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T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous. To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation. Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination. Gene expression analyses identified two evenly sized and distinct subgroups, \"Th2-high\" and \"Th2-low\" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation. Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

Background The ratio of T helper 1 (Th1) to T helper 2 (Th2) as well as T helper 17 (Th17) to regulatory T cells (Treg) represents the state and direction of immune response. Recent studies demonstrated that dexmedetomidine reduced the secretion of inflammatory cytokines. We performed this study to investigate the effect of different doses of intraoperative dexmedetomidine on the expression of Th1, Th2, T17 and Treg cytokines and their ratios. Methods Seventy-five patients undergoing laparoscopic cholecystectomy were randomly separated into one of three groups: the full dose group ( n  = 25), in which dexmedetomidine was infused with a 1.0 μg/kg loading followed by an infusion of 0.5 μg/kg/min after anaesthetic induction, or the half dose group ( n  = 26), in which the dose was half of that of full dose group, or the saline group ( n  = 24) which was control. T cell cytokines were quantified by sandwich enzyme-linked immunoassay for blood samples taken after anaesthetic induction (T0), at the end of surgery (T1), and 60 min after surgery (T2). IFN-gamma/IL-4 and IL-17/IL-10, which represent the ratio of Th1/Th2 and Th17/Treg cytokines, respectively, were calculated as indices of immune cell levels based upon serum cytokines levels in place of direct measurements. C-reactive protein (CRP) concentrations were measured on the next day following surgery. Results The full dose group was associated with higher ratios of IFN-gamma/IL-4 than those of half dose group and control [10.1 vs. 1.9 at T1 ( P  = 0.041) compared with half dose group, and 10.1 vs. 0.2 at T1 ( P  = 0.031), 7.4 vs. 0.1 at T2 ( P  = 0.025) compared with control]. IL-17/IL-10 ratios were higher in the full dose group than those in control [4.2 vs. 0.6 at T1 ( P  = 0.013), 3.0 vs. 0.3 at T2 ( P  = 0.011)]. The CRP levels were lower in the dexmedetomidine-treated groups in a dose-dependent manner. Conclusions Dexmedetomidine exhibits immunomodulatory effects, shifting the Th1/Th2 and T17/Treg cytokine balance toward Th1 and T17, respectively, in a dose-dependent pattern in patients with surgical and anaesthetic stress. Trial registration Clinical Research Information Service, Republic of Korea (CRIS); KCT0000503 ; Registration date: Aug 13, 2012.

Infliximab has been shown to induce clinical response and remission in ulcerative colitis (UC). To characterize the biological response of patients to infliximab, we analyzed the mRNA expression patterns of mucosal colonic biopsies taken from UC patients enrolled in the Active Ulcerative Colitis Trial 1 (ACT1) study. Biopsies were obtained from 48 UC patients before treatment with 5 or 10 mg/kg infliximab, and at 8 and 30 weeks after treatment (n = 113 biopsies). Global gene expression profiling was performed using Affimetrix GeneChip Human Genome U133 Plus 2.0 arrays. Expression profiling results for selected genes were confirmed using qPCR. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Unlike responders, non-responders do not effectively modulate T(H₁), T(H₂), and T(H₁₇) pathways. Gene expression can differentiate placebo and infliximab responders. Analysis of mRNA expression in mucosal biopsies following infliximab treatment provided insight into the response to therapy and molecular mechanisms of non-response.

Vitamin A derivatives such as retinoic acid may improve the impaired balance of CD4+ T cells in autoimmune and inflammatory diseases. This study is a double-blind randomized trial to evaluate the effect of vitamin A (as form of retinyl palmitate) supplementation on multiple sclerosis (MS) patients. Thirty-nine patients were enrolled and randomly assigned to two groups. Both groups were followed for 6 months. The experimental group received 25,000 IU of retinyl palmitate daily, while the control group received a placebo. Before and after the study, the expression of interferon gamma (IFN-γ) and T-bet genes was evaluated in peripheral blood mononuclear cells of patients by RT-PCR. The results showed that after 6 months of supplementation, expression of IFN-γ and T-bet was significantly decreased. These data suggest that retinyl palmitate supplementation can modulate the impaired balance of Th1 and Th2 cells and vitamin A products that may be involved in the therapeutic mechanism of vitamin A in MS patients. This study provides information regarding the decreased gene expression of IFN-γ and T-bet in MS by retinyl palmitate supplementation.

Background Antenatal vitamin D 3 (vitD 3 ) supplementation significantly increases maternal and neonatal 25-hydroxyvitamin D 3 (25(OH)D 3 ) concentration, yet the effect of an improvement in maternal-fetal vitamin D status on the neonatal immune response is unclear. Method To assess the effect of prenatal vitD 3 supplementation on cord blood T cell function, healthy pregnant Bangladeshi women ( n  = 160) were randomized to receive either oral 35,000 IU/week vitD 3 or placebo from 26 to 29 weeks of gestation to delivery. In a subset of participants ( n  = 80), cord blood mononuclear cells (CBMC) were cultured, non-adherent lymphocytes were isolated to assess T cell cytokine responses to phytohemagglutinin (PHA) and anti-CD3/anti-CD28 (iCD3/iCD28), measured by multiplex assay. In 12 participants, lymphocyte gene expression profiles were analyzed by PCR array. Result In supplemented group, increased concentrations of IL-10 ( P  < 0.000) and TNF-α ( P  = 0.05) with iCD3/iCD28 stimulation and IFN-γ ( p  = 0.05) with PHA stimulation were obtained compared to placebo group. No differences in the gene expression profile were noted between the two groups. However, PHA stimulation significantly induced the expression of genes encoding Th1 and Th2 cytokines and down-regulated a number of genes involved in T-cell development, proliferation and differentiation of B cells, signal transduction pathway, transcriptional regulation and pattern recognition receptors (PRRs) in the vitamin D group (vitD group). Conclusion Third-trimester high-dose vitD 3 supplementation in healthy pregnant women had balanced effects on biomarkers of cord blood Th1 and Th2 responses. Trial registration ClinicalTrials.gov ( NCT01126528 ).

Recurrent respiratory papillomatosis (RRP), characterized by the recurrent growth of benign tumors of the respiratory tract, is caused by infection with human papillomavirus (HPV), predominantly types 6 and 11. Surgical removal of these lesions can be required as frequently as every 3 to 4 wks to maintain a patent airway. There is no approved medical treatment for this disease. In this study, we have characterized the T(H)2-like chemokine profile (CCL17, CCL18, CCL20, CCL22) in patients with RRP and asked whether it was modulated in patients who had achieved significant clinical improvement. CCL17, CCL18 and CCL22 messenger RNAs (mRNAs) were increased in papillomas compared with clinically normal laryngeal epithelium of the RRP patients. Overall, CCL20 mRNA expression was not increased, but there was intense, selective CCL20 protein expression in the basal layer of the papillomas. Patients with RRP expressed more CCL17 (p = 0.003), CCL18 (p = 0.0003), and CCL22 (p = 0.007) in their plasma than controls. Plasma CCL18 decreased over time in three patients enrolled in a pilot clinical trial of celecoxib, and the decrease occurred in conjunction with clinical improvement. There was a significant correlation between sustained clinical remission in additional patients with RRP and reduced levels of CCL17 (p = 0.01), CCL22 (p = 0.002) and CCL18 (p = 0.05). Thus, the change in expression of these three plasma T(H)2-like chemokines may, with future studies, prove to serve as a useful biomarker for predicting disease prognosis.

Low-dose IL-2 treatment alters the abundance of regulatory T cells, IL-17-producing T cells and follicular helper T cells, but not of T helper type 1 and 2 cells, in patients with SLE. Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4 + T cells. The homeostasis of CD4 + T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (T reg ) cells, follicular helper T (T FH ) cells and IL-17-producing helper T (T H 17) cells, but not T H 1 or T H 2 cells, accompanied by marked reductions of disease activity in patients with SLE.

Background Interferon (IFN)-β therapy in multiple sclerosis (MS) has been suggested to promote a deviation from T lymphocyte production of pathogenic Th1 cytokines to less detrimental Th2 cytokines, but this is still controversial. We studied patterns of in vivo blood mononuclear cell (MNC) and whole blood cytokine and transcription factor mRNA expression before and during IFN-β therapy in MS. Methods Twenty patients with relapsing–remitting MS were sampled before and after 3 months of treatment with IFN-β along with 15 healthy volunteers. An additional 39 patients and 50 healthy volunteers served to confirm initial findings. mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (PCR). Results We found elevated expression of interleukin (IL)-23 and IL-10 in untreated MS patients. IFN-β therapy increased IL-10 and decreased IL-23 expression independently of any Th1 or Th2 cytokines. The largest changes in cytokine mRNA levels occurred early (~9–12 h) after an IFN-β injection. Conclusion We found no evidence of a Th1- or Th2-mRNA-promoting effect of IFN-β therapy. The therapeutic effect of IFN-β is more likely attributable to the induction of the regulatory cytokine IL-10. The elevated IL-23 mRNA levels in MS patients are noteworthy in view of the newly discovered IL-23-driven Th17 T-cell subset, which is crucial in animal models of MS. Since IFN-β therapy resulted in decreased IL-23 mRNA levels, the Th17 axis could be another target of IFN-β therapy.

Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (T H 2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings. ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.