A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d

PLOS ONE, Feb 2011

Background Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth. Methods and Findings This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti-HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29–28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60–21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42–114.66) were associated with preterm labor and delivery. Conclusions A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions.

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A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d

and C4d. PLoS ONE 6(2): e16806. doi:10.1371/journal.pone.0016806 A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d JoonHo Lee 0 Roberto Romero 0 Yi Xu 0 Jung-Sun Kim 0 Vanessa Topping 0 Wonsuk Yoo 0 Juan Pedro Kusanovic 0 Tinnakorn Chaiworapongsa 0 Sonia S. Hassan 0 Bo Hyun Yoon 0 Chong Jai Kim 0 Haibin Wang, Chinese Academy of Sciences, China 0 1 Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services , Bethesda, Maryland, and Detroit, Michigan , United States of America, 2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, United States of America, 3 Center for Molecular Medicine and Genetics, Wayne State University , Detroit, Michigan , United States of America, 4 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 5 Translational Research and Clinical Epidemiology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, United States of America, 6 Department of Obstetrics and Gynecology, So tero del Rio Hospital , Santiago , Chile , 7 Department of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Cato lica de Chile , Santiago , Chile , 8 Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea, 9 Department of Pathology, Wayne State University School of Medicine , Detroit, Michigan , United States of America Background: Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth. Methods and Findings: This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal antiHLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p,0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p,0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p,0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p,0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29-28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60-21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42-114.66) were associated with preterm labor and delivery. Conclusions: A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibodymediated rejections with links to fetal graft-versus-host disease and alloimmune reactions. - Funding: This work was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Preterm birth is the leading cause of perinatal mortality and morbidity worldwide [1]. Moreover, the rate of preterm birth has been rising in most developed countries, ranging from 5% to 13% of all deliveries [2,3]. The socioeconomic impact of preterm birth cannot be overestimated, and the cost of preterm birth is $26 billion per year in the United States [4,5]. While preterm birth is known to be associated with various obstetric disorders such as intra-uterine infection/inflammation and preeclampsia [1,6], the causes and precise mechanisms are not fully understood. A robust clinico-pathologic classification of heterogeneous varieties of preterm birth is fundamental to the diagnosis, prognosis, and design of ideal therapeutic interventions. Therefore, the elucidation of the essential pathophysiology of different types of preterm birth is an urgent and important matter. The fetus is the most successful semi-allograft. (...truncated)


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JoonHo Lee, Roberto Romero, Yi Xu, Jung-Sun Kim, Vanessa Topping, Wonsuk Yoo, Juan Pedro Kusanovic, Tinnakorn Chaiworapongsa, Sonia S. Hassan, Bo Hyun Yoon, Chong Jai Kim. A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d, PLOS ONE, 2011, Volume 6, Issue 2, DOI: 10.1371/journal.pone.0016806