The peripheral whole-blood transcriptome of acute pyelonephritis in human pregnancy^a

Abstract

Objective Human pregnancy is characterized by activation of the innate immune response and suppression of adaptive immunity. The former is thought to provide protection against infection to the mother, and the latter, tolerance against paternal antigens expressed in fetal cells. Acute pyelonephritis is associated with an increased risk of acute respiratory distress syndrome and sepsis in pregnant (vs. nonpregnant) women. The objective of this study was to describe the gene expression profile (transcriptome) of maternal whole blood in acute pyelonephritis. Method A case-control study was conducted to include pregnant women with acute pyelonephritis (n=15) and women with a normal pregnancy (n=34). Affymetrix HG-U133 Plus 2.0 arrays (Affymetrix, Santa Clara, CA, USA) were used for gene expression profiling. A linear model was used to test the association between the presence of pyelonephritis and gene expression levels while controlling for white blood cell count and gestational age. A fold change of 1.5 was considered significant at a false discovery rate of 0.1. A subset of differentially expressed genes (n=56) was tested with real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) (cases, n=19; controls, n=59). Gene ontology and pathway analysis were applied. Results A total of 983 genes were differentially expressed in acute pyelonephritis: 457 were up-regulated and 526 were down-regulated. Significant enrichment of 300 biological processes and 63 molecular functions was found in pyelonephritis. Significantly impacted pathways in pyelonephritis included a) cytokine-cytokine receptor interaction; b) T-cell receptor signaling; c) Jak-STAT signaling; and d) complement and coagulation cascades. Of 56 genes tested by qRT-PCR, 48 (85.7%) had confirmation of differential expression. Conclusion This is the first study of the transcriptomic signature of whole blood in pregnant women with acute pyelonephritis. Acute infection during pregnancy is associated with the increased expression of genes involved in innate immunity and the decreased expression of genes involved in lymphocyte function.

Inflammation-Induced Adverse Pregnancy and Neonatal Outcomes Can Be Improved by the Immunomodulatory Peptide Exendin-4

“…The systemic administration of a microbial product induced a severe maternal cytokine response but a mild fetal cytokine response, which caused preterm birth and neonatal death. A systemic maternal inflammatory response is observed in women with clinical chorioamnionitis ( 18 ) and acute pyelonephritis ( 104 , 105 ), both clinical conditions associated with preterm birth ( 106 – 109 ) and adverse neonatal outcomes ( 107 , 108 ). However, clinical chorioamnionitis results from intra-amniotic infection ( 15 – 18 , 98 ), a condition which was not present in our model.…”

Endocan, a putative endothelial cell marker, is elevated in preeclampsia, decreased in acute pyelonephritis, and unchanged in other obstetrical syndromes

“…This is a puzzling observation, given that our systematic studies of the behavior of cytokines [230], chemokines [231], complement [232,233] in acute pyelonephritis and preeclampsia suggest that both conditions are associated with a pro-inflammatory state. However, studies of the transcriptome of peripheral blood in patients with preeclampsia [234] and pyelonephritis [235] suggest that the molecular details of the inflammatory response differ. Further work is required to understand the similarities and differences in the systemic and local inflammatory response in these two conditions.…”

CXCL10 and IL‐6: Markers of two different forms of intra‐amniotic inflammation in preterm labor

“…Tolerance is a specific immunological term that refers to “the active state of antigen‐specific non‐responsiveness” leading to diminished reactivity to paternal antigens expressed by the placenta and/or fetus; it is considered key for successful pregnancy . The mechanisms responsible for tolerance in pregnancy include the following: (i) T‐cell chemokine gene silencing in the decidual cells; (ii) a suppressive role of regulatory T cells; (iii) expression of non‐classical major histocompatibility complex molecules on trophoblast cells that do not elicit a maternal immune response; (iv) changes in tryptophan catabolisms; (v) T‐cell apoptosis; (vi) complement; and (vii) costimulatory molecules such as the programmed death ligand . Other mechanisms for tolerance are not currently understood.…”