γδ T cell profiling in a cohort of preterm infants reveals elevated frequencies of CD83+ γδ T cells in sepsis.

Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.

Aspectes perinatals del nadons prematurs nascuts per pneumònia covid-19 materna greu / Prematuridad por neumonía covid-19 materna grave / Preterm births due to severe maternal covid-19 pneumonia

Fonament. En els mesos de juliol i agost del 2021, coincidint amb l’onada de SARS-CoV-2 a causa de la variantdelta del virus i amb la vacunació poblacional encara incompleta, a l’hospital Vall d’Hebron hi va haver diversosingressos de nounats prematurs a causa de pneumòniagreu per covid-19 materna, en ser aquest un centre dereferència per a gestants amb covid-19 greu. En aquesttreball es recullen les característiques més rellevantsd’aquesta població.Objectiu. Descriure l’experiència amb nounats prematurs acausa de pneumònia greu per SARS-CoV-2 materna.Mètode. Es tracta d’un treball descriptiu que reuneix elscasos atesos a l’Hospital Vall d’Hebron (Barcelona) durantdos mesos, i en mostra les característiques clíniques principals.Resultats. La majoria dels pacients van ser negatius per aSARS-CoV-2 en els aspirats fets durant l’ingrés, no van requerir suport respiratori perllongat ni van presentar patologies importants més enllà de les associades a la prematuritat. Destaca la freqüència de símptomes gastrointestinals iproblemes en l’alimentació, probablement causats per ladificultat d’accés a la llet materna pròpia per gravetat clínicao derivats de la inflamació en el context perinatal.Conclusions. Es tracta d’una mostra petita, de manera quesón necessaris més estudis per poder extreure’n conclusions. (AU)

Fundamento. En los meses de julio y agosto de 2021, coincidiendocon la ola de SARS-CoV-2 debida a la variante delta del virus y ala vacunación poblacional incompleta, en el Hospital Vall d’Hebronhubo varios ingresos de recién nacidos prematuros debido a neumonía grave materna, al ser este un centro de referencia paragestantes con infección por covid-19 grave. En este trabajo serecogen las características más relevantes de dicha población.Objetivo. Describir la experiencia con recién nacidos prematuros acausa de neumonía grave por covid-19 materna. Método. Se trata de un trabajo descriptivo que reúne los casosatendidos en nuestro hospital durante dos meses y muestra susprincipales características clínicas.Resultados.La mayoría de los pacientes fueron negativos paraSARS-CoV-2 en los aspirados realizados durante su ingreso, norequirieron soporte respiratorio prolongado ni presentaron patologías importantes más allá de las asociadas a su prematuridad.Destaca la frecuencia de síntomas gastrointestinales y problemasen la alimentación, probablemente debidos a la dificultad en elacceso a leche materna propia por gravedad clínica y/o derivadosde la inflamación en el contexto perinatal.Conclusiones. Se trata de una muestra pequeña, por lo que sonnecesarios más estudios para poder extraer conclusiones. (AU)

Background. During the months of July and August of 2021, duringthe SARS-CoV-2 delta variant wave in the context of incompletevaccination of the population in Spain, several premature newborns due to severe maternal pneumonia were admitted in Hospital Vall d’Hebron, which is a reference center for pregnant womenwith severe Covid-19 infections. In this study we describe the essential characteristics of this population.Objective. To describe the experience with premature neonates secondary to severe SARS-CoV-2 maternal pneumonia.Method. Descriptive study of the clinical characteristics of all thesenewborns admitted during the months of July and August of 2021.Results. Most of the patients were negative for SARS-CoV-2 in themicrobiological tests performed, most of them did not require prolonged respiratory support and most of them did not present significant pathologies beyond those associated with their prematurity.There was a high frequency of gastrointestinal symptoms and feeding problems, mostly related to difficulties in accessing to breastmilk due to maternal clinical severity and possibly to perinatalinflammatory context.Conclusions. Considering the small sample size, more studies arenecessary to further describe this population. (AU)

Oropharyngeal administration of mother's own milk influences levels of salivary sIgA in preterm infants fed by gastric tube.

The aim of the present study was to explore the effect of oropharyngeal mother's milk administration on salivary secretory immunoglobulin A (sIgA) levels in preterm infants fed by gastric tube. Infants (n = 130) with birth weight < 1500 g were randomly allocated into two groups which both received breast milk for enteral nutrition. The experimental group (n = 65) accepted oropharyngeal mother's milk administration before gastric tube feeding for 14 days after birth. The control group (n = 65) accepted oropharyngeal 0.9% normal saline administration. Saliva concentration of sIgA were assessed at the 2 h, 7th and 14th day after birth. The level of salivary sIgA in experimental group were significantly higher than those in control group on the 7th day after birth (p < 0.05), but there were no differences in salivary sIgA levels on the 14th day between the two groups. The results of quantile regression analysis showed that oropharyngeal mother's milk administration, delivery mode and gestational age had significant effects on the increase of sIgA. SIgA in experimental group and the total number of intervention had a significant positive correlation (p < 0.05). Oropharyngeal mother's milk administration can improve salivary sIgA levels of preterm infants.

The levels of pro- and anti-inflammatory cytokines in premature infants with perinatal infections.

Intrauterine infections are an urgent problem of modern neonatology. One of the causes of intrauterine infective foetal lesions is physiological immunosuppression. The purpose of this study is to investigate the cytokine status in newborns infected with perinatal infections, depending on their body weight. The study examined 145 newborns. Taking into account their body weight, they were divided into 2 groups: main and secondary. The study was conducted in the immunological laboratory of the Medical Centre of Marat Ospanov West Kazakhstan Medical University in the city of Aktobe, with the determination of the level of IgM and IgG to the herpes simplex virus (HSV) types 1, 2, cytomegalovirus (CMV), and chlamydia using the MULTISKANASCENT analyser with the "Chemo" T system. The main results of this study are the predominance of the anti-inflammatory component in both normal weight and underweight infants, which is evidence of the Th-cell-mediated immune response prevalence. The applied value of this study lies in the possibility of applying its results in practice to obtain effective methods to counteract the occurrence and development of intrauterine infections.

Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation.

Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O2) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O2 = 65%) or hypoxia (O2 = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O2, subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65% or 3% O2 together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. Downregulation of two major transcriptional factors, early growth response gene (Egr)-2 and growth factor independence 1 (Gfi1), were identified to play a role in the exaggerated pro-inflammatory response of preterm MФ to LPS insult after priming with 65% or 3% O2. Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.

Immune Profiling of Cord Blood From Preterm and Term Infants Reveals Distinct Differences in Pro-Inflammatory Responses.

Background: Preterm infants are highly vulnerable to infectious disease. While many factors are likely to contribute to this enhanced susceptibility, the immature nature of the preterm immune system is postulated as one key factor. Methods: In our study, we used high-dimensional flow cytometry and cytokine assays to characterise the immune profiles in 25 preterm (range: 30.4-34.1 weeks gestational age) and 25 term infant (range: 37-40 weeks gestational age) cord blood samples. Results: We found that preterm infants exhibit reduced frequencies of monocytes, CD56bright NK cells, CD8+ T-cells, γδ T-cells and an increased frequency of intermediate monocytes, CD4+ T-cells, central memory CD4+ and CD8+ T-cells, Tregs and transitional B-cells compared to term infants. Pro-inflammatory cytokines IL-1ß, IL-6 and IL-17A were lower in preterm infants in addition to chemokines IL-8, eotaxin, MIP-1α and MIP-1ß. However, IL-15 and MCP-1 were higher in preterm infants. Conclusion: Overall, we identify key differences in pro-inflammatory immune profiles between preterm and term infants. These findings may help to explain why preterm infants are more susceptible to infectious disease during early life and facilitate the development of targeted interventions to protect this highly vulnerable group.

Maternal and Infant Immune Repertoire Sequencing Analysis Identifies Distinct Ig and TCR Development in Term and Preterm Infants.

Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. Whereas many studies have investigated the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. In this study, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries, hypothesizing that the high prevalence of infection in patients with PTL may result in specific changes in the T cell and B cell repertoires. We analyzed TCR ß-chain (TCR-ß) and IgH diversity, CDR3 lengths, clonal sharing, and preferential usage of variable and joining gene segments. Both TCR-ß and IgH repertoires had shorter CDR3s compared with those in maternal blood. In cord blood samples, we found that CDR3 lengths correlated with gestational age, with shorter CDR3s in preterm neonates suggesting a less developed repertoire. Preterm cord blood displayed preferential usage of a number of genes. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features and convergence with maternal TCR-ß clones compared with that of term infants. The higher clonal convergence in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients and contribute to a better understanding of neonate immune repertoire development and potential changes associated with PTL.

Aberrant gut-microbiota-immune-brain axis development in premature neonates with brain damage.

Premature infants are at substantial risk for suffering from perinatal white matter injury. Though the gut microbiota has been implicated in early-life development, a detailed understanding of the gut-microbiota-immune-brain axis in premature neonates is lacking. Here, we profiled the gut microbiota, immunological, and neurophysiological development of 60 extremely premature infants, which received standard hospital care including antibiotics and probiotics. We found that maturation of electrocortical activity is suppressed in infants with severe brain damage. This is accompanied by elevated γδ T cell levels and increased T cell secretion of vascular endothelial growth factor and reduced secretion of neuroprotectants. Notably, Klebsiella overgrowth in the gut is highly predictive for brain damage and is associated with a pro-inflammatory immunological tone. These results suggest that aberrant development of the gut-microbiota-immune-brain axis may drive or exacerbate brain injury in extremely premature neonates and represents a promising target for novel intervention strategies.

The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II.

Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.

Effects of Total Enteral Nutrition on Early Growth, Immunity, and Neuronal Development of Preterm Infants.

The feeding of colostrum and mother's transitional milk improves immune protection and neurodevelopmental outcomes. It also helps with gut maturation and decreases the risks of infection. The supply of nutrients from human milk (HM) is not adequate for preterm infants, even though preterm mother's milk contains higher concentrations of protein, sodium, zinc, and calcium than mature HM. The human milk fortifiers, particularly those with protein, calcium, and phosphate, should be used to supplement HM to meet the necessities of preterm infants. The management of fluid and electrolytes is a challenging aspect of neonatal care of preterm infants. Trace minerals such as iron, zinc, copper, iodine, manganese, molybdenum, selenium, chromium, and fluoride are considered essential for preterm infants. Vitamins such as A, D, E, and K play an important role in the prevention of morbidities, such as bronchopulmonary dysplasia, retinopathy of prematurity, and intraventricular hemorrhage. Therefore, supplementation of HM with required nutrients is recommended for all preterm infants.

Complementary Feeding: Recommendations for the Introduction of Allergenic Foods and Gluten in the Preterm Infant.

BACKGROUND: The aim of this systematic review is to analyze the available literature on the introduction of allergenic foods and gluten among preterm infants. METHODS: A systematic review of published studies concerning the introduction of gluten and allergenic foods in preterm infants was performed on PubMed and on the Cochrane Library. RESULTS: Of the 174 PubMed results, 15 papers were considered suitable for the review. A total of 83 records were identified through the Cochrane Library search; eight papers were included in the review. Additional papers were identified from the reference lists of included studies. A secondary search was conducted on the same databases to find recommendations and advice regarding healthy full-term infants that could be translated to preterm infants. Therefore, 59 additional papers were included in the review. CONCLUSIONS: Current guidelines for the introduction of solid food cannot be directly transposed to preterm infants. Further research is needed to provide evidence-based guidelines regarding weaning in preterm infants. To date, we can suggest that in preterm infants allergenic foods and gluten may be introduced when complementary feeding is started, any time after 4 months of corrected age, avoiding delayed introduction and irrespective of infants' relative risk of developing allergy. Avoiding large amounts of gluten during the first few weeks after gluten introduction and during infancy is advised, despite limited evidence to support this recommendation.

The effect of early probiotic exposure on the preterm infant gut microbiome development.

Premature birth, especially if born before week 32 of gestation, is associated with increased risk of neonatal morbidity and mortality. Prophylactic use of probiotics has been suggested to protect preterm infants via supporting a healthy gut microbiota (GM) development, but the suggested strains and doses vary between studies. In this study, we profiled the GM of 5, 10 and 30-day fecal samples from two cohorts of preterm neonates (born <30 weeks of gestation) recruited in the same neonatal intensive care unit. One cohort (n = 165) was recruited from September 2006 to January 2009 before probiotics were introduced in the clinic. The second cohort (n = 87) was recruited from May 2010 to October 2011 after introducing Lacticaseibacillus rhamnosus GG and Bifidobacterium animalis ssp. lactis BB-12 supplementation policy. Through V3-V4 region 16S rRNA gene amplicon sequencing, a distinct increase of L. rhamnosus and B. animalis was found in the fecal samples of neonates supplemented with probiotics. During the first 30 days of life, the preterm GM went through similarly patterned progression of bacterial populations. Staphylococcus and Weissella dominated in early samples, but was gradually overtaken by Veillonella, Enterococcus and Enterobacteriaceae. Probiotic supplementation was associated with pronounced reduction of Weissella, Veillonella spp. and the opportunistic pathogen Klebsiella. Potential nosocomial pathogens Citrobacter and Chryseobacterium species also gradually phased out. In conclusion, probiotic supplementation to preterm neonates affected gut colonization by certain bacteria, but did not change the overall longitudinal bacterial progression in the neonatal period.Abbreviations: GM: Gut microbiota; ASV: Amplicon sequence variant; NEC: Necrotizing enterocolitis; DOL: Days of life; NICU: Neonatal intensive care unit; ESPGHAN: European Society for Pediatric Gastroenterology, Hepatology and Nutrition; Db-RDA: Distance-based redundancy analysis; PERMANOVA: Permutational multivariate analysis of variance; ANCOM: Analysis of compositions of microbiomes; LGG: Lacticaseibacillus (former Lactobacillus) rhamnosus GG; BB-12: Bifidobacterium animalis ssp. lactis BB-12; DGGE: Denaturing Gradient Gel Electrophoresis.

Estradiol correlates with the accumulation of Monocytic Myeloid-Derived Suppressor Cells in Pre-term birth: A possible explanation of immune suppression in pre-term babies.

Synergistic interplay of immune endocrine interaction is prerequisite for an effective maternal fetal tolerance. Pre-term birth (PTB) may be a consequence of altered immune-endocrine crosstalk during third trimester resulting in early breakdown of this tolerance. Myeloid derived suppressor cells (MDSCs), a heterogenous population of immature immune cells are increased in pregnant women and healthy newborns, but their role in PTB still remains obscure. We now report that granulocytic MDSCs (G-MDSCs) is decreased in women delivering prematurely, suggesting their potential role in maintaining maternal fetal tolerance. Interestingly, in contrast statistically significant increase in MDSCs and monocytic MDSCs (M-MDSCs) along with positive correlation with cord serum estradiol (E2), and overexpressed ER-α in placental tissue suggested E2 mediated accumulation of M-MDSCs in PTB babies. MDSCs mediated immune suppression is accompanied with subsequent decline in total T cells and its subtypes: Th and Tc in PTB babies, which signifies their potential contribution towards the impaired immune system of PTB babies.

Immune Response of Indian Preterm Infants to Pentavalent Vaccine Varies With Component Antigens and Gestational Age.

Childhood vaccination plays critical role in protecting infants from several dreaded diseases. Of the global 15 million preterm (PT) infants with compromised immune system born annually, India contributes to >3.5 million. Generation of adequate vaccine-induced immune response needs to be ensured of their protection. Immune response of Indian PT (n = 113) and full-term (FT, n = 80) infants to pentavalent vaccine administered as per the national recommendation was studied. Antibody titers against component antigens of pentavalent vaccine, immune cells profiling (T and B cells, monocytes and dendritic cells) and plasma cytokines were determined pre- and post-vaccination. Additionally, cell-mediated recall immune responses to pentavalent antigens were evaluated after short time antigenic exposure to infant PBMCs. Irrespective of gestational age (GA), all the infants developed adequate antibody response against tetanus, diphtheria, and protective but lower antibody levels for Haemophilus influenzae type-b and hepatitis B in preterm infants. Lower (~74%) protective antibody response to pertussis was independent of gestational age. PT-infants exhibited lower frequencies of CD4 T cells/dendritic cells/monocytes, increased plasma IL-10 levels and lower proliferation of central and effector memory T cells than in term-infants. Proliferative central memory response of FT-infants without anti-pertussis antibodies suggests protection from subsequent infection. Responder/non-responder PT-infants lacked immunological memory and could be infected with Bordetella. For hepatitis B, the recall response was gestational age-dependent and antibody status-independent. Humoral/cellular immune responses of PT-infants were dependent on the type of the immunogen. Preterm infants born before 32 weeks of gestation may need an extra dose of pentavalent vaccine for long lived robust immune response.

Prenatal Immunity and Influences on Necrotizing Enterocolitis and Associated Neonatal Disorders.

Prior to birth, the neonate has limited exposure to pathogens. The transition from the intra-uterine to the postnatal environment initiates a series of complex interactions between the newborn host and a variety of potential pathogens that persist over the first few weeks of life. This transition is particularly complex in the case of the premature and very low birth weight infant, who may be susceptible to many disorders as a result of an immature and underdeveloped immune system. Chief amongst these disorders is necrotizing enterocolitis (NEC), an acute inflammatory disorder that leads to necrosis of the intestine, and which can affect multiple systems and have the potential to result in long term effects if the infant is to survive. Here, we examine what is known about the interplay of the immune system with the maternal uterine environment, microbes, nutritional and other factors in the pathogenesis of neonatal pathologies such as NEC, while also taking into consideration the effects on the long-term health of affected children.

Factors That Influence Infant Immunity and Vaccine Responses.

The neonatal period and early infancy are times of increased vulnerability to infection. The immune system of infants undergoes rapid changes and a number of factors can influence the maturation and function of the early infant immune system, amongst these factors are maternal infections and immunity. Infants who are HIV-exposed, but uninfected show important immune alterations, which are likely to be associated with the increased morbidity and mortality observed in these infants. Maternally derived antibodies are crucial in early life to protect infants from infection during the time when their own immune system is becoming more experienced and fully mature. However, maternal antibodies can also interfere with the infant's own antibody responses to primary vaccination. Preterm infants are particularly vulnerable to infection, having not had the opportunity to benefit from the transplacental transfer of maternal antibodies in late pregnancy. In addition, further differences have been observed in the innate and adaptive immune system between preterm and term infants. Here, we focus on maternal influences on the infant immune system, using HIV and maternal vaccination as examples and finish by considering how prematurity impacts infant immune responses to vaccination.

Identification of Inflammatory Genes, Pathways, and Immune Cells in Necrotizing Enterocolitis of Preterm Infant by Bioinformatics Approaches.

BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most serious gastrointestinal disease-causing high morbidity and mortality in premature infants. However, the underlying mechanism of the pathogenesis of NEC is still not fully understood. METHODS: RNA sequencing of intestinal specimens from 9 NEC and 5 controls was employed to quantify the gene expression levels. RNA sequencing was employed to quantify the gene expression levels. DESeq2 tool was used to identify the differentially expressed genes. The biological function, pathways, transcription factors, and immune cells dysregulated in NEC were characterized by gene set enrichment analysis. RESULTS: In the present study, we analyzed RNA sequencing data of NECs and controls and revealed that immune-related pathways were highly activated, while some cellular responses to external stimuli-related pathways were inactivated in NEC. Moreover, B cells, macrophages M1, and plasma cells were identified as the major cell types involved in NEC. Furthermore, we also found that inflammation-related transcription factor genes, such as STAT1, STAT2, and IRF2, were significantly activated in NEC, further suggesting that these TFs might play critical roles in NEC pathogenesis. In addition, NEC samples exhibited heterogeneity to some extent. Interestingly, two subgroups in the NEC samples were identified by hierarchical clustering analysis. Notably, B cells, T cells, Th1, and Tregs involved in adaptive immune were predicted to highly infiltrate into subgroup I, while subgroup II was significantly infiltrated by neutrophils. The heterogeneity of immune cells in NEC indicated that both innate and adaptive immunes might induce NEC-related inflammatory response. CONCLUSIONS: In summary, we systematically analyzed inflammation-related genes, signaling pathways, and immune cells to characterize the NEC pathogenesis and samples, which greatly improved our understanding of the roles of inflammatory responses in NEC.

Lung CD103+dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection.

Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a+ CD103+ dendritic cells (DCs), pro-inflammatory responses, and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103+ DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, 2-day-old C57BL/6J, CD103+ DC-deficient Batf3-/- or Clec9agfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared with wild-type mice, hyperoxia-exposed Batf3-/- mice showed reduced levels of IL-12p40, IFN-γ, and TNF-α, fewer IFN-γ-producing CD4+ T cells, and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9agfp-/- mice. Furthermore, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A+ cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103+ DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103+ DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.

The association of γδ-T cells with bronchopulmonary dysplasia in premature infants.

BACKGROUND: As the survival rate of premature infants increases, the incidence of bronchopulmonary dysplasia (BPD), a chronic complication of premature infants, is also higher than before. The pathogenesis of BPD is complicated, and immune imbalance and inflammatory response may play important roles in it. OBJECTIVE: To investigate the correlation between lymphocyte subsets in peripheral blood, especially γδ-T cells, and BPD of preterm infants. MATERIALS AND METHOD: The study was carried out with the peripheral blood of premature infants (GA < 32 weeks, BW < 1500 g), which were collected at 24 h or 3-4 weeks after birth. The infants were divided into non-BPD groups and BPD groups that were classified as mild or moderate and severe in preterm infants based on the magnitude of respiratory support at 28 days age and 36 weeks postmenstrual age. The γδ-T, CD3+, CD4+, CD8+ and total lymphocyte subsets in peripheral blood were detected by flow cytometry. RESULTS: The percentages of T lymphocyte subsets in peripheral blood were not different between BPD and non-BPD within 24 h after birth. And no significant difference was found in T lymphocyte subsets among neonates with BPD of different severities. However, the infants who developed BPD had a significant increase in γδ-T cells compared to non-BPD ones within 3-4 weeks after birth. CONCLUSIONS: It seems that γδ-T cells in peripheral blood are correlated with BPD. However, the causality of BPD and various lymphocytes remains unclear, which need to be further studied.