Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5

Frascoli, Michela; Jeanty, Cerine; Fleck, Shannon; Moradi, Patriss W.; Keating, Sheila M.; Mattis, Aras N.; Tang, Qizhi; MacKenzie, Tippi C.

doi:10.4049/jimmunol.1502587

Cited by 17 publications

(15 citation statements)

References 58 publications

(59 reference statements)

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“…While Group 3 ILCs exist in the fetal murine intestine early in pregnancy, a particular subset which is only a fraction of murine intestinal ILCs seems to rapidly expand shortly after birth 140 , which may be related to the colonization of the fetal gut by commensal microbes. Moreover, fetuses with gastroschisis had increased Group 2 and Group 3 ILCs in the sections of intestine exposed to the amniotic fluid, suggesting that these cells participate in the inflammatory environment that leads to fetal bowel damage 128 .…”

Section: Discussionmentioning

confidence: 99%

“…Yet, the number of macrophages and/or ILCs is increased in pathological conditions in which fetal organs are exposed to the amniotic fluid (e.g. neural tube defects 118, 120–125 and gastroschisis 118, 126–128 ). The number of amniotic fluid neutrophils, on the other hand, is a useful marker for intra-amniotic inflammation 23, 27, 67–69, 129–132 .…”

Section: Introductionmentioning

confidence: 99%

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The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies

Gomez‐Lopez

Romero

et al. 2018

American J Rep Immunol

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Problem The immune cellular composition of amniotic fluid is poorly understood. Herein, we determined the immunophenotype of amniotic fluid: 1) immune cells during the second and third trimester; 2) T cells and innate lymphoid cells (ILCs); and 3) immune cells during intra-amniotic infection/inflammation. Method of Study Amniotic fluid samples (n=57) were collected from women from 15-40 weeks of gestation without intra-amniotic infection/inflammation. Samples from women with intra-amniotic infection/inflammation were also included (n=9). Peripheral blood mononuclear cells from healthy adults were used as controls (n=3). Immunophenotyping was performed using flow cytometry. Results In the absence of intra-amniotic infection/inflammation, the amniotic fluid contained several immune cell populations from 15-40 weeks. Among these immune cells: 1) T cells and ILCs were greater than B cells and NK cells between 15 to 30 weeks; 2) T cells were most abundant between 15 to 30 weeks; 3) ILCs were most abundant between 15 to 20 weeks; 4) B cells were scarce between 15 to 20 weeks; yet, they increased and were constant after 20 weeks; 5) NK cells were greater between 15 to 30 weeks than at term; 6) ILCs expressed high levels of RORγt, CD161, and CD103 (i.e. Group 3 ILCs); 7) T cells expressed high levels of RORγt; 8) neutrophils increased as gestation progressed; and 9) monocytes/macrophages emerged after 20 weeks and remained constant until term. All of the amniotic fluid immune cells, except ILCs, were increased in the presence of intra-amniotic infection/inflammation. Conclusions The amniotic fluid harbors a diverse immune cellular composition during normal and complicated pregnancies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies

Gomez‐Lopez

Romero

et al. 2018

American J Rep Immunol

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“…Engagement of CD161, coexpressed on the majority of intestinal PLZF + CD4 + T cells, inhibited TCR-mediated activation in a fetal-specific manner. PLZF + CD4 + T cells with enhanced capacity for Th1 cytokine production accumulated in the cord blood of infants with gastroschisis, an abdominal wall defect associated with systemic inflammation originating from intestinal injury (30), and were also increased in the cord blood of preterm infants. Finally, dexamethasone, routinely prescribed to pregnant women in impending preterm labor, inhibited Th1 cyto- mucosal memory T cells (34,35), most fetal intestinal PLZF + CD4 + T cells were CD69 + , and a fraction of these (~20%) also expressed CD103, suggestive of a T resident memory (TRM) phenotype (Supplemental Figure 2, C and D).…”

Section: Introductionmentioning

confidence: 99%

“…ples were excluded in the case of known maternal infection, intrauterine fetal demise, and/or known or suspected chromosomal abnormality. Approval for cord blood collections from live infants with gastroschisis (>35 weeks GA) was obtained from the UCSF Research Protection program, and samples were obtained from infants enrolled for a separate study between November 2009 and December 2012 (30). PTB cord blood samples were collected from live preterm infants (<37 weeks GA) at University College Hospital, London (London, United Kingdom) and the Homerton University Hospital (London, United Kingdom) with ethical permission granted by the South Central-Oxford A Research Ethics Committee between June 2017 and June 2018.…”

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confidence: 99%

CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells

Halkias¹,

Rackaityte²,

Hillman³

et al. 2019

Journal of Clinical Investigation

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109

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BACKGROUND. While the human fetal immune system defaults to a program of tolerance, there is a concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response, with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. METHODS.We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with proinflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared with that of healthy term controls. RESULTS.We identified a transcriptionally distinct population of CD4 + T cells characterized by expression of the transcription factor promyelocytic leukemia zinc finger (PLZF). PLZF + CD4 + T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced proinflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFN-γ in a fetal-specific manner. IFN-γ-producing PLZF + CD4 + T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. CONCLUSION.Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies. cells in the development of protective immunity and their contribution to perinatal immune dysregulation is not known.Here, we performed a detailed analysis of human CD4 + T cell phenotype and function in fetal lymphoid and mucosal tissues. We show that Vα7.2 -PLZF + TCR-αβ + CD4 + T cells (herein referred to as PLZF + CD4 + T cells) specifically accumulated in the fetal intestine and were absent from the adult. Fetal PLZF + CD4 + T cells represent a transcriptionally unique subset of CD4 + T cells that are distinct from either innate-like, semi-invariant Va7.2 + T cells or PLZF -CD4 + T cells. Consistent with a primarily T effector memo-memory originates in utero. Innate-like T cells with rapid effector functions, such as γδ T cells, mucosa-associated invariant T (MAIT) cells, and innate-like NKT cells, are also present in fetal tissues (23)(24)(25). Promyelocytic leukemia zinc finger (PLZF), a transcriptional regulator that directs the differentiation of innate-like T cells (26,27), is widely expressed in human immune cells and is commonly associated with expression of CD161, a C-type lectin receptor (28). The human fetal thymus uniquely produces a subset of CD4 + T cells, distinct from NKT cells and MAIT cells, that expresses the transcription factor PLZF (29). However, the role of fetal PLZF ...

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“…Increased VEGF levels reflect an attempt by the fetus/newborn to enlarge the pulmonary vascular bed in the hypoplastic lungs to alleviate pulmonary hypertension (15), while MCP-1 contributes to recruitment and activation of monocytes, which promote inflammation and pulmonary fibrosis (16). Increased MCP-1 levels were also reported in the cord blood of gastroschisis patients as a result of chronic inflammation in the intestines exposed to amniotic fluid during development (17). Our findings are also consistent with the reports demonstrating leukocyte infiltration in the intestinal wall and increased levels of proinflammatory cytokines in the amniotic fluid in gastroschisis patients (18).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic renal injury in newborns with abdominal compartment syndrome (clinical and experimental study)

et al. 2017

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BackgroundSurgical treatment for gastroschisis and congenital diaphragmatic hernia (CDH) commonly leads to abdominal compartment syndrome (ACS) associated with hypoxic renal injury. We hypothesized that measurement of urinary and serum concentrations of vascular endothelial growth factor (VEGF), π-glutathione S-transferase (π-GST), and monocyte chemoattractant protein-1 (MCP-1) may serve for noninvasive detection of hypoxic renal injury in such patients.MethodsIntra-abdominal pressure (IAP), renal excretory function, and the biomarker levels were analyzed before, 4, and 10 days after surgery. Association between the biomarker levels and renal histology was investigated using an original model of ACS in newborn rats.ResultsFour days after surgery, IAP increased, renal excretory function decreased, and the levels of VEGF, π-GST, and MCP-1 increased, indicating renal injury. Ten days after surgery, IAP partially decreased, renal excretory function completely restored, but the biomarker levels remained elevated, suggesting the ongoing kidney injury. In the model of ACS, increase in the biomarker levels was associated with progressing kidney morphological alteration.ConclusionSurgical treatment for gastroschisis and CDH is associated with prolonged hypoxic kidney injury despite complete restoration of renal excretory function. Follow-up measurement of VEGF, π-GST, and MCP-1 levels may provide a better tool for noninvasive assessment of renal parenchyma in newborns with ACS.

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Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5

Cited by 17 publications

References 58 publications

The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies

The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies

CD161 contributes to prenatal immune suppression of IFN-γ–producing PLZF+ T cells

Hypoxic renal injury in newborns with abdominal compartment syndrome (clinical and experimental study)

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