmental outcome at 2 years of age (odds ratio, 3.19; 95% confidence interval, 1.26–8.09).
      • Torrance H.L.
      • Bloemen M.C.
      • Mulder E.J.
      • et al.
      Predictors of outcome at 2 years of age after early intrauterine growth restriction.
      The mechanisms whereby VUE may lead to small-for-gestational-age fetuses with an abnormal Doppler velocimetry of the umbilical artery are unknown. Becroft et al
      • Becroft D.M.
      • Thompson J.M.
      • Mitchell E.A.
      Placental villitis of unknown origin: epidemiologic associations.
      argued that the extent of the placental parenchymal damage by VUE is not sufficient to restrict fetal growth, because only 0.01-5% of the villous tree is affected. We propose that the most likely mechanism whereby VUE compromises fetal growth is a systemic fetal inflammatory response (a fetal inflammatory response syndrome, type 2).
      Diffuse chronic villitis has been associated with neurologic impairment in other studies.
      • Redline R.W.
      Severe fetal placental vascular lesions in term infants with neurologic impairment.
      • Scher M.S.
      • Trucco G.S.
      • Beggarly M.E.
      • Steppe D.A.
      • Macpherson T.A.
      Neonates with electrically confirmed seizures and possible placental associations.
      VUE is more frequent in the placenta of the smaller twin compared to the larger twin in dichorionic pregnancies.
      • Eberle A.M.
      • Levesque D.
      • Vintzileos A.M.
      • Egan J.F.
      • Tsapanos V.
      • Salafia C.M.
      Placental pathology in discordant twins.
      • Jacques S.M.
      • Qureshi F.
      Chronic villitis of unknown etiology in twin gestations.
      Interestingly, the incidence of VUE is higher in placentas from patients who had ovum donation.
      • Styer A.K.
      • Parker H.J.
      • Roberts D.J.
      • Palmer-Toy D.
      • Toth T.L.
      • Ecker J.L.
      Placental villitis of unclear etiology during ovum donor in vitro fertilization pregnancy.
      • Perni S.C.
      • Predanic M.
      • Cho J.E.
      • Baergen R.N.
      Placental pathology and pregnancy outcomes in donor and non-donor oocyte in vitro fertilization pregnancies.
      • Gundogan F.
      • Bianchi D.W.
      • Scherjon S.A.
      • Roberts D.J.
      Placental pathology in egg donor pregnancies.
      Pregnancy in cases of ovum donation represents a total allograft rather than a semiallograft. These results strengthen the case for an immunologic origin of VUE.

      Chronic chorioamnionitis

      Definition and cellular composition

      Chronic chorioamnionitis is defined by the infiltration of mononuclear cells into the chorioamniotic membranes or the chorionic plate. The typical lesion shows patchy or diffuse infiltration of maternal CD8+ T cells (Figure 7). The extent and severity of T-cell infiltration is less than the neutrophilic infiltration in cases of acute chorioamnionitis.
      • Gersell D.J.
      • Phillips N.J.
      • Beckerman K.
      Chronic chorioamnionitis: a clinicopathologic study of 17 cases.
      • Gersell D.J.
      Chronic villitis, chronic chorioamnionitis, and maternal floor infarction.
      • Jacques S.M.
      • Qureshi F.
      Chronic chorioamnionitis: a clinicopathologic and immunohistochemical study.
      The primary locus of interaction is between maternal CD8+ T cells and the fetal cells at the choriodecidual border in the chorion laeve.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      Trophoblast damage by CD8+ T cells in the form of apoptosis can be demonstrated with the use of double immunofluorescence staining with antibodies against CD8 and M30 (an epitope associated with cleavage of cytokeratin 18 during apoptosis).
      • Krol J.
      • Mengele K.
      • Ottl-Mantchenko I.
      • et al.
      Ex vivo detection of apoptotic trophoblast cells applying flow cytofluorometry and immunocytochemistry using M30 antibody directed to the cytokeratin 18 neo-epitope.
       Figure 8 shows direct contact between CD8+ T cells and trophoblasts that express M30. Trophoblast apoptosis often leads to thinning of the chorionic trophoblast layer with a “moth-eaten” appearance of the choriodecidual border.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      Figure thumbnail gr7
      Figure 7The mechanisms and progression of chronic chorioamnionitis
      A, Increased concentration of the intraamniotic T-cell chemokine CXCL10 (and increased expression of CXCL9, -10, and -11 in the chorioamniotic membranes) induces migration of CXCR3+ T cells from the decidua (maternal tissue) into the chorioamniotic membranes (fetal tissue). B, T cells (a blue nucleus, originally located in the decidua; left side of the figure) migrate into the chorioamniotic membranes (amniotropism; right side). The term amniotropic implies that the T cells are migrating toward the amnion.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.
      Figure thumbnail gr8
      Figure 8Chorionic trophoblast apoptosis by cytotoxic T cells
      A, Confocal microscopic image with immunofluorescence of the chorioamniotic membranes in a case with chronic chorioamnionitis. Nuclei of all cells are stained blue. Green shows staining with an antibody against CD8. These cells are CD8+ cytotoxic T cells of maternal origin infiltrating the chorion (fetal). M30, an antibody against an epitope of cytokeratin 18 produced during apoptosis, detects the positive trophoblast that has undergone apoptosis. Apoptotic cells are depicted in red. Direct contact between cytotoxic CD8+ T cells (green) and the apoptotic trophoblast (red) is indicated with white arrows, and represents the cytotoxic effect of maternal CD8+ T cells in the induction of apoptosis of fetal cells. B, Light microscopic image shows chorionic trophoblast apoptosis with increased cytoplasmic eosinophilia and pyknotic nuclei (arrows). Loss of trophoblasts results in a shaggy and irregular choriodecidual border (moth-eaten appearance). Hematoxylin and eosin stain; original magnification (A and B), 200×.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Grading

      We proposed a grading system to assess the severity of chronic chorioamnionitis.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      Grade 0 indicates the absence of inflammation; grade 1 indicates that there are >2 foci of inflammation or patchy inflammation; and grade 2 indicates that diffuse inflammation is present. The stage of inflammation was scored as 1 if amniotropic lymphocytic infiltration was limited to the chorionic trophoblast layer sparing the chorioamniotic connective tissue, and as stage 2 if lymphocytic infiltration into the chorioamniotic connective tissue was noted (Figure 9). Importantly, cases with mild inflammatory lesions have significantly higher amniotic fluid CXCL10 concentrations than those without these lesions. The substantial increase in the amniotic fluid CXCL10 concentration in cases with low-grade, low-stage inflammation underscores that the lesion can be associated with a unique form of intraamniotic inflammation, which is characterized by an increase in T-cell chemokines, but not necessarily amniotic fluid interleukin (IL)-6, a marker of acute inflammation.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      Figure thumbnail gr9
      Figure 9Microscopic staging of chronic chorioamnionitis
      A, Normal chorioamniotic membranes with amnion, chorion, and decidua. B, Stage 1 chronic chorioamnionitis shows T-cell infiltration confined to the chorionic trophoblast layer. The choriodecidual border is studded with lymphocytes; the chorioamniotic connective tissue is spared. The arrows indicate infiltration of T cells along the choriodecidual border. C, In stage 2 chronic chorioamnionitis, lymphocytic infiltration into the chorioamniotic connective tissue is clearly seen. The arrows indicate infiltration of T cells into the amniotic connective tissue below the epithelium of the amnion at the top of the picture. Original magnification (A-C), 200×.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Pathogenesis

      The choriodecidual junction is a large interface between the mother and fetus (Figure 1); maternal immune cells in the decidua can recognize fetal cells, specifically chorionic trophoblasts (ie, chorion laeve). Under normal circumstances, an inflammatory response in the choriodecidual junction does not occur. The mechanisms responsible for the tolerogenic state in pregnancy include (1) expression of nonpolymorphic HLA-G by trophoblasts
      • Kovats S.
      • Main E.K.
      • Librach C.
      • Stubblebine M.
      • Fisher S.J.
      • Demars R.
      A class I antigen, HLA-G, expressed in human trophoblasts.
      • Mcmaster M.T.
      • Librach C.L.
      • Zhou Y.
      • et al.
      Human placental HLA-G expression is restricted to differentiated cytotrophoblasts.
      • Ishitani A.
      • Sageshima N.
      • Lee N.
      • et al.
      Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition.
      • Hunt J.S.
      • Petroff M.G.
      • Mcintire R.H.
      • Ober C.
      HLA-G and immune tolerance in pregnancy.
      and (2) T-cell chemokine gene silencing in the decidual cells, as shown by Nancy et al.
      • Nancy P.
      • Tagliani E.
      • Tay C.S.
      • Asp P.
      • Levy D.E.
      • Erlebacher A.
      Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface.
      Other mechanisms have been implicated, such as a role for regulatory T cells,
      • Aluvihare V.R.
      • Kallikourdis M.
      • Betz A.G.
      Regulatory T cells mediate maternal tolerance to the fetus.
      • Somerset D.A.
      • Zheng Y.
      • Kilby M.D.
      • Sansom D.M.
      • Drayson M.T.
      Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.
      • Zenclussen A.C.
      • Gerlof K.
      • Zenclussen M.L.
      • et al.
      Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model.
      • Sasaki Y.
      • Sakai M.
      • Miyazaki S.
      • Higuma S.
      • Shiozaki A.
      • Saito S.
      Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases.
      tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO),
      • Munn D.H.
      • Zhou M.
      • Attwood J.T.
      • et al.
      Prevention of allogeneic fetal rejection by tryptophan catabolism.
      T-cell apoptosis,
      • Hunt J.S.
      • Vassmer D.
      • Ferguson T.A.
      • Miller L.
      Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus.
      complement,
      • Holmes C.H.
      • Simpson K.L.
      • Wainwright S.D.
      • et al.
      Preferential expression of the complement regulatory protein decay accelerating factor at the fetomaternal interface during human pregnancy.
      • Hsi B.L.
      • Hunt J.S.
      • Atkinson J.P.
      Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells.
      and costimulatory molecules such as the programmed death ligand 1.
      • Guleria I.
      • Khosroshahi A.
      • Ansari M.J.
      • et al.
      A critical role for the programmed death ligand 1 in fetomaternal tolerance.
      The mechanisms that are implicated in fetomaternal tolerance are shown in the Table. A full discussion of this subject is outside the scope of this review.
      TableProposed mechanisms implicated in the tolerogenic state of pregnancy
      Expression of nonclassic major histocompatibility complex molecules by trophoblasts
      • Kovats S.
      • Main E.K.
      • Librach C.
      • Stubblebine M.
      • Fisher S.J.
      • Demars R.
      A class I antigen, HLA-G, expressed in human trophoblasts.
      • Mcmaster M.T.
      • Librach C.L.
      • Zhou Y.
      • et al.
      Human placental HLA-G expression is restricted to differentiated cytotrophoblasts.
      • Ishitani A.
      • Sageshima N.
      • Lee N.
      • et al.
      Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition.
      • Hunt J.S.
      • Petroff M.G.
      • Mcintire R.H.
      • Ober C.
      HLA-G and immune tolerance in pregnancy.
      • Larsen M.H.
      • Hviid T.V.
      Human leukocyte antigen-G polymorphism in relation to expression, function, and disease.
      Chemokine gene silencing by methylation in decidual stromal cells limits T-cell access to the placenta
      • Nancy P.
      • Tagliani E.
      • Tay C.S.
      • Asp P.
      • Levy D.E.
      • Erlebacher A.
      Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface.
      Regulatory T cells
      • Aluvihare V.R.
      • Kallikourdis M.
      • Betz A.G.
      Regulatory T cells mediate maternal tolerance to the fetus.
      • Somerset D.A.
      • Zheng Y.
      • Kilby M.D.
      • Sansom D.M.
      • Drayson M.T.
      Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.
      • Zenclussen A.C.
      • Gerlof K.
      • Zenclussen M.L.
      • et al.
      Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model.
      • Sasaki Y.
      • Sakai M.
      • Miyazaki S.
      • Higuma S.
      • Shiozaki A.
      • Saito S.
      Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases.
      Maternal T-cell apoptosis
      • Hunt J.S.
      • Vassmer D.
      • Ferguson T.A.
      • Miller L.
      Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus.
      • Uckan D.
      • Steele A.
      • Cherry
      • et al.
      Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion.
      Increased tryptophan catabolism by the enzyme indoleamine 2,3-dioxygenase
      • Munn D.H.
      • Zhou M.
      • Attwood J.T.
      • et al.
      Prevention of allogeneic fetal rejection by tryptophan catabolism.
      • Kudo Y.
      • Boyd C.A.
      Human placental indoleamine 2,3-dioxygenase: cellular localization and characterization of an enzyme preventing fetal rejection.
      • Mellor A.L.
      • Sivakumar J.
      • Chandler P.
      • et al.
      Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy.
      • Mellor A.L.
      • Chandler P.
      • Lee G.K.
      • et al.
      Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy.
      • Kudo Y.
      The role of placental indoleamine 2,3-dioxygenase in human pregnancy.
      Increased expression of programmed death ligand 1
      • Guleria I.
      • Khosroshahi A.
      • Ansari M.J.
      • et al.
      A critical role for the programmed death ligand 1 in fetomaternal tolerance.
      • Habicht A.
      • Dada S.
      • Jurewicz M.
      • et al.
      A link between PDL1 and T regulatory cells in fetomaternal tolerance.
      • D’addio F.
      • Riella L.V.
      • Mfarrej B.G.
      • et al.
      The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance.
      Expression of high levels of complement regulatory proteins (decay accelerating factor, membrane co-factor protein, CD59)
      • Holmes C.H.
      • Simpson K.L.
      • Wainwright S.D.
      • et al.
      Preferential expression of the complement regulatory protein decay accelerating factor at the fetomaternal interface during human pregnancy.
      • Hsi B.L.
      • Hunt J.S.
      • Atkinson J.P.
      Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells.
      • Holmes C.H.
      • Simpson K.L.
      • Okada H.
      • et al.
      Complement regulatory proteins at the feto-maternal interface during human placental development: distribution of CD59 by comparison with membrane cofactor protein (CD46) and decay accelerating factor (CD55).
      • Tedesco F.
      • Narchi G.
      • Radillo O.
      • Meri S.
      • Ferrone S.
      • Betterle C.
      Susceptibility of human trophoblast to killing by human complement and the role of the complement regulatory proteins.
      • Xu C.
      • Mao D.
      • Holers V.M.
      • Palanca B.
      • Cheng A.M.
      • Molina H.
      A critical role for murine complement regulator crry in fetomaternal tolerance.
      • Girardi G.
      • Bulla R.
      • Salmon J.E.
      • Tedesco F.
      The complement system in the pathophysiology of pregnancy.
      • Girardi G.
      Complement inhibition keeps mothers calm and avoids fetal rejection.
      Progesterone
      • Stites D.P.
      • Bugbee S.
      • Siiteri P.K.
      Differential actions of progesterone and cortisol on lymphocyte and monocyte interaction during lymphocyte activation: relevance to immunosuppression in pregnancy.
      • Siiteri P.K.
      • Febres F.
      • Clemens L.E.
      • Chang R.J.
      • Gondos B.
      • Stites D.
      Progesterone and maintenance of pregnancy: is progesterone nature’s immunosuppressant?.
      • Szekeres-Bartho J.
      • Wegmann T.G.
      A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance.
      • Mao G.
      • Wang J.
      • Kang Y.
      • et al.
      Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice.
      • Lee J.H.
      • Ulrich B.
      • Cho J.
      • Park J.
      • Kim C.H.
      Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells.
      Activation of placental exosomes
      • Mincheva-Nilsson L.
      • Nagaeva O.
      • Chen T.
      • et al.
      Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival.
      • Mincheva-Nilsson L.
      • Baranov V.
      The role of placental exosomes in reproduction.
      and placental endogenous retroviral envelope proteins
      • Mangeney M.
      • Renard M.
      • Schlecht-Louf G.
      • et al.
      Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins.
      • Tolosa J.M.
      • Schjenken J.E.
      • Clifton V.L.
      • et al.
      The endogenous retroviral envelope protein syncytin-1 inhibits LPS/PHA-stimulated cytokine responses in human blood and is sorted into placental exosomes.
      that have the following properties
       Shift of the immune response from Th1/Th17 toward a Th2/Treg cell response
      • Sabapatha A.
      • Gercel-Taylor C.
      • Taylor D.D.
      Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences.
      • Taylor D.D.
      • Akyol S.
      • Gercel-Taylor C.
      Pregnancy-associated exosomes and their modulation of T cell signaling.
       Inhibit natural cell killer cytotoxicity against trophoblast
      • Mincheva-Nilsson L.
      • Nagaeva O.
      • Chen T.
      • et al.
      Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival.
      • Hedlund M.
      • Stenqvist A.C.
      • Nagaeva O.
      • et al.
      Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function.
       Immunosuppressive properties including Fas ligand,
      • Uckan D.
      • Steele A.
      • Cherry
      • et al.
      Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion.
      • Makrigiannakis A.
      • Zoumakis E.
      • Kalantaridou S.
      • et al.
      Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance.
      • Frangsmyr L.
      • Baranov V.
      • Nagaeva O.
      • Stendahl U.
      • Kjellberg L.
      • Mincheva-Nilsson L.
      Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level.
      • Stenqvist A.C.
      • Nagaeva O.
      • Baranov V.
      • Mincheva-Nilsson L.
      Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus.
      programmed death ligand 1, major histocompatibility complex molecules, etc.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.
      Chronic chorioamnionitis was first described by Gersell et al
      • Gersell D.J.
      • Phillips N.J.
      • Beckerman K.
      Chronic chorioamnionitis: a clinicopathologic study of 17 cases.
      in a case series of 17 placentas in which the inflammatory infiltrate in the chorioamniotic membranes consisted predominantly of lymphocytes. Importantly, an extensive study of amniotic fluid and placental microbiology, as well as immunohistochemical staining and maternal serology, did not show evidence of infection with either bacteria or viruses.
      • Gersell D.J.
      • Phillips N.J.
      • Beckerman K.
      Chronic chorioamnionitis: a clinicopathologic study of 17 cases.
      Patients had no clinical evidence of infection, such as fever, flu-like symptoms, or a rash; however, preterm birth occurred in 76% of patients (13/17). Before this seminal observation, few reports had documented a chronic inflammatory infiltration of the fetal membranes in patients with maternal rubella infection
      • Garcia A.G.
      • Marques R.L.
      • Lobato Y.Y.
      • Fonseca M.E.
      • Wigg M.D.
      Placental pathology in congenital rubella.
      and toxoplasmosis.
      • Garcia A.G.
      Congenital toxoplasmosis in two successive sibs.
      Subsequently, Qureshi and Jacques
      • Jacques S.M.
      • Qureshi F.
      Chronic chorioamnionitis: a clinicopathologic and immunohistochemical study.
      reported 31 cases of chronic chorioamnionitis and emphasized that 71% of the cases (22/31) had VUE, which suggests a common immunologic cause for the two lesions. Immunohistochemistry showed that the predominant cells were CD8+ T lymphocytes, that 39% of the cases (12/31) were associated with preterm birth, and that 16% of the cases (5/31) were small for gestational age.
      • Jacques S.M.
      • Qureshi F.
      Chronic chorioamnionitis: a clinicopathologic and immunohistochemical study.
      The chemotactic gradient that favors migration of T cells from the decidua into the chorioamniotic membranes has been proposed to be increased concentrations of the chemokine CXCL10 in amniotic fluid and overexpression of CXCL9, CXCL10, and CXCL11 in the chorioamniotic membranes.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      Therefore, the gradient of T-cell chemokine concentrations leads to CXCR3+ T-cell chemotaxis into the chorioamniotic membranes and the chorionic plate. This is analogous to the situation of acute chorioamnionitis in that elevated amniotic fluid neutrophil chemokines (such as IL-8),
      • Romero R.
      • Ceska M.
      • Avila C.
      • Mazor M.
      • Behnke E.
      • Lindley I.
      Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition.
      • Cherouny P.H.
      • Pankuch G.A.
      • Romero R.
      • et al.
      Neutrophil attractant/activating peptide-1/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants.
      • Puchner T.
      • Egarter C.
      • Wimmer C.
      • Lederhilger F.
      • Weichselbraun I.
      Amniotic fluid interleukin-8 as a marker for intraamniotic infection.
      • Gomez R.
      • Ghezzi F.
      • Romero R.
      • Munoz H.
      • Tolosa J.E.
      • Rojas I.
      Premature labor and intra-amniotic infection: clinical aspects and role of the cytokines in diagnosis and pathophysiology.
      • Yoon B.H.
      • Romero R.
      • Jun J.K.
      • et al.
      Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia.
      • Ghezzi F.
      • Gomez R.
      • Romero R.
      • et al.
      Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia.
      • Hsu C.D.
      • Meaddough E.
      • Aversa K.
      • et al.
      Elevated amniotic fluid levels of leukemia inhibitory factor, interleukin 6, and interleukin 8 in intra-amniotic infection.
      • Hsu C.D.
      • Meaddough E.
      • Aversa K.
      • Copel J.A.
      The role of amniotic fluid L-selectin, GRO-alpha, and interleukin-8 in the pathogenesis of intraamniotic infection.
      • Figueroa R.
      • Garry D.
      • Elimian A.
      • Patel K.
      • Sehgal P.B.
      • Tejani N.
      Evaluation of amniotic fluid cytokines in preterm labor and intact membranes.
      • Yoneda S.
      • Shiozaki A.
      • Ito M.
      • et al.
      Accurate prediction of the stage of histological chorioamnionitis before delivery by amniotic fluid IL-8 level.
      promote chemotaxis of neutrophils. Chronic chorioamnionitis is also characterized by distinct changes in the amniotic fluid proteome compared to acute chorioamnionitis.
      • Ogge G.
      • Romero R.
      • Lee D.C.
      • et al.
      Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome.
      Among patients with preterm labor, 31 differentially expressed proteins have been identified in chronic chorioamnionitis compared to cases with either acute chorioamnionitis or controls without inflammatory lesions. Of interest is that the amniotic fluid concentration of glycodelin-A is decreased in chronic chorioamnionitis.
      • Ogge G.
      • Romero R.
      • Lee D.C.
      • et al.
      Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome.
      This molecule has been implicated in the maintenance of maternal tolerance against the semiallogeneic placenta/fetus.
      • Alok A.
      • Mukhopadhyay D.
      • Karande A.A.
      Glycodelin A, an immunomodulatory protein in the endometrium, inhibits proliferation and induces apoptosis in monocytic cells.

      Clinical significance

      The prevalence of chronic chorioamnionitis in the “great obstetrical syndromes”
      • Romero R.
      Prenatal medicine: the child is the father of the man, 1996.
      • Di Renzo G.C.
      The great obstetrical syndromes.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
      is displayed in Figure 10. The frequency in patients with spontaneous preterm labor and delivery is 34% and in patients with preterm prelabor rupture of the membranes is 39%.
      • Kim C.J.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth.
      In a separate study of consecutive cases of 1206 preterm deliveries, chronic chorioamnionitis was the most common lesion (20.8%) and was particularly common among late preterm births, which represent 70% of all preterm deliveries.
      • Lee J.
      • Kim J.S.
      • Park J.W.
      • et al.
      Chronic chorioamnionitis is the most common placental lesion in late preterm birth.
      Importantly, we found that 60% of cases of fetal death had evidence of chronic chorioamnionitis and high amniotic fluid concentrations of CXCL10, which suggests that some cases of unexplained fetal death may represent an extreme form of maternal anti-fetal rejection.
      • Lee J.
      • Romero R.
      • Dong Z.
      • et al.
      Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies.
      • Lannaman K.
      • Romero R.
      • Chaemsaithong P.
      • et al.
      Fetal death: an extreme form of maternal anti-fetal rejection (Abstract 497).
      Figure thumbnail gr10
      Figure 10The frequency of chronic chorioamnionitis in the “Great Obstetrical Syndromes”
      Modified from Kim CJ, Romero R, Kusanovic JP, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Mod Pathol 2010;23:1000-11. and Lee J, Romero R, Dong Z, et al. Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies. Histopathology 2011;59:928-38.
      The frequency is notably higher in fetal death, preterm prelabor rupture of the membranes, and preterm labor/delivery.
      PROM, prelabor rupture of the membranes.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.

      Chronic deciduitis

      Chronic deciduitis is diagnosed by the presence of lymphocytes and plasma cells in the basal plate of the placenta (Figures 1 and 11).
      • Khong T.Y.
      • Bendon R.W.
      • Qureshi F.
      • et al.
      Chronic deciduitis in the placental basal plate: definition and interobserver reliability.
      • Kraus F.T.
      • Redline R.W.
      • Gersell D.J.
      • Nelson D.M.
      • Dicke J.M.
      Inflammation and infection. Placental Pathology: Atlas of Nontumor Pathology (First Series, Fascicle 3).
      Chronic microbial infection or immune mechanisms have been implicated in the etiology of chronic deciduitis. Originally recognized by Naeye
      • Naeye R.L.
      Functionally important disorders of the placenta, umbilical cord, and fetal membranes.
      when reviewing the placentas from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke (a study of nearly 40,000 pregnancies in which clinical outcomes and placentas were collected prospectively), chronic deciduitis was thought to be present in 1-2% of all pregnancies and to be associated with fetal growth restriction and fetal death. However, the original description involved infiltration of chronic inflammatory cells in both the decidua basalis and capsularis; therefore, chronic chorioamnionitis as well as chronic deciduitis of the basal plate may have been included in Naeye’s original report.
      • Naeye R.L.
      Functionally important disorders of the placenta, umbilical cord, and fetal membranes.
      Figure thumbnail gr11
      Figure 11Chronic deciduitis
      A, Normal basal plate along with an anchoring villus (asterisk). This image has cross-sections of villi and the intervillous space. The basal plate of the placenta is the horizontal tissue at the bottom of the picture. B, Dense infiltration of the basal plate of the placenta and anchoring villi with mononuclear and plasma cells. Basal villitis (asterisk) is present. C, Immunostaining confirms the presence of CD138+ positive plasma cells (brown color) in the basal plate. Original magnification (A-C), 200×.
      Kim. Chronic inflammatory lesions of the placenta. Am J Obstet Gynecol 2015.
      Bendon and Miller
      • Bendon R.W.
      • Miller M.
      Routine pathological examination of placentae from abnormal pregnancies.
      focused attention on a lesion in the basal plate of the placenta whose prominent feature was the infiltration of plasma cells. The frequency of the lesion was 4% (25/600) in placentas examined because of complications of pregnancy requiring admission to a neonatal intensive care unit. Bendon and Miller emphasized that plasma cells were normally not seen in the decidua parietalis of the same placentas and proposed an immune origin for the lesion based on the proximity of the plasma cells to trophoblast cells.
      • Bendon R.W.
      • Miller M.
      Routine pathological examination of placentae from abnormal pregnancies.
      Adverse pregnancy outcome was common among these 25 cases: there were 5 infants with intrauterine growth restriction, 5 fetal deaths, and 3 mothers with systemic lupus erythematosus. Of interest is that recurrent lesions were observed in 3 patients.
      • Bendon R.W.
      • Miller M.
      Routine pathological examination of placentae from abnormal pregnancies.
      The precise definition of chronic deciduitis in the basal plate was established by an international collaborative effort reported by Khong et al,
      • Khong T.Y.
      • Bendon R.W.
      • Qureshi F.
      • et al.
      Chronic deciduitis in the placental basal plate: definition and interobserver reliability.
      in which 30 slides of placental sections were distributed to 6 experienced perinatal/placental pathologists to determine the degree of concordance in the identification of chronic deciduitis. Pathologists scored the presence or absence of a lesion, its extent (focal, multifocal, or diffuse), severity (mild, moderate, or severe), and the presence or absence of plasma cells; however, no prespecified definitions were provided to the pathologists, and the first round of examinations was used to generate diagnostic criteria for defining the lesion.
      • Khong T.Y.
      • Bendon R.W.
      • Qureshi F.
      • et al.
      Chronic deciduitis in the placental basal plate: definition and interobserver reliability.
      The study concluded that the diagnosis should be made on the presence of severe and extensive lymphocyte infiltration and the presence of plasma cells.
      • Khong T.Y.
      • Bendon R.W.
      • Qureshi F.
      • et al.
      Chronic deciduitis in the placental basal plate: definition and interobserver reliability.
      Recently, the scoring system for chronic deciduitis has been proposed.
      • Maroun L.L.
      • Mathiesen L.
      • Hedegaard M.
      • Knudsen L.E.
      • Larsen L.G.
      Pathologic evaluation of normal and perfused term placental tissue.
      The criterion for the diagnosis of chronic deciduitis is the presence of ≥50 lymphocytes/per high-power field (grade 1). Grade 2 and grade 3 chronic deciduitis are characterized by the presence of lymphocytes in multiple and diffuse foci on at least 1 slide, respectively.
      • Maroun L.L.
      • Mathiesen L.
      • Hedegaard M.
      • Knudsen L.E.
      • Larsen L.G.
      Pathologic evaluation of normal and perfused term placental tissue.
      This classification correlates well with that of Khong et al.
      • Khong T.Y.
      • Bendon R.W.
      • Qureshi F.
      • et al.
      Chronic deciduitis in the placental basal plate: definition and interobserver reliability.
      The association between chronic deciduitis and preterm labor without clinical chorioamnionitis was first reported by Edmondson et al
      • Edmondson N.
      • Bocking A.
      • Machin G.
      • Rizek R.
      • Watson C.
      • Keating S.
      The prevalence of chronic deciduitis in cases of preterm labor without clinical chorioamnionitis.
      after examination of placentas from 39 patients with idiopathic preterm labor and 39 age-matched control placentas of singleton pregnancies (induced because of fetal congenital anomalies, excluding aneuploidy). The frequency of chronic deciduitis was significantly higher in patients with preterm labor than in a control group (41% vs 15%; P = .02).
      • Edmondson N.
      • Bocking A.
      • Machin G.
      • Rizek R.
      • Watson C.
      • Keating S.
      The prevalence of chronic deciduitis in cases of preterm labor without clinical chorioamnionitis.
      Evidence that chronic deciduitis may have an immune origin has been suggested because this lesion is associated with basal villitis and is frequent in the basal plate of the placenta of pregnancies that result from egg donation vs nondonor in vitro fertilization pregnancies. In one study, the frequency of chronic deciduitis was 42% in egg donation pregnancies (14/33) and 1.6% in the control pregnancies (1/60; P = .001).
      • Perni S.C.
      • Predanic M.
      • Cho J.E.
      • Baergen R.N.
      Placental pathology and pregnancy outcomes in donor and non-donor oocyte in vitro fertilization pregnancies.
      However, in a subsequent study, the frequency was 2.8% after oocyte donation vs 1.8% in non-oocyte donor in vitro fertilization (P = .03).
      • Gundogan F.
      • Bianchi D.W.
      • Scherjon S.A.
      • Roberts D.J.
      Placental pathology in egg donor pregnancies.

      Chronic placental inflammation as maternal anti-fetal rejection

      The placenta and fetus express both paternal and maternal antigens; they are semiallografts.
      • Erlebacher A.
      Mechanisms of T cell tolerance towards the allogeneic fetus.
      • Koch C.A.
      • Platt J.L.
      Natural mechanisms for evading graft rejection: the fetus as an allograft.
      • Chaouat G.
      • Petitbarat M.
      • Dubanchet S.
      • Rahmati M.
      • Ledee N.
      Tolerance to the foetal allograft?.
      The syncytiotrophoblast is in direct contact with maternal blood, and the chorion laeve with the decidua; thus, the maternal immune system is exposed to paternal antigens expressed by the fetus.
      • Moffett A.
      • Loke C.
      Immunology of placentation in eutherian mammals.
      • Erlebacher A.
      • Vencato D.
      • Price K.A.
      • Zhang D.
      • Glimcher L.H.
      Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus.
      Immune tolerance is a requirement for successful pregnancy.
      • Erlebacher A.
      Why isn’t the fetus rejected?.
      • Trowsdale J.
      • Betz A.G.
      Mother’s little helpers: mechanisms of maternal-fetal tolerance.
      • Rowe J.H.
      • Ertelt J.M.
      • Xin L.
      • Way S.S.
      Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.
      • Betz A.G.
      Immunology: tolerating pregnancy.
      • Aluvihare V.R.
      • Kallikourdis M.
      • Betz A.G.
      Regulatory T cells mediate maternal tolerance to the fetus.
      • Szekeres-Bartho J.
      Immunological relationship between the mother and the fetus.
      • Erlebacher A.
      Immunology of the maternal-fetal interface.
      Immune effector cells with fetal specificity are selectively “silenced” during pregnancy by complex mechanisms.
      • Rowe J.H.
      • Ertelt J.M.
      • Xin L.
      • Way S.S.
      Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.
      • Betz A.G.
      Immunology: tolerating pregnancy.
      A full discussion of the mechanisms responsible for tolerance during pregnancy is outside the scope of this article; however, the main mechanisms are listed in the Table.
      In solid organ transplantation, breakdown of tolerance leads to rejection of the graft and, ultimately, organ injury.
      • Le Moine A.
      • Goldman M.
      • Abramowicz D.
      Multiple pathways to allograft rejection.
      • Colvin R.B.
      • Smith R.N.
      Antibody-mediated organ-allograft rejection.
      • Alegre M.L.
      • Florquin S.
      • Goldman M.
      Cellular mechanisms underlying acute graft rejection: time for reassessment.
      • Kim I.K.
      • Bedi D.S.
      • Denecke C.
      • Ge X.
      • Tullius S.G.
      Impact of innate and adaptive immunity on rejection and tolerance.
      • Cornell L.D.
      • Smith R.N.
      • Colvin R.B.
      Kidney transplantation: mechanisms of rejection and acceptance.
      • Nankivell B.J.
      • Alexander S.I.
      Rejection of the kidney allograft.
      • Wood K.J.
      • Goto R.
      Mechanisms of rejection: current perspectives.
      • Ali J.M.
      • Bolton E.M.
      • Bradley J.A.
      • Pettigrew G.J.
      Allorecognition pathways in transplant rejection and tolerance.
      Allograft rejection results from cellular and/or humoral (antibody-mediated) immune response(s) by the recipient of a graft.
      • Le Moine A.
      • Goldman M.
      • Abramowicz D.
      Multiple pathways to allograft rejection.
      • Colvin R.B.
      • Smith R.N.
      Antibody-mediated organ-allograft rejection.
      • Alegre M.L.
      • Florquin S.
      • Goldman M.
      Cellular mechanisms underlying acute graft rejection: time for reassessment.
      • Kim I.K.
      • Bedi D.S.
      • Denecke C.
      • Ge X.
      • Tullius S.G.
      Impact of innate and adaptive immunity on rejection and tolerance.
      • Cornell L.D.
      • Smith R.N.
      • Colvin R.B.
      Kidney transplantation: mechanisms of rejection and acceptance.
      • Nankivell B.J.
      • Alexander S.I.
      Rejection of the kidney allograft.
      • Wood K.J.
      • Goto R.
      Mechanisms of rejection: current perspectives.
      • Ali J.M.
      • Bolton E.M.
      • Bradley J.A.
      • Pettigrew G.J.
      Allorecognition pathways in transplant rejection and tolerance.
      The major histocompatibility complex class I and II molecules include HLA; this system is implicated in the rejection of solid organs
      • Mckenna R.M.
      • Takemoto S.K.
      • Terasaki P.I.
      Anti-HLA antibodies after solid organ transplantation.
      • Ho E.K.
      • Vlad G.
      • Colovai A.I.
      • et al.
      Alloantibodies in heart transplantation.
      • Howell W.M.
      • Carter V.
      • Clark B.
      The HLA system: immunobiology, HLA typing, antibody screening and crossmatching techniques.
      • Ayala Garcia M.A.
      • Gonzalez Yebra B.
      • Lopez Flores A.L.
      • Guani Guerra E.
      The major histocompatibility complex in transplantation.
      • Mahdi B.M.
      A glow of HLA typing in organ transplantation.
      and bone marrow transplants.
      • Buckley R.H.
      Transplantation immunology: organ and bone marrow.
      We propose that disruption of the tolerogenic state of normal pregnancy leads to maternal anti-fetal rejection, placental damage, and complications of pregnancy (ie, fetal growth restriction and spontaneous preterm labor). The extreme form of graft failure in organ transplantation is extensive damage of the transplanted organ; the equivalent to this in pregnancy would be fetal death caused by maternal anti-fetal rejection.
      • Lee J.
      • Romero R.
      • Dong Z.
      • et al.
      Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies.
      • Lannaman K.
      • Romero R.
      • Chaemsaithong P.
      • et al.
      Fetal death: an extreme form of maternal anti-fetal rejection (Abstract 497).
      The two mechanisms of allograft rejection are cell- (T-cell) and antibody-mediated.
      • Le Moine A.
      • Goldman M.
      • Abramowicz D.
      Multiple pathways to allograft rejection.
      • Colvin R.B.
      • Smith R.N.
      Antibody-mediated organ-allograft rejection.
      • Alegre M.L.
      • Florquin S.
      • Goldman M.
      Cellular mechanisms underlying acute graft rejection: time for reassessment.
      • Kim I.K.
      • Bedi D.S.
      • Denecke C.
      • Ge X.
      • Tullius S.G.
      Impact of innate and adaptive immunity on rejection and tolerance.
      • Cornell L.D.
      • Smith R.N.
      • Colvin R.B.
      Kidney transplantation: mechanisms of rejection and acceptance.
      • Nankivell B.J.
      • Alexander S.I.
      Rejection of the kidney allograft.
      • Wood K.J.
      • Goto R.
      Mechanisms of rejection: current perspectives.
      • Ali J.M.
      • Bolton E.M.
      • Bradley J.A.
      • Pettigrew G.J.
      Allorecognition pathways in transplant rejection and tolerance.
      In the context of pregnancy, the histopathologic manifestations of cell-mediated rejection are VUE and chronic chorioamnionitis. In the former, the battleground for rejection is the chorionic villi, where maternal T-cells infiltrate the villous tree; in the latter, the battleground is the extraplacental choriodecidual interface, where maternal T-cells infiltrate the chorioamniotic membranes. A cell-mediated feature of maternal anti-fetal rejection can be detected in maternal systemic circulation in patients with chronic chorioamnionitis.
      • Xu Y.
      • Tarquini F.
      • Romero R.
      • et al.
      Peripheral CD300a+CD8+ T lymphocytes with a distinct cytotoxic molecular signature increase in pregnant women with chronic chorioamnionitis.
      The proportion of CD300a+ cytotoxic T lymphocytes is increased significantly in patients with chronic chorioamnionitis than in those without this lesion.
      • Xu Y.
      • Tarquini F.
      • Romero R.
      • et al.
      Peripheral CD300a+CD8+ T lymphocytes with a distinct cytotoxic molecular signature increase in pregnant women with chronic chorioamnionitis.
      Moreover, we have found an increased number of CD300a+CD8+ T cells, which overexpress messenger RNA of granzyme genes (GZMA, GZMB, and GZMK), granulysin, and perforin. This indicated that CD300a+CD8+ T lymphocytes have a more cytotoxic phenotype.
      • Xu Y.
      • Tarquini F.
      • Romero R.
      • et al.
      Peripheral CD300a+CD8+ T lymphocytes with a distinct cytotoxic molecular signature increase in pregnant women with chronic chorioamnionitis.
      Antibody-mediated rejection has been reported in both VUE
      • Rudzinski E.
      • Gilroy M.
      • Newbill C.
      • Morgan T.
      Positive C4d immunostaining of placental villous syncytiotrophoblasts supports host-versus-graft rejection in villitis of unknown etiology.
      • Ito Y.
      • Matsuoka K.
      • Uesato T.
      • et al.
      Increased expression of perforin, granzyme B, and C5b-9 in villitis of unknown etiology.
      and chronic chorioamnionitis.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Maternal HLA panel-reactive antibodies in early gestation positively correlate with chronic chorioamnionitis: evidence in support of the chronic nature of maternal anti-fetal rejection.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery.
      The effector mechanism for rejection in antibody-mediated allograft damage involves complement activation. Deposition of complement C4d in the umbilical vein endothelium in mothers with complications of pregnancy and detectable maternal anti-fetal antibodies has been demonstrated in patients with both chronic chorioamnionitis
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d.
      and VUE.
      • Lee K.A.
      • Kim Y.W.
      • Shim J.Y.
      • et al.
      Distinct patterns of C4d immunoreactivity in placentas with villitis of unknown etiology, cytomegaloviral placentitis, and infarct.
      • Rudzinski E.
      • Gilroy M.
      • Newbill C.
      • Morgan T.
      Positive C4d immunostaining of placental villous syncytiotrophoblasts supports host-versus-graft rejection in villitis of unknown etiology.
      The most frequent alloantigens involved in transplant rejection are encoded by the major histocompatibility complex genes or HLA in humans.
      • Li X.C.
      • Raghavan M.
      Structure and function of major histocompatibility complex class I antigens.
      • Petersdorf E.W.
      The major histocompatibility complex: a model for understanding graft-versus-host disease.
      • Petersdorf E.W.
      Genetics of graft-versus-host disease: the major histocompatibility complex.
      The degree of HLA mismatch between the donor and the recipient is a risk factor for rejection, as is the presence of existing donor-specific antibodies in the recipient.
      • Kissmeyer-Nielsen F.
      • Olsen S.
      • Petersen V.P.
      • Fjeldborg O.
      Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells.
      • Sumitran-Holgersson S.
      HLA-specific alloantibodies and renal graft outcome.
      • Lee P.C.
      • Zhu L.
      • Terasaki P.I.
      • Everly M.J.
      HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss.
      • Gloor J.M.
      • Winters J.L.
      • Cornell L.D.
      • et al.
      Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation.
      • Montgomery R.A.
      • Cozzi E.
      • West L.J.
      • Warren D.S.
      Humoral immunity and antibody-mediated rejection in solid organ transplantation.
      • Focosi D.
      • Vistoli F.
      • Boggi U.
      Rejection of the kidney allograft.
      • Montgomery R.A.
      • Lonze B.E.
      • King K.E.
      • et al.
      Desensitization in HLA-incompatible kidney recipients and survival.
      • Mohan S.
      • Palanisamy A.
      • Tsapepas D.
      • et al.
      Donor-specific antibodies adversely affect kidney allograft outcomes.
      • Thaunat O.
      Humoral immunity in chronic allograft rejection: puzzle pieces come together.
      Sensitization of mothers to fetal-specific HLA antigens occurs frequently during pregnancy, increases with gestational age and parity, and traditionally has been considered benign.
      • Honger G.
      • Fornaro I.
      • Granado C.
      • Tiercy J.M.
      • Hosli I.
      • Schaub S.
      Frequency and determinants of pregnancy-induced child-specific sensitization.
      • Jones M.
      • Jeal H.
      • Harris J.M.
      • et al.
      Association of maternal anti-HLA class II antibodies with protection from allergy in offspring.
      • Masson E.
      • Vidal C.
      • Deschamps M.
      • Bongain S.
      • Thevenin C.
      • Dupont I.
      • et al.
      Incidence and risk factors of anti-HLA immunization after pregnancy.
      • Lashley E.E.
      • Meuleman T.
      • Claas F.H.
      Beneficial or harmful effect of antipaternal human leukocyte antibodies on pregnancy outcome? A systematic review and meta-analysis.
      However, we have recently demonstrated that maternal HLA sensitization diagnosed in the mid trimester is a risk factor for spontaneous preterm delivery (odds ratio, 2.8; P = .01),
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery.
      and the strength of the association increases (odds ratio, 5.9; 95% confidence interval, 1.6–21.83; P = .008) when patients experience spontaneous preterm labor.
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d.
      Maternal HLA sensitization is necessary, but not sufficient, for antibody-mediated maternal anti-fetal rejection. Antibodies specific to fetal antigens also must cross the placenta, activate complement, and damage the semiallograft (placenta and/or fetus); we have reported that this occurs in cases of chronic chorioamnionitis and massive perivillous fibrin deposition, also known as maternal floor infarction.
      • Romero R.
      • Whitten A.
      • Korzeniewski S.J.
      • et al.
      Maternal floor infarction/massive perivillous fibrin deposition: a manifestation of maternal antifetal rejection?.
      In both conditions, the following evidence supports maternal anti-fetal rejection: (1) maternal HLA sensitization, (2) fetal HLA-specific antibodies, (3) complement deposition in the umbilical vein, and (4) chronic chorioamnionitis or VUE.
      • Lee J.
      • Romero R.
      • Chaiworapongsa T.
      • et al.
      Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response.
      We consider preterm labor/delivery,
      • Lee J.
      • Romero R.
      • Xu Y.
      • et al.
      Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery.
      fetal growth restriction, fetal death
      • Lee J.
      • Romero R.
      • Dong Z.
      • et al.
      Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies.
      • Lannaman K.
      • Romero R.
      • Chaemsaithong P.
      • et al.
      Fetal death: an extreme form of maternal anti-fetal rejection (Abstract 497).
      and maternal floor infarction
      • Romero R.
      • Whitten A.
      • Korzeniewski S.J.
      • et al.
      Maternal floor infarction/massive perivillous fibrin deposition: a manifestation of maternal antifetal rejection?.
      to be the clinical manifestations of graft injury. The latter group of patients can be identified by assessing the concentration of maternal plasma angiogenic/anti-angiogenic factors in early pregnancy.
      • Whitten A.E.
      • Romero R.
      • Korzeniewski S.J.
      • et al.
      Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction); a placental lesion associated with recurrent miscarriage and fetal death.
      Why some sensitized mothers experience maternal anti-fetal rejection and others do not requires further investigation.

      Fetal inflammatory response syndrome, type 2

      When maternal anti-fetal antibodies cross the placenta and induce an alloimmune reaction (Figure 12), this can lead to a systemic fetal inflammatory response; however, this process is different from fetal systemic inflammation that is observed in the context of intrauterine infection.
      • Lee J.
      • Romero R.
      • Chaiworapongsa T.
      • et al.
      Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response.
      • Gomez R.
      • Romero R.
      • Ghezzi F.
      • Yoon B.H.
      • Mazor M.
      • Berry S.M.
      The fetal inflammatory response syndrome.
      • Yoon B.H.
      • Romero R.
      • Park J.S.
      • et al.
      The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis.
      • Goncalves L.F.
      • Chaiworapongsa T.
      • Romero R.
      Intrauterine infection and prematurity.
      • Gotsch F.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      The fetal inflammatory response syndrome.
      • Romero R.
      • Dey S.K.
      • Fisher S.J.
      Preterm labor: one syndrome, many causes.
      In microbial invasion of the amniotic cavity, bacteria lead to the activation of the innate immune system and the production of neutrophil chemokines (eg, IL-8), which generate a chemotactic gradient that attracts neutrophils from the decidua into the chorioamniotic membranes and leads to acute chorioamnionitis.
      • Romero R.
      • Ceska M.
      • Avila C.
      • Mazor M.
      • Behnke E.
      • Lindley I.
      Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition.