Immunized ER-β−/− and WT donors

LNC were sorted for CD11b

Immunized ER-β−/− and WT donors

LNC were sorted for CD11b/CD11c+ DC and CD11b/CD11c− (non-DC) fractions. The DC fractions were from ER-β−/− or WT mice, whereas non-DC fractions were all from WT mice. Cells from various ER-β−/− and WT donors were mixed with the ratios of DC (3%) and non-DC (97%) based on the immune cell composition KPT-330 mw of non-manipulated immunized donor LNC, then stimulated with autoantigen before adoptive transfer into ER-β ligand- or vehicle-treated recipient mice (Fig. 5A). As shown in Fig. 5B, ER-β ligand-treated mice adoptively transferred with WT DC (green) had reduced EAE disease severity compared with ER-β ligand-treated mice that were adoptively transferred ER-β−/− DC (orange). These results demonstrated that ER-β ligand treatment during the effector phase of EAE acts at least in part on ER-β-expressing DC. Previously, our lab showed that ER-β ligand treatment was neuroprotective in active EAE without altering cytokine production of autoantigen-specific selleck chemicals immune cells in the periphery and without reducing the level of CNS inflammation. Specifically, ER-β ligand treatment preserved axon densities and myelin staining late in disease despite persistent inflammation in the CNS 16. However, it remained unknown whether qualitative differences might exist in the inflammatory

infiltrates of ER-β ligand-treated EAE mice. Therefore, in the present study, we examined immune cells in the CNS of EAE mice treated with ER-β ligand. We found that ER-β ligand treatment conferred clinical protection in the effector phase of adoptive EAE and reduced the percentage of DC in the target organ. DC isolated from the CNS of ER-β ligand-treated EAE mice exhibited decreased TNF-α production. Finally, we showed that ER-β ligand treatment in EAE conferred disease protection through ER-β expressed

on DC. This is the first study elucidating an in vivo immunomodulatory role for ER-β during autoimmune demyelinating disease. DC are emerging as critical mediators of inflammation in a variety of organ-specific autoimmune diseases such as rheumatoid arthritis, psoriasis, and EAE due to their efficient antigen-presenting ability 20, 26, 28–31. CNS DC are critical to EAE Tau-protein kinase pathogenesis, as DC infiltrates in the CNS during EAE preferentially localize with effector TC at sites of inflammation and they alone can activate infiltrating naïve TC to differentiate and perpetuate inflammation 20, 28. Our finding of quantitative and qualitative effects of ER-β ligand treatment on CNS DC, which occurred in a setting of improved clinical and neuropathologic disease corroborates other studies showing that CNS DC play a critical role in EAE disease severity 32–34. Further, ER-β ligand treatment can now be considered as a novel treatment strategy targeting DC in the CNS. DC are excellent targets for organ-specific autoimmune diseases for several reasons.

Cell viability was determined by Trypan blue exclusion in human a

Cell viability was determined by Trypan blue exclusion in human acute monocytic leukaemia cell line (THP-1) cells treated for 24 h with different concentrations of tumour necrosis factor (TNF)-α and/or interferon (IFN)-γ as indicated. Grey bars correspond to the cytokine concentration selected for further studies; TNF-α (10 ng/ml) and IFN-γ (200 UI/ml). Fig. S3. Kinetic of transglutaminase

2 (TG2) induction by tumour necrosis factor (TNF)α + interferon (IFN)-γ. Caco-2 and human acute monocytic leukaemia cell line (THP-1) cells were incubated for different times with TNF-α (10 ng/ml) and IFN-γ (200 UI/ml). Levels of TG2 transcript were determined by quantitative real time–polymerase chain reaction (RT–PCR). Results were normalized against β-actin and relative TG2 mRNA levels were referred to the non-stimulated control (value = 1). Data represent means ± standard error of the mean (n = 3). The Mann–Whitney U-test Small molecule library cell line was performed: *P < 0·05; **P < 0·01. "
“Citation Sater MS, Finan RR, Al-Hammad SA, Mohammed FA, Issa AA, Almawi WY. High frequency of anti-protein Z IgM and IgG autoantibodies in women with idiopathic recurrent spontaneous miscarriage. Am J Reprod Immunol 2011; 65: 526–531 Problem  Protein Z (PZ) system is an anticoagulant pathway Imatinib ic50 involved in the physiologic regulation of coagulation, and PZ deficiency reportedly enhances prothrombophilic mechanisms, including those

implicated with idiopathic recurrent miscarriage (RSM). We investigate plasma anti-PZ IgM and IgG levels in RSM women and in multiparous control women. Methods  Anti-PZ IgM and IgG levels were measured in 265 RSM women and 283 age-matched control women by ELISA. Results  Elevated anti-PZ IgG (P < 0.001) and IgM (P < 0.001) titers were seen in patients. The areas under the curves for ROC curve for anti-PZ IgM (0.898 ± 0.044) and IgG (0.898 ± 0.042) demonstrated no variation in diagnostic capacity. Molecular motor Multivariate analysis confirmed the association of elevated anti-PZ IgM [adjusted odds ratio, aOR (95% CI) = 6.46 (2.44–17.11)] and IgG [aOR (95% CI) = 7.44 (2.54–21.79)] as independent predictors of RSM after adjusting for confounding covariates and demonstrated a clear gradation of increasing RSM risk associated with

increased antibody titers. Conclusion  The presence of anti-PZ IgM and IgG antibodies are risk factors for RSM. “
“Ifng/Ifngr1 are the main genes that are associated with tuberculosis. We continued to search for other functional single nucleotide polymorphisms (SNP) and investigated their influence on patients with tuberculosis in the Chinese population. Seven SNP located in the ifng and ifngr1 genes were genotyped by ligase detection reaction in 222 cases and 188 ethnically matched controls. A significant genetic association between rs7749390 (located on the exon/intron splice site of the ifngr1 gene) and tuberculosis was observed, and the log-additive model was accepted as the best inheritance model to fit these data (OR: 1.35, 95% CI: 1.02–1.80, P = 0.038).

02, 95% CI 1 01–1 03 (P < 0 001) Most CKD patients treated with

02, 95% CI 1.01–1.03 (P < 0.001). Most CKD patients treated with ESA require concomitant iron supplementation, particularly when targeting higher haemoglobin levels. This raises the intriguing

possibility that iron therapy may be an important effect modifier contributing to the complex relationship between INCB024360 ESA dose, haemoglobin level and clinical outcomes. Previous epidemiologic data have linked augmented body iron stores and/or increasing IV iron doses with heightened risks of both cardiovascular disease28–30 and bacterial infections,31 although other studies have refuted these findings.32 High ferritin and low transferrin saturation values have similarly been associated with increased mortality,33,34 but these traditional iron markers may have been confounded

by non-iron-related conditions, such as infection, inflammation and protein-energy malnutrition. The effect of iron therapy on mortality has not been systematically CH5424802 studied in an ESA RCT and patients with iron deficiency or iron overload were specifically excluded from the four largest ESA trials. In the Normal Haematocrit Cardiac Trial, more patients received intravenous iron in the normal haematocrit group than in the low haematocrit group (85.1% vs 75.4%, P < 0.001), although serum ferritin levels at 12 months were lower in the former (391 ± 424 vs 503 ± 442 ng/mL, P = 0.005) and transferrin saturation values were comparable between the two groups.9 The odds ratio of mortality for patients in the normal haematocrit group who received intravenous iron dextran during the 6 months before death or censoring was 2.4 compared with those who did not receive intravenous iron (P < 0.001). During the 6 months period before death, the average doses of intravenous iron dextran

in the normal and low haematocrit groups were 214 ± 190 and 145 ± 179 mg/4 weeks period, respectively. On the other hand, more patients in the placebo group received intravenous iron than in the darbepoetin group in the TREAT trial (20.4% vs 14.8%, P < 0.001).10 In the CREATE trial, 52% and 42% of patients in high and low haemoglobin groups received at least one dose of intravenous iron.14 Similarly, overall use of iron was comparable Thalidomide in high (52%) and low (48.3%) haemoglobin groups in the CHOIR trial.12 None of these RCTs provided more data on iron therapy, iron studies and outcomes. Consequently, based on trial information to date, there is insufficient evidence to conclude whether iron loading contributed to the poorer outcomes associated with targeting higher haemoglobin levels with ESA. Currently, there is a reasonable body of evidence to indicate more harm than benefit from targeting higher haemoglobin levels with ESA therapy. Patients requiring higher doses of ESA experience increased mortality at any haemoglobin level and patients achieving target haemoglobin levels have better outcomes than those who fail to achieve.

Female BALB/c mice were housed in the Medical Research Facility,

Female BALB/c mice were housed in the Medical Research Facility, University of Aberdeen. The work conformed to the UK Animal (Scientific Procedures) Act (1986) and was carried out with UK Home Office project license approval. Female B6D2F1/Crl mice (Charles River, Morrisville, NC, USA) were housed at the Piedmont Research Center contract research organization, Morrisville, North Carolina, USA. Piedmont specifically complies with the recommendations of the Guide for Care and Use of Laboratory

Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care. The animal care and use program at Piedmont is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International, which assures compliance Kinase Inhibitor Library mouse with accepted standards for the care and use of laboratory animals. Anti-CD3 mAb (OKT-3, ECACC, Salisbury, UK), or tuberculin Selleck Sorafenib purified protein derivative PPD (Statens Serum Institut, Copenhagen, Denmark) were each added to cultures at 10 μg/mL, unless stated otherwise. SEB (Sigma-Aldrich, Poole, Dorset, UK) was used to stimulate cultures at 2 μg/mL, unless stated otherwise. Cell proliferation in cultures was measured from 3H thymidine incorporation in triplicate samples using a 1450 Microbeta liquid scintillation counter (LKB Wallac, Turku, Finland). Results are presented as mean cpm ±SD or as stimulation index of autologous unfractionated cells. ELISA for cytokines

produced in cultures were based on previously published methods [51]. The Ab pairs for human cytokines were: anti-IFN-γ (clones NIB42 and 4S.B3 BD Biosciences, Oxford, UK), anti-IL-17A Tryptophan synthase (clones eBio64CAP17 and eBio64DEC17, eBiosciences, Hatfield, UK), and for mouse:

anti-IFN-γ (clones AN-18 and R4–6A2) and IL-17A (clones TC11–18H10.1 and TC11–8H4.1, all BD Biosciences). All cytokine standards were from Peprotech EC Ltd. (London, UK). Bound Ab was detected using streptavidin-labeled alkaline phosphatase with a phosphatase substrate (both Sigma Aldrich), and absorbance measured at 450 nm (corrected with a reference reading at 492 nm) with a Multiskan MS microplate photometer (Life and Laboratory Sciences, Basingstoke, UK). Cell culture supernatant levels of cytokine were measured in stimulated vs. nonstimulated control wells following 5 days culture of PBMCs or fractionated T-cell subsets at 37°C, 5% CO2, unless stated otherwise in individual experiments. Ab JMW-3B3 (IgG1λ) specific for the soluble, but not membrane-bound, isoform of human CTLA-4 was produced by standard hybridoma technologies after immunization of BALB/c mice with a peptide, K120-M137, unique to the C terminus of sCTLA-4 (Supporting Information Fig. 1 and 2). Commercially available antibodies that do not discriminate between the isoforms (pan-specific) were obtained from several sources (Human clones: BNI3, AbD Serotec, Kidlington, UK; 14d3, eBioscience; AS-32P, Ab solutions, Mountain View, CA, USA, ANC.

Accordingly, IL-9 production by Th9 cells strictly correlated wit

Accordingly, IL-9 production by Th9 cells strictly correlated with IRF4 expression, and Irf4–/– CD4+ T cells failed to differentiate into IL-9 producers under Th9-inducing conditions [44]. Conversely, transient deletion of IRF4 in wild-type (WT) CD4+ T cells prevented the differentiation of Th9 cells. At the molecular level, IRF4 directly induced IL-9 expression by binding to and activating the Il9 promoter. The importance of IRF4 for Th9 development in vivo was shown in a mouse model for allergic asthma, in which Irf4–/– mice were totally resistant to the induction of allergic airway disease. Importantly, reconstitution of the mice with WT Th9 cells restored asthma symptoms, demonstrating not only

the importance of IRF4 for U0126 Th9 development in vivo, but also AZD2014 purchase a role for Th9 cells during allergic airway disease [44]. Consistent with the finding that AICEs are present in the upstream regulatory elements of the Il9 and Il10 genes [16], BATF cooperates with IRF4 for the induction

of IL-9 [42]. Accordingly, mouse and human Th9 cells depend on BATF for IL-9 production. Similarly to IRF4, BATF expression in Th cells promotes allergic airway inflammation [42]. As Th9-cell differentiation was in addition described to depend on the ETS transcription factor PU.1 [45], IRF4 might also regulate Th9-cell differentiation via EICE binding in concert with PU.1. Finally, for the induction of IL-9 production, IRF4 cooperates with SMAD2 and SMAD3 proteins, which are induced by TGF-β signaling [21], indicating multiple mechanisms and interaction partners utilized by IRF4 during Th9-cell differentiation (Fig. 1A). The relevance of IRF4 for the in vivo development of Th17 cells has been demonstrated in several

autoimmune disease models, in which pathogenic Th17 cells play a central role. Irf4–/– mice have been shown to be totally resistant to the induction of experimental autoimmune encephalomyelitis (EAE), which is a mouse model for multiple sclerosis (MS), and this resistance correlated with lack of Th17-cell differentiation [46]. Reconstitution of Irf4–/– mice with WT CD4+ T cells restored Leukocyte receptor tyrosine kinase their susceptibility to the disease and the transferred cells developed a Th17 phenotype, again pointing to a T-cell intrinsic defect of Irf4–/–CD4+ T cells [46]. Furthermore, IRF4 deficiency was protective in T-cell-dependent colitis models, such as transfer colitis and oxazolone-induced as well as trinitrobenzene sulfonic acid induced colitis [47]. Again, resistance to colitis induction correlated with defective differentiation of naïve Irf4–/–CD45RBhighCD4+ T cells into Th17 cells, along with reduced IL-6 production by Irf4–/– mucosal T cells. Consistent with these findings, IRF4 levels were augmented in patients with inflammatory bowel disease and correlated with enhanced production of IL17 and IL22 mRNA [47, 48]. Thus, lack of IRF4 seems to cause resistance to Th17-mediated autoimmune diseases.

A key feature

of T gondii pathogenesis is the parasite’s

A key feature

of T. gondii pathogenesis is the parasite’s ability to cross formidable biological barriers in the infected host and enter tissues such as the brain, eye, and placenta. The dissemination of T. gondii into these organs underlies the severe disease that accompanies human toxoplasmosis. In this review we will focus on seminal studies as well as exciting recent findings that have shaped our current understanding of the cellular and click here molecular mechanisms by which T. gondii journeys throughout the host and enters the vital organs to cause disease. This article is protected by copyright. All rights reserved. “
“Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, with remarkable variability in disease severity. An exaggerated proinflammatory response and influx of leukocytes is part of the pathogenesis of severe RSV disease. Here, we show an increase in proinflammatory cytokine production by human immune cells after stimulation with RSV and muramyl dipeptide (MDP), which is recognized

by nucleotide-binding oligomerization domain containing 2 (NOD2). PBMCs from Crohn’s disease patients homozygous for the 3020insC mutation in the NOD2 gene did not show a synergistic response to stimulation with RSV and MDP, suggesting that NOD2 is essential for the observed synergy. Further experiments aimed at identifying the viral ligand indicated that viral RNA plays an essential role in the recognition of RSV. Stimulation with RSV or Poly(I:C) induced Pifithrin-�� manufacturer IFN-β expression, which resulted in an increased expression of the viral receptors TLR3 and RIG-I, as well as an increased NOD2 expression. Our data indicate that IFN-β induction by viral RNA is an essential first step in 2-hydroxyphytanoyl-CoA lyase the increased proinflammatory response to MDP. We hypothesize that the enhanced proinflammatory response to MDP following RSV infection may be an important factor in determining the outcome of the severity of disease. Worldwide, millions of people die of infectious diseases. The vast majority of these infections are caused by pathogens that invade the host via mucosal surfaces, that is,

the gastrointestinal, reproductive, and respiratory tracts. Because these surfaces are in direct contact with the external environment, they rapidly become colonized by both Gram-positive as well as Gram-negative bacteria following birth, reaching an estimated density of 1013–1014 bacteria during adulthood. Although these bacteria are separated from the human body by an epithelial cell layer covered with mucus, many microbial products are still translocated across the mucosal barrier, where they are recognized by innate immune cells and skew the immune response. Clarke et al. have recently shown that gut-derived peptidoglycan is essential for systemic NOD1 and NOD2-dependent NF-κB activation [[1]]. Thus, translocation of peptidoglycan from the gut into the circulation results not only in local activation, but is also able to induce systemic effects.

Peripheral blood mononuclear cells (PBMCs) were

Peripheral blood mononuclear cells (PBMCs) were CP-690550 mw isolated by Ficoll density gradient centrifugation of blood

obtained from buffy coats from healthy donors. PBMCs (200 × 106 cells/ml) were incubated for 2 h at 37°C in 5% CO2 in 25 cm2 flask plates. After washing, the adherent monocytes were cultured in the presence of 500 U/ml of IL-4 and 1000 U/ml of GM-CSF in RPMI-1640 medium with 10% human serum at 37°C in a humidified atmosphere of 5% CO2, obtaining 90% DC purity at day 7. ABC inhibitors were added once after 48 h of monocyte isolation: MDR1 inhibitor (PSC833, 5 μM), MRP1 and MRP2 inhibitors (MK571, 50 μM) and probenecid (PBN), 2·5 μM. Cells were kept at 37°C in a humidified atmosphere with 5% CO2. Medium with supplements and inhibitors was changed every second day and prior to experiments. The gating of DC populations was validated in our previous selleck screening library study [8]. Lymphocytes were obtained by Ficoll-Percoll gradient and purified by non-adherence. Immature DCs (2 × 106 cells/ml RPMI 10% human serum) were exposed at day 5 to hypoxia conditions for 48 h [8]. Hypoxic (0·5% oxygen) conditions were generated at day 5, exposing iDCs to hypoxia (0·5% O2, 5% CO2) in a hypoxia atmosphere-controlled incubator (Binder), keeping cells unmanipulated for 48 h,

thereby avoiding O2 pressure changes. To compare with a standard stimulus for DCs maturation, LPS (2 μg/ml) was added for 24 h at day 6 after PBMC isolation. Flow cytometry (fluorescence-activated cell sorting: FACS) analysis was performed using a FACS Canto and diva software (Becton Dickinson). The study subpopulation was defined using different cell markers: CD3 for lymphocytes, CD14 for monocytes, CD20 for B cells and CD56 to stain natural killer (NK) cells. Thereafter, FACS was performed at day 7 of DCs to assess mean fluorescence and expression of mature cell phenotype. CD14, CD11c and CD123 were used to identify the DC nature and different markers were used to define the mature population of DCs (mDCs) (CD40/CD80/CD83/CD86/CD54/HLA-DR). To assess the DC phenotype, we

used the markers according to standard MYO10 methods in the literature for DCs [18-20]. Incubation was carried out at 4°C for 30 min. Apoptosis was measured by annexin-V using flow cytometry. Intracellular HIF-1α was assessed by flow cytometry (FACS Canto; Becton Dickinson). DCs were identified with two membrane markers as HLA-DR+ and CD11c+. After phenotyping, cells were permeabilized with saponine buffer (Sigma, Madrid) and labelled with HIF-1α or isotype control (R&D Systems). Intracellular HIF-1α was analysed in the double-positive region for HLA-DR+ and CD11c+. To assess Pgp and MRP1 expression in iDCs and mDCs, double-surface immunostaining and dual-colour flow cytometry of freshly isolated PBMCs were carried out following incubation overnight at 37°C in human serum.

Thus, different cell populations coming from the draining area of

Thus, different cell populations coming from the draining area of peripheral LN were identified, and after antigen administration were analysed in more detail. Numerous studies focus on the presence of pLN for immune response induction. One study concerns the impact of the cervical LN (cLN) of rats in activation of the immune system after antigen was microinfused into the cerebrospinal

fluid [38]. It was shown that the cLN respond in an antibody producing manner for antigen which comes from the central nervous Selleckchem LY294002 system, and furthermore, after removing the LN, the antigen-specific antibody titre in the serum was perceptably reduced. It was concluded that the LN is important for the induction of a humoral immune response to central nervous system antigens

[38]. After recognizing the cLN as the brain-draining LN, Phillips et al. hypothesized that the LN play a role in multiple sclerosis (MS) as well as in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. MS is thought to be an organ-specific autoimmune disorder and/or a chronic inflammatory disease of the central nervous system [39] (for more detail see [40]). Genetic risk factors [human leucocyte antigen (HLA) haplotypes] and also environmental factors (Epstein–Barr virus, smoking and sunlight Poziotinib nmr exposure) were identified in MS development [40]. Pathological demyelination of different brain areas (cerebrum, brain stem or spinal cord) with axonal destruction was found. So far, CD4+ T cells Janus kinase (JAK) and CD8+ T cells (adaptive immune system) have also been related to the disease, as well as natural killer (NK) cells, which belong to the innate immune system. All these cells were detected in higher numbers in the patients or specifically in the lesions [39,40]. Furthermore, anti-inflammatory therapies and immune modulation are beneficial to the disease process [39]. The deep and superficial cLN were removed, EAE was induced and a reduced enhancement of the disease was found. Different areas in the brain were analysed for EAE lesions and significant differences were found between LN-resected and LN-bearing rats [17]. It was concluded

that removing the LN leads to a break in the pathway of immune cells into the brain which reduces the lesions found normally in EAE. More than 10 years later this study was repeated and expanded by van Zwam et al., who were able to show variations at different stages of the disease (acute, chronic and chronic relapsing EAE) which seem to be cLN-dependent. Furthermore, they concluded that tolerance of antigen from the brain is not induced in the cLN [27]. Thus, they believe that the brain-draining LN could be a useful target for therapeutic strategies against MS. The effect of cLN dissection on immunoglobulin (Ig) production and S. pneumoniae colonization after nasal vaccination with pneumococcal polysaccharide was also analysed.

Furthermore, compared with uninfected controls,

Furthermore, compared with uninfected controls, NVP-BKM120 price patients co-infected with S. mansoni and S. haematobium produce significantly greater amounts of immunoregulatory IL-10 when stimulated with 0-3 h RP but not with the control ligand zymosan. Although the sample sizes in each of our three groups (un-infected, S. mansoni-infected, and S. mansoni and S. haematobium co-infected) were limited, this initial investigation showing

a significant 0–3 h RP-specific up-regulation of IL-10 in co-infected patients highlights the potential importance of E/S products released from the invasive stage of the parasite in schistosome-infected humans. This provides justification for further larger studies of human immune responsiveness to cercarial E/S antigens. By collecting WB culture supernatants 24 h after stimulation, we specifically targeted the early production of cytokines released by innate immune cells in WB such as monocytes. We had previously shown using murine macrophages that 0–3 h RP induces abundant IL-10 within 24 h, as well as IL-12p40 and IL-6, and that cytokine production was largely dependent upon functional TLR4 [8]. Helminth E/S products, such as 0–3 h RP, are known to have greater stimulatory activity with regard to innate cytokine Dorsomorphin in vitro production than preparations dominated by somatic components (e.g. soluble whole cercariae) [8], which may be more relevant to stimulation of the acquired immune response. We compared

the cytokine response to 0–3 h RP with zymosan Vasopressin Receptor (derived from the yeast Saccharomyces) as a control ligand as like 0–3 h RP, it is biochemically heterogeneous and enriched for glycosylated proteins [9]. Zymosan, like 0–3 h RP, also stimulates innate immune cells to drive CD4+ lymphocytes

towards a Th2 phenotype [25]. Schistosome infection status at the time of sample collection from individuals in the endemic region was the major factor in determining whether stimulation of WB cells using 0–3 h RP enhances levels of IL-10. Co-infection with S. mansoni and S. haematobium was associated with the highest production of 0–3 h RP-specific IL-10 relative to uninfected participants. This was not observed in response to the control ligand zymosan or in spontaneous IL-10 production by un-stimulated WB (data not shown). The production of IL-10 can be usefully expressed as ratio compared with production of pro-inflammatory TNFα. As a precedent for this, urinary tract morbidity in S. haematobium-infected patients was linked to a lower ratio of IL-10: TNFα production as part of the acquired immune response [28]. Here, we found that the ratio of 0–3 h RP-specific IL-10: TNFα was higher in infected than in uninfected individuals, supporting the hypothesis that cercarial E/S stimulates a regulatory immune phenotype through enhancement of innate/early IL-10 production relative to the production of the pro-inflammatory cytokine TNFα [5, 27]. The higher ratio of IL-10: TNFα in subjects co-infected with S.

Gram-positive bacteria were the only of the microbes tested that

Gram-positive bacteria were the only of the microbes tested that induced IL-12 secretion, and only in mDC cultures, which is consistent with previous findings in both cord and adult cells [41, 42]. However, IL-12 secretion could not be correlated with the induction of Th1 cytokine secretion, as S. aureus was the only microbe to induce both IL-12 and Th1 cytokine secretion. As we only measured IL-12 p40 and not the biologically active IL-12

p70, we cannot deduce from this study whether any of the tested bacteria did indeed induce IL-12 p70. However, Gram-positive bacteria are known for their capacity to induce IL-12 p70 in both adults and newborns [41, 42]. Yet, others have Selleck DZNeP shown that the synthesis of IL-12 p70 is impaired in newborns [21, 43] and that lymphocytes from cord blood lack IL-12 receptor β1 expression [44], which may explain the absent correlation between IL-12 secretion and Th1 cytokine secretion. Furthermore, the use of UV-inactivated bacteria could also explain the lack of IL-12 secretion

in bacteria stimulated cultures. However, it has previously been shown that live S. aureus and E. coli are equally effective in inducing IL-12 as dead bacteria of the same species, at least in monocytes from adult blood [42]. Instead, we found that Th1 cytokine induction was correlated with IFN-α secretion, which is in line with previous findings in adults [19, 45–47]. The only two microbes, influenza virus and S. aureus, that induced Th1 cytokine secretion in cord pDC were also potent inducers of IFN-α. Our previous findings [3], and this

paper, thus show that pDC from newborns can secrete large amounts of IFN-α upon stimulation with certain OTX015 order selected microbes. The use of non-replicating virus instead of replication-competent virus may of course explain why some of the virus tested did not induce any IFN-α/β responses. Yet, HSV-1 did not induce any IFN-α in cord pDC despite the ability of replication-deficient HSV in inducing strong type I interferon responses in adult cells [48, 49]. However, cord pDC have an impaired IFN-α/β signalling capacity [23], which is as a result Roflumilast of a defect in interferon regulatory factor (IRF)-7-mediated responses in pDC from newborns [50]. This could explain why HSV-1, which bind and signal via TLR-9, was refractory in activating cord pDC and perhaps also explain why some of the other viruses tested did not promote IFN-α responses. There is increasing evidence that the cytokine pattern in newborns is associated with the propensity to develop allergic disease. Studies suggest that children that develop allergies later in life and/or with a family history of allergy are Th2 skewed at birth, even though conflicting data exists [38, 51–54]. Elevated levels of IL-13 [55–57] and decreased levels of IFN-γ [51, 58, 59] in cord T cells has been shown to be risk factors for developing allergic disease later in life, even though the role of IFN-γ is less clear-cut [55].