Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IgG, IgA, and IgE production by newborn B cells is limited both in vivo and in vitro in various activation conditions, whereas IgM production is readily detectable. It has been suggested that the Ig heavy chain switch inability could be the consequence of T and B cell immaturity. As the interaction between CD40 (expressed on B cells) and its ligand CD40-L (expressed on activated T cells) triggers a key signal required for isotype switching, we studied the expression and function of these two components in normal fetuses, newborns, and infants, compared with adults. CD40-L expression was not inducible in 28 of 30 specimens of newborn cord-blood T cells following incubation with PMA and ionomycin, whereas activation markers such as CD69 were inducible. CD40-L expression was triggered by activation of T cells from infants > 3 wk of age. Surprisingly, T cells from 19- to 28-wk-old fetuses also expressed CD40-L following activation. CD40-L expression on newborn T lymphocytes was induced on T cell lines generated in the presence of PHA and maintained with IL-2 following further stimulation with PMA and ionomycin. CD40-L mRNA transcripts and intracytoplasmic protein expression following activation of newborn T cells were strongly decreased, leading to undetectable protein membrane detection. These results point to a possible transcriptional down-regulation of CD40-L expression by neonatal T lymphocytes. In addition, fetal and cord-blood B cells were poorly able to switch to IgG or IgA by stimulation with CD40 agonists (Ab or soluble CD40-L) in the presence of IL-4 or IL-10 as also detected with surface IgD+ adult B cells. Both phenomena could contribute to the neonatal Ig switch inability, although distinct underlying regulatory mechanisms are probably involved, as suggested by different in vivo time courses.
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PMID:Undetectable CD40 ligand expression on T cells and low B cell responses to CD40 binding agonists in human newborns. 753 Jul 39

The physiologically low or absent IgG2 responses of infants have been attributed to T or B cell functional immaturity. We have analyzed the capacity of adult and neonatal T lymphocytes to secrete IgG2 switch factor (IgG2-SF) and the capacity of neonatal B cells to respond to such factors. The IgG2-SF capacity was assessed on CD40-activated naive B cells, measuring IgG2 by ELISA in supernatants of cultures performed in the presence of IL-10. T cells secreted IgG2-SF together with IL-2 and IFN-gamma, after activation with a combination of anti-CD2, anti-CD28 and phorbol myristate acetate (Th1-like activation). In contrast, activation with anti-CD3 and anti-CD28, which yielded IL-4 and IL-10 but neither IL-2 nor IFN-gamma (Th2-like activation), did not result in the secretion of IgG2-SF. The supernatant of activated neonatal T cells contained IgG2-SF. Neonates' B cells produced almost as much IgG2 as did naive adult B cells. The effect of IgG2-SF was further demonstrated by its ability to induce 3-15% of CD40-activated naive B cells to express cytoplasmic IgG2 regardless of the presence of IL-10. This study demonstrates that: (i) IgG2 switch can be T cell dependent in humans, (ii) IgG2-SF is produced with Th1-like cytokines and (iii) low IgG2 responses in infants do not result from either an inability of T cells to produce IgG2-SF or an inability of B cells to undergo IgG2 switch in vitro.
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PMID:Delayed IgG2 humoral response in infants is not due to intrinsic T or B cell defects. 892 28

Neonates are more susceptible to infection than adults and exhibit more intense or prolonged clinical symptoms. The extent to which deficiencies in T cell or antigen presenting cell (APC) function underlie hyporesponsiveness is incompletely understood. Here, immune function of cord blood mononuclear cells (CBMC), from healthy, full-term neonates was compared with adult PBMC. As widely reported, polyclonally-stimulated T cell proliferation was found to be equivalent, while IFN gamma responses were markedly lower amongst neonates. Reasoning that such stimuli may elicit responses qualitatively different from those that would be obtained following MHC-dependent, cognate T cell activation, alloantigen-specific responses were evaluated. Strikingly, neonates exhibited IFN gamma, IL-4 and IL-10 production equal to adults in short term primary culture. Both the frequency (Fisher's p < 0.0004) and intensity (< 7.5 vs 36.5 pg/ml; Wilcoxon P = 0.005) of alloantigen stimulated IL-5 responses were elevated among neonates, a finding equally evident using irradiated adult or neonatal cells as stimulators. Finally, the relative capacity of neonatal APC as stimulators of cytokine synthesis was assessed by a novel approach using CBMC as both responders and stimulators in MLR. Irradiated neonatal cells consistently stimulated similar proliferative but substantially lower IFN gamma responses than did adult APC, independent of responder origin. The data argue; (i) T cells are largely immunocompetent at birth, (ii) accessory cell function is not fully mature, and (iii) the widely observed hyporesponsiveness to pathogenes may be primarily due to immaturity of APC function or costimulator molecule expression.
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PMID:Analysis of neonatal T cell and antigen presenting cell functions. 943 98

The synthesis of IgE class antibodies takes place in plasma cells after activation of B lymphocytes by two different signals. The presence of interleukin-4 (IL-4) in the microenvironment and intimate contact between B and T cells through the CD-40 molecule and its specific ligand (CD-40L) are necessary. Lymphocyte activation also can be induced by mast cells. IgE does not cross the placenta, but fetuses are capable of synthesizing it. We attempted to identify children at high risk of atopy by determining IgE in umbilical cord blood. The system was not entirely satisfactory because many other factors are involved, but it demonstrated that intrauterine sensitization can occur. IgE-mediated allergy is conditioned by the predominance of Th2 lymphocytes (secretors of IL-4, IL-5, and IL-10) over Th1 lymphocytes (secretors of IL-12 and IFN gamma). This imbalance is physiological in the fetus and Th1 stimulation causes miscarriage. At birth, the functional predominance of Th2 continues, probably because of the immaturity of the dendritic antigen-presenting cells. An irregular maturation process takes place in the following months; for instance, while the intestinal mucosa tends towards tolerance and matures more rapidly, the respiratory mucosa tends toward the Th1 response and is slower. It is likely that sensitization during fetal and neonatal life is interesting because it generates type Th2 memory cells that can predispose toward atopic responses in the future.
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PMID:[Synthesis and modulation of IgE in the newborn infant]. 967 88

Aspirin is the most commonly used analgesic and antiinflammatory agent. In this study, at physiological concentrations, it profoundly inhibited CD40, CD80, CD86, and MHC class II expression on murine, GM-CSF + IL-4 stimulated, bone marrow-derived myeloid dendritic cells (DC). CD11c and MHC class I expression were unaffected. The inhibitory action was dose dependent and was evident at concentrations higher than those necessary to inhibit PG synthesis. Experiments with indomethacin revealed that the effects of aspirin on DC maturation were cyclooxygenase independent. Nuclear extracts of purified, aspirin-treated DC revealed a decreased NF-kappaB DNA-binding activity, whereas Ab supershift analysis indicated that aspirin targeted primarily NF-kappaB p50. Unexpectedly, aspirin promoted the generation of CD11c+ DC, due to apparent suppression of granulocyte development. The morphological and ultrastructural appearance of aspirin-treated cells was consistent with immaturity. Aspirin-treated DC were highly efficient at Ag capture, via both mannose receptor-mediated endocytosis and macropinocytosis. By contrast, they were poor stimulators of naive allogeneic T cell proliferation and induced lower levels of IL-2 in responding T cells. They also exhibited impaired IL-12 expression and did not produce IL-10 after LPS stimulation. Assessment of the in vivo function of aspirin-treated DC, pulsed with the hapten trinitrobenzenesulfonic acid, revealed an inability to induce normal cell-mediated contact hypersensitivity, despite the ability of the cells to migrate to T cell areas of draining lymphoid tissue. These data provide new insight into the immunopharmacology of aspirin and suggest a novel approach to the manipulation of DC for therapeutic application.
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PMID:Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. 1139 Apr 49

Infant survival depends on the ability to respond effectively and appropriately to environmental challenges. Infants are born with a degree of immunological immaturity that renders them susceptible to infection and abnormal dietary responses (allergies). T-lymphocyte function is poorly developed at birth. The reduced ability of infants to respond to mitogens may be the result of the low number of CD45RO+ (memory/antigen-primed) T cells in the infant or the limited ability to produce cytokines [particularly interferon-y, interleukin (IL)-4, and IL-10. There have been many important changes in optimizing breast milk substitutes for infants; however, few have been directed at replacing factors in breast milk that convey immune benefits. Recent research has been directed at the neurological, retinal, and membrane benefits of adding 20:4n-6 (arachidonic acid; AA) and 22:6n-3 (docosahexaenoic acid; DHA) to infant formula. In adults and animals, feeding DHA affects T-cell function. However, the effect of these lipids on the development and function of the infant's immune system is not known. We recently reported the effect of adding DHA + AA to a standard infant formula on several functional indices of immune development. Compared with standard formula, feeding a formula containing DHA + AA increased the proportion of antigen mature (CD45RO+) CD4+ cells, improved IL-10 production, and reduced IL-2 production to levels not different from those of human milk-fed infants. This review will briefly describe T-cell development and the potential immune effect of feeding long-chain polyunsaturated fatty acids to the neonate.
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PMID:Polyunsaturated fatty acids and T-cell function: implications for the neonate. 1172 54

To evaluate the development of the neonatal immune system, we measured T lymphocyte response to Con A, intracellular IL-2, IL-4, IFN-gamma and IL-10 production, and natural killer cell (NKC) activity in 12 very preterm, 12 preterm and 20 term neonates, 10 children and 10 adults. Immunoproliferation to Con A was significantly lower in cord blood than in children or adults. The percentage of CD4+ lymphocytes was significantly higher in newborns while CD8+ cells were higher at older ages, with a resulting gradual decline of the CD4+/CD8+ ratio. The percentage of IL-2-producing CD4+ and CD8+ cells was higher in all newborn groups than in children and adults, while the percentage of IL-4-producing cells was higher for CD8+ and lower for CD4+ cells in cord blood than in children and adults. Neonates had substantially lower percentages of CD4+ and CD8+ IFN-gamma-producing cells. A significant negative correlation was observed between gestational age and IFN-gamma-CD4+-, IL-2-CD8+-, and IL-10- CD4+-producing cells. In addition, a positive correlation was found between gestational age and IL-10-CD8+-producing cells. Percentages of CD4+/CD45RA+ cells were higher and CD4+/CD45RO+ percentages were lower in newborns than in children and adults. NKC activity in infants was significantly correlated with gestational age and significantly impaired compared to children and adults. On the whole, these results suggest a gradual development of immunity during gestation and show significant immaturity of cellular immune response at birth. The reduction of NKC activity, the lower proliferative response of T cells, the reduced cytotoxic response and a dysregulated cytokine production may contribute to the neonatal increased risk of infection and to the low incidence of graft-versus-host disease after cord blood transplantation.
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PMID:Age-related changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children and adults. 1459 40

To test whether reduced immune responsiveness in early life may be related to the immaturity of neonatal antigen-presenting cells, we comparatively assessed the phenotypic and functional characteristics of dendritic epidermal leukocytes (DEL) and epidermal Langerhans cells (LC) in newborn (NB) and adult mice, respectively. We report that purified, 3-day-cultured DEL do not acquire the morphology and phenotype typical of LC and are significantly weaker stimulators of naive, allogeneic CD4+ and CD8+ T cells than LC. Freshly isolated DEL are twice as efficient as LC in the uptake of fluorescein isothiocyanate-conjugated tracers but are not able to present these to antigen-specific T cell hybridomas. To clarify the underlying cause, cytokine expression of NB and adult epidermal cells (EC) was examined. We found that DEL express considerable amounts of interleukin (IL)-10, that IL-10 in NB EC supernatants partially inhibits LC maturation, and that DEL-enriched EC from IL-10-/- mice induce stronger primary T cell responses compared with those from IL-10+/+ mice. We conclude that IL-10 is one of the factors preventing maturation and differentiation of DEL into immunocompetent LC in intrauterine life and is at least partly responsible for the poor immune responsiveness of neonates.
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PMID:Autocrine IL-10 partially prevents differentiation of neonatal dendritic epidermal leukocytes into Langerhans cells. 1519 30

Monocyte-derived dendritic cells (DCs) were used as an in vitro model of myeloid DCs in order to determine a minimum marker pattern with which to characterize and distinguish different stages of DC activation and maturation. Phenotypic changes induced on immature DCs by two prototypic stimuli, poly I:C and CD40 ligation, were first examined. Both elicited HLA-DR, CD40, CD86 and CXCR4 upregulation, and CCR5 downregulation, but only CD40 ligand-stimulated DCs became CD83(+)\CCR7(+), whereas poly I:C-stimulated DCs expressed lower CD83 levels and were mostly CCR7(--). CD40 ligation and poly I:C elicited increased production of inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha, of IL-10 and the CCL5 chemokine, but profiles differed as to higher IL-10, IL-12 and CCL22 (a CCR4 ligand important for T cell recruitment) levels for the former, and of CCL4 and CCL5 for the latter. Thus, a limited set of phenotypic markers, cytokine and chemokine production assays, may be used to distinguish the three stages in the life of DCs: immaturity, activation and full maturation. The ability of purified protein derivative-loaded DCs to stimulate autologous T cells to produce IL-2, IL-4 and interferon-gamma indeed depended on their activation stage and endocytic activity, which decreased upon maturation. We then examined whether ligation of CD4, CCR5 and\or CXCR4, the receptor and coreceptors of human immunodeficiency virus envelope gp120, respectively, affected DC activation or maturation, neither a monoclonal antibody to the gp120-binding site on CD4 nor CCL5 nor CXCL12, the natural ligands of CCR5 and CXCR4, respectively, nor gp120 altered the DC activation and maturation processes.
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PMID:Double-stranded RNA stimulation or CD40 ligation of monocyte-derived dendritic cells as models to study their activation and maturation process. 1531 72

The susceptibility to infections and the strong Th2 bias observed in neonates are thought to be due to the immaturity of the dendritic cell (DC) compartment. We show that neonatal DCs, like their adult counterparts, elicit Th1 responses. We also demonstrate that during potentially harmful systemic inflammation, after Toll-like receptor (TLR) 9 triggering, neonatal B cells produce high concentrations of IL-10, preventing optimal IL-12 secretion by neonatal DCs and, thus, Th1 priming. Although both CD5+ and CD5- B cell subsets respond to CpG ODN stimulation, we found that only CD5+ B cells produce IL-10. Therefore, these results show the regulatory role of CD5+ B cells on DC activation in vivo for Th1/Th2 polarization and highlight the paradoxical effects of TLR triggering in vivo.
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PMID:Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. 1584 51


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