Innate Lymphoid Cells in the Maternal and Fetal Compartments

Pregnancy success is orchestrated by the complex balance between the maternal and fetal immune systems. Herein, we summarize the potential role of innate lymphoid cells (ILCs) in the maternal and fetal compartments. We reviewed published literature describing different ILC subsets [ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells] in the uterus, decidua, fetal tissues [liver, secondary lymphoid organs (SLO), intestine, and lung] and amniotic cavity. ILC1s, ILC2s, and ILC3s are present in the murine uterus prior to and during pregnancy but have only been detected in the non-pregnant endometrium in humans. Specifically, ILC2s reside in the murine uterus from mid-pregnancy to term, ILC1s increase throughout gestation, and ILC3s remain constant. Yet, LTi cells have only been detected in the non-pregnant murine uterus. In the human decidua, ILC1s, ILC3s, and LTi-like cells are more abundant during early gestation, whereas ILC2s increase at the end of pregnancy. Decidual ILC1s were also detected during mid-gestation in mice. Interestingly, functional decidual ILC2s and ILC3s increased in women who underwent spontaneous preterm labor, indicating the involvement of such cells in this pregnancy complication. Fetal ILCs exist in the liver, SLO, intestine, lung, and amniotic cavity. The fetal liver is thought to be the source of ILC progenitors since the differentiation of these cells from hematopoietic stem cells occurs at this site, and mature ILC subsets can be found in this compartment as well. The interaction between LTi cells and specialized stromal cells is important during the formation of SLO. Mature ILCs are found at the mucosal surfaces of the lung and intestine, from where they can extravasate into the amniotic cavity. Amniotic fluid ILCs express high levels of RORγt, CD161, and CD103, hallmarks of ILC3s. Such cells are more abundant in the second trimester than later in gestation. Although amniotic fluid ILC3s produce IL-17A and TNFα, indicating their functionality, their numbers in patients with intra-amniotic infection/inflammation remain unchanged compared to those without this pregnancy complication. Collectively, these findings suggest that maternal (uterine and decidual) ILCs play central roles in both the initiation and maintenance of pregnancy, and fetal ILCs participate in the development of immunity

Maternal circulating leukocytes display early chemotactic responsiveness during late gestation

Abstract Background Parturition has been widely described as an immunological response; however, it is unknown how this is triggered. We hypothesized that an early event in parturition is an increased responsiveness of peripheral leukocytes to chemotactic stimuli expressed by reproductive tissues, and this precedes expression of tissue chemotactic activity, uterine activation and the systemic progesterone/estradiol shift. Methods Tissues and blood were collected from pregnant Long-Evans rats on gestational days (GD) 17, 20 and 22 (term gestation). We employed a validated Boyden chamber assay, flow cytometry, quantitative real time-polymerase chain reaction, and enzyme-linked immunosorbent assays. Results We found that GD20 maternal peripheral leukocytes migrated more than those from GD17 when these were tested with GD22 uterus and cervix extracts. Leukocytes on GD20 also displayed a significant increase in chemokine (C-C motif) ligand 2 (Ccl2) gene expression and this correlated with an increase in peripheral granulocyte proportions and a decrease in B cell and monocyte proportions. Tissue chemotactic activity and specific chemokines (CCL2, chemokine (C-X-C motif) ligand 1/CXCL1, and CXCL10) were mostly unchanged from GD17 to GD20 and increased only on GD22. CXCL10 peaked on GD20 in cervical tissues. As expected, prostaglandin F2α receptor and oxytocin receptor gene expression increased dramatically between GD20 and 22. Progesterone concentrations fell and estradiol-17β concentrations increased in peripheral serum, cervical and uterine tissue extracts between GD20 and 22. Conclusion Maternal circulating leukocytes display early chemotactic responsiveness, which leads to their infiltration into the uterus where they may participate in the process of parturition

CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses

Neonatal CD71+ erythroid cells are thought to have immunosuppressive functions. Recently, we demonstrated that CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm labor (PTL) are reduced to levels similar to those of term neonates; yet, their functional properties are unknown. Herein, we investigated the functionality of CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm or term labor. CD71+ erythroid cells from neonates born to women who underwent PTL displayed a similar mRNA profile to that of those from term neonates. The direct contact between preterm or term neonatal CD71+ erythroid cells and maternal mononuclear immune cells, but not soluble products from these cells, induced the release of proinflammatory cytokines and a reduction in the release of TGFâ β. Moreover, PTLâ derived neonatal CD71+ erythroid cells (1) modestly altered CD8+ T cell activation; (2) inhibited conventional CD4+ and CD8+ Tâ cell expansion; (3) suppressed the expansion of CD8+ regulatory T cells; (4) regulated cytokine responses mounted by myeloid cells in the presence of a microbial product; and (5) indirectly modulated Tâ cell cytokine responses. In conclusion, neonatal CD71+ erythroid cells regulate neonatal Tâ cell and myeloid responses and their direct contact with maternal mononuclear cells induces a proinflammatory response. These findings provide insight into the biology of neonatal CD71+ erythroid cells during the physiologic and pathologic processes of labor.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/1/jlb10051_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/2/jlb10051-sup-0003-TableS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/3/jlb10051-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/4/jlb10051-sup-0001-Figures.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/5/jlb10051.pd

Amniotic fluid neutrophils can phagocytize bacteria: A mechanism for microbial killing in the amniotic cavity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138926/1/aji12723_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138926/2/aji12723.pd

Intra‐Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116331/1/aji12443_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116331/2/aji12443.pd

Inflammasome assembly in the chorioamniotic membranes during spontaneous labor at term

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137494/1/aji12648.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137494/2/aji12648_am.pd

Inflammasome activation during spontaneous preterm labor with intraâ amniotic infection or sterile intraâ amniotic inflammation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146295/1/aji13049.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146295/2/aji13049_am.pd

The amniotic fluid cell-free transcriptome in spontaneous preterm labor

The amniotic fluid (AF) cell-free RNA was shown to reflect physiological and pathological processes in pregnancy, but its value in the prediction of spontaneous preterm delivery is unknown. Herein we profiled cell-free RNA in AF samples collected from women who underwent transabdominal amniocentesis after an episode of spontaneous preterm labor and subsequently delivered within 24 h (n = 10) or later (n = 28) in gestation. Expression of known placental single-cell RNA-Seq signatures was quantified in AF cell-free RNA and compared between the groups. Random forest models were applied to predict time-to-delivery after amniocentesis. There were 2385 genes differentially expressed in AF samples of women who delivered within 24 h of amniocentesis compared to gestational age-matched samples from women who delivered after 24 h of amniocentesis. Genes with cell-free RNA changes were associated with immune and inflammatory processes related to the onset of labor, and the expression of placental single-cell RNA-Seq signatures of immune cells was increased with imminent delivery. AF transcriptomic prediction models captured these effects and predicted delivery within 24 h of amniocentesis (AUROC = 0.81). These results may inform the development of biomarkers for spontaneous preterm birth

Are B cells altered in the decidua of women with preterm or term labor?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149277/1/aji13102_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149277/2/aji13102.pd

Human βâ defensinâ 1: A natural antimicrobial peptide present in amniotic fluid that is increased in spontaneous preterm labor with intraâ amniotic infection

ProblemHuman βâ defensins (HBDs) are antimicrobial peptides that participate in the soluble innate immune mechanisms against infection. Herein, we determined whether HBDâ 1 was present in amniotic fluid during normal pregnancy and whether its concentrations change with intraâ amniotic inflammation and/or infection.Method of StudyAmniotic fluid was collected from 219 women in the following groups: (a) midtrimester who delivered at term (n = 35); (b) term with (n = 33) or without (n = 17) labor; (c) preterm labor with intact membranes who delivered at term (n = 29) or who delivered preterm with (n = 19) and without (n = 29) intraâ amniotic inflammation and infection or with intraâ amniotic inflammation but without infection (n = 21); and (d) preterm prelabor rupture of membranes (pPROM) with (n = 19) and without (n = 17) intraâ amniotic inflammation/infection. Amniotic fluid HBDâ 1 concentrations were determined using a sensitive and specific ELISA kit.Results(a) HBDâ 1 was detectable in all amniotic fluid samples; (b) amniotic fluid concentrations of HBDâ 1 were changed with gestational age (midtrimester vs term no labor), being higher in midtrimester; (c) amniotic fluid concentrations of HBDâ 1 were similar between women with and without spontaneous labor at term; (d) among patients with spontaneous preterm labor, amniotic fluid concentrations of HBDâ 1 in women with intraâ amniotic inflammation/infection and in those with intraâ amniotic inflammation without infection were greater than in women without intraâ amniotic inflammation or infection who delivered preterm or at term; and (e) the presence of intraâ amniotic inflammation and infection in patients with pPROM did not change amniotic fluid concentrations of HBDâ 1.ConclusionHBDâ 1 is a physiological constituent of amniotic fluid that is increased in midtrimester during normal pregnancy and in the presence of culturable microorganisms in the amniotic cavity. These findings provide insight into the soluble host defense mechanisms against intraâ amniotic infection.Amniotic fluid concentrations of human beta defensinâ 1 (HBDâ 1) in women with spontaneous preterm labor and intact membranes. Red lines indicate medians with interquartile ranges.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146360/1/aji13031.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146360/2/aji13031_am.pd