PMID- 23905683 OWN - NLM STAT- MEDLINE DCOM- 20140331 LR - 20211021 IS - 1600-0897 (Electronic) IS - 1046-7408 (Print) IS - 1046-7408 (Linking) VI - 70 IP - 4 DP - 2013 Oct TI - 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. PG - 265-84 LID - 10.1111/aji.12142 [doi] AB - BACKGROUND: The human fetus is able to mount a systemic inflammatory response when exposed to microorganisms. This stereotypic response has been termed the 'fetal inflammatory response syndrome' (FIRS), defined as an elevation of fetal plasma interleukin-6 (IL-6). FIRS is frequently observed in patients whose preterm deliveries are associated with intra-amniotic infection, acute inflammatory lesions of the placenta, and a high rate of neonatal morbidity. Recently, a novel form of fetal systemic inflammation, characterized by an elevation of fetal plasma CXCL10, has been identified in patients with placental lesions consistent with 'maternal anti-fetal rejection'. These lesions include chronic chorioamnionitis, plasma cell deciduitis, and villitis of unknown etiology. In addition, positivity for human leukocyte antigen (HLA) panel-reactive antibodies (PRA) in maternal sera can also be used to increase the index of suspicion for maternal anti-fetal rejection. The purpose of this study was to determine (i) the frequency of pathologic lesions consistent with maternal anti-fetal rejection in term and spontaneous preterm births; (ii) the fetal serum concentration of CXCL10 in patients with and without evidence of maternal anti-fetal rejection; and (iii) the fetal blood transcriptome and proteome in cases with a fetal inflammatory response associated with maternal anti-fetal rejection. METHOD OF STUDY: Maternal and fetal sera were obtained from normal term (n = 150) and spontaneous preterm births (n = 150). A fetal inflammatory response associated with maternal anti-fetal rejection was diagnosed when the patients met two or more of the following criteria: (i) presence of chronic placental inflammation; (ii) >/=80% of maternal HLA class I PRA positivity; and (iii) fetal serum CXCL10 concentration >75th percentile. Maternal HLA PRA was analyzed by flow cytometry. The concentrations of fetal CXCL10 and IL-6 were determined by ELISA. Transcriptome analysis was undertaken after the extraction of total RNA from white blood cells with a whole-genome DASL assay. Proteomic analysis of fetal serum was conducted by two-dimensional difference gel electrophoresis. Differential gene expression was considered significant when there was a P < 0.01 and a fold-change >1.5. RESULTS: (i) The frequency of placental lesions consistent with maternal anti-fetal rejection was higher in patients with preterm deliveries than in those with term deliveries (56% versus 32%; P < 0.001); (ii) patients with spontaneous preterm births had a higher rate of maternal HLA PRA class I positivity than those who delivered at term (50% versus 32%; P = 0.002); (iii) fetuses born to mothers with positive maternal HLA PRA results had a higher median serum CXCL10 concentration than those with negative HLA PRA results (P < 0.001); (iv) the median serum CXCL10 concentration (but not IL-6) was higher in fetuses with placental lesions associated with maternal anti-fetal rejection than those without such lesions (P < 0.001); (v) a whole-genome DASL assay of fetal blood RNA demonstrated differential expression of 128 genes between fetuses with and without lesions associated with maternal anti-fetal rejection; and (vi) comparison of the fetal serum proteome demonstrated 20 proteins whose abundance differed between fetuses with and without lesions associated with maternal anti-fetal rejection. CONCLUSION: We describe a systemic inflammatory response in human fetuses born to mothers with evidence of maternal anti-fetal rejection. The transcriptome and proteome of this novel type of fetal inflammatory response were different from that of FIRS type I (which is associated with acute infection/inflammation). CI - Published 2013. This article is a U.S. Government work and is in the public domain in the U.S.A. FAU - Lee, Joonho AU - Lee J AD - Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, USA. FAU - Romero, Roberto AU - Romero R FAU - Chaiworapongsa, Tinnakorn AU - Chaiworapongsa T FAU - Dong, Zhong AU - Dong Z FAU - Tarca, Adi L AU - Tarca AL FAU - Xu, Yi AU - Xu Y FAU - Chiang, Po Jen AU - Chiang PJ FAU - Kusanovic, Juan Pedro AU - Kusanovic JP FAU - Hassan, Sonia S AU - Hassan SS FAU - Yeo, Lami AU - Yeo L FAU - Yoon, Bo Hyun AU - Yoon BH FAU - Than, Nandor Gabor AU - Than NG FAU - Kim, Chong Jai AU - Kim CJ LA - eng GR - ZIA HD002400-22/ImNIH/Intramural NIH HHS/United States GR - HHSN275201300006C/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20130730 PL - Denmark TA - Am J Reprod Immunol JT - American journal of reproductive immunology (New York, N.Y. : 1989) JID - 8912860 RN - 0 (Chemokine CXCL10) RN - 0 (HLA Antigens) RN - 0 (Inflammation Mediators) RN - 0 (Isoantibodies) RN - 0 (Proteome) SB - IM MH - Adolescent MH - Adult MH - Chemokine CXCL10/blood MH - Chorioamnionitis/diagnosis/*immunology MH - Female MH - Fetal Blood/immunology/*metabolism MH - Fetus/immunology MH - Gene Expression Profiling MH - HLA Antigens/immunology MH - Histocompatibility, Maternal-Fetal/genetics MH - Humans MH - Inflammation Mediators/*metabolism MH - Isoantibodies/blood MH - Placenta/*immunology MH - Pregnancy/immunology MH - Premature Birth/diagnosis/*immunology MH - Proteome MH - Young Adult PMC - PMC3939790 MID - NIHMS481678 OTO - NOTNLM OT - Apolipoprotein C-III OT - CD 34 OT - CXCL10 OT - chronic placental inflammation OT - pregnancy COIS- Conflict of Interest The authors have no financial conflicts of interest. EDAT- 2013/08/03 06:00 MHDA- 2014/04/01 06:00 PMCR- 2014/10/01 CRDT- 2013/08/03 06:00 PHST- 2013/04/29 00:00 [received] PHST- 2013/05/07 00:00 [accepted] PHST- 2013/08/03 06:00 [entrez] PHST- 2013/08/03 06:00 [pubmed] PHST- 2014/04/01 06:00 [medline] PHST- 2014/10/01 00:00 [pmc-release] AID - 10.1111/aji.12142 [doi] PST - ppublish SO - Am J Reprod Immunol. 2013 Oct;70(4):265-84. doi: 10.1111/aji.12142. Epub 2013 Jul 30.