Together, FCAS, MWS and CINCA syndrome are grouped and called CAPS. These syndromes are characterized by recurrent fevers, leukocytosis, elevated acute phase proteins, myalgias and generalized fatigue. CINCA syndrome is a severe form of CAPS beginning in neonatal life. The term “cryopyrin” was coined by Hoffman during his studies regarding the mutation in FCAS 15. Epigenetics inhibitor Upon exposure to cold, the affected subjects develop fevers, leukocytosis and generalized flu-like symptoms, hence the use of “cryo” for cold and “pyrin” for fever. Blood monocytes from these patients release more IL-1β upon incubation in the cold as compared with monocytes from persons without the mutation 21. CAPS patients

treated with either anakinra 23, 44, 45, a soluble IL-1 receptor (rilonacept) 17 or a monoclonal

anti-human IL-1β (canakinumab) 29, experience a rapid, sustained and near complete resolution of the disease. Of particular importance is the amelioration of the central nervous system abnormalities in children with CINCA during sustained treatment with anakinra 23 or canakinumab 46. Colchicine is routinely used to prevent attacks of FMF 47. Although the mechanism of action of colchicine in FMF is poorly understood, one effect of colchicine is a reduction in the migration of monocytes into an inflamed area 47. Because oral colchicine is converted in the liver to an active compound by p450 cytochrome C, some patients are resistant to colchicine because they harbor a mutation in p450 cytochrome C. As a result, these patients are treated with anakinra. Other patients are intolerant of the loose stools associated with colchicine BTK inhibitor manufacturer use. Anakinra brings about a rapid cessation of the local and systemic inflammation of an attack. However, periodic anakinra is effective in preventing FMF attacks when administered early during the prodrome and in some patients daily anakinra is used. Colchicine-resistant Branched chain aminotransferase FMF disease severity can present as

bilateral pneumonia; initiation of anakinra therapy in such patients has been shown to result in a rapid improvement in clinical symptoms as well as radiographic resolution within 2 days 48. Since TRAPS was originally believed to be due to a lack of endogenous soluble TNF-α receptor, disease activity was thought to be best controlled by administration of agents that neutralized TNF-α such as etanercept and infliximab. However, TRAPS turns out to be an IL-1β-mediated auto-inflammatory disease and optimally responsive to IL-1β blockade. Blood monocytes from TRAPS patients release IL-1β in greater amounts than cells from healthy subjects 13, a characteristic of auto-inflammatory diseases. In fact, treating patients with TRAPS with infliximab worsened disease severity 13, 49. Another characteristic of patients with auto-inflammatory diseases is the response to reducing IL-1β activity, which is observed in patients who are refractory to corticosteroids, cyclosporine, azathiaprine or colchicine.

Gray’s analysis suggests that in hypertensive people with type 2 diabetes and with normal AER, control of BP based on beta blockers appears superior from a cost perspective to control based on ACEi.31 According to Kasiske

et al.32 and Weidmann et al.,33 it is important to note that this does not apply to people with increased AER, in whom treatment with renin angiotensin system inhibitors has been shown to reduce AER to a greater clinical extent than treatment with other agents. Howard et al. undertook cost-effectiveness modelling of ‘opportunistic screening and best-practice management of diabetes, elevated BP and proteinuria among Australian adults’.34 Cass et al. used the model outcomes as input to the companion KHA report.3 The study modelled the health outcomes of Life Years Saved and Quality Adjusted Life Years Saved. On the basis of the models Cass et al. concluded ZD1839 that the best available evidence supports screening and intensive management of three risk factors for CKD, namely diabetes, high BP and protein in urine.3 The KHA report included modelling the cost-effectiveness of screening for proteinuria and subsequent treatment with an ACEi for people with diabetes with or without elevated BP. The authors noted that there was very limited data on both screening and treatment in normotensive patients, and thus model results are indicative only and suggested ‘some benefit

under optimistic assumptions’ with results considered as being of an exploratory nature only. Howard et al. resolved that further check details trials were required in order to determine the cost-effectiveness of ACEi interventions

in microalbuminuric normotensive type 2 diabetes.34 Palmer et al. completed a health economic analysis of screening (microalbuminuria and overt nephropathy) and optimal treatment of nephropathy in hypertensive type 2 diabetes within the USA health care system.1 The inputs to the economic modelling was based on estimates derived from a review of clinical trials. The modelling indicated screening for early stage nephropathy and optimal treatment (use of 300 mg irbesartan) in addition to the patients current treatment, results in a 44% reduction in the cumulative incidence of ESKD. The incremental costs-effectiveness ratio was in the order of $US20 000 per QALY gained for screening Protein tyrosine phosphatase and optimized treatment compared with no screening. A 77% probability that screening and optimized therapy would be considered cost-effective was calculated assuming a willingness to pay threshold of $US50 000. Overall the authors considered that the modelling showed that screening and optimized treatment (with an ARB) to ‘represent excellent value in a US setting’. In relation to screening and treatment with an ACEi for the early detection and treatment of kidney disease, Craig et al. considered that while this was a promising primary prevention strategy for the prevention of ESKD, there was inadequate trial data to support population wide adoption (i.e.

Both examinations showed many abnormal processes in oligodendroglial-like cells with round nuclei. In contrast, few reactive astrocytes that demonstrated immunoreactivity for glial fibrillary acidic protein were found in this area. Tau accumulation

was present in 37% of cases. There was no correspondence with the regions showing increasing numbers of nestin or CD34-positive cells. There were no significant associations between epileptic Poziotinib supplier clinical parameters and the incidences of the abovementioned immunopositive cells. CD34-positive cells and nestin-positive cells are found as frequently as balloon cells and are associated with abnormal reconstitution of the cortex. These findings support the assertion that increases in the numbers of these cells might contribute to promoting epilepsy. In check details addition, these immunopositive cells

are valuable findings for the pathological identification of epileptogenic lesions. “
“One of the insidious biological features of gliomas is their potential to extensively invade normal brain tissue, yet molecular mechanisms that dictate this locally invasive behavior remain poorly understood. To investigate the molecular basis of invasion by malignant gliomas, proteomic analysis was performed using a pair of canine glioma subclones – J3T-1 and J3T-2 – that show different invasion phenotypes in rat brains but have similar genetic backgrounds. Two-dimensional protein electrophoresis of whole-cell lysates of J3T-1 (angiogenesis-dependent invasion phenotype) and J3T-2 (angiogenesis-independent invasion phenotype) was performed. Twenty-two distinct spots were recognized when significant alteration was defined as more than 1.5-fold change in spot intensity between J3T-1 and J3T-2. Four proteins that demonstrated increased expression in J3T-1, and 14 proteins that demonstrated increased expression in J3T-2 were identified using liquid chromatography-mass spectrometry analysis. One of the proteins

identified was annexin A2, which was expressed at higher levels in J3T-1 Fossariinae than in J3T-2. The higher expression of annexin A2 in J3T-1 was corroborated by quantitative RT-PCR of the cultured cells and immunohistochemical staining of the rat brain tumors. Moreover, immunohistochemical analysis of human glioblastoma specimens showed that annexin A2 was expressed at high levels in the tumor cells that formed clusters around dilated vessels. These results reveal differences in the proteomic profiles between these two cell lines that might correlate with their different invasion profiles. Thus, annexin A2 may be related to angiogenesis-dependent invasion. “
“Calcium dyshomeostasis is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer’s disease. However, much of the previous research has focused on changes in neuronal calcium signalling.

Volume and pressures were recorded at various sensations up to maximal capacity (MCC). Maximal capacity was considered a volume with strong feeling of fullness in lower CHIR99021 abdomen or filling pressure of 30 cmH2O, whichever was reached earlier. At the end of the filling phase, the patient was asked to void in the uroflowmeter. He was encouraged to void with pelvic-floor relaxation along with Crede’s maneuver/straining. The following definitions were used: (i) Pouch compliance = MCC/end.fill.Ppouch; (ii) MCC = voided volume + PVR. This definition was used rather

than “volume filled” to account for the urine production during the study; (iii) clinically significant incontinence = leakage of over a few drops of urine. Urethral pressure profilometry was performed after filling 100 mL infusate into the pouch. The catheter was pulled at a constant rate (2 mm/sec) using motor-driven automated catheter puller and urethral pressures were recorded. The above evaluation was conducted initially at least 6 weeks after surgery and later at least 3 months after the initial

evaluation. All patients were counseled and trained to void on schedule by sphincter relaxation along with Crede’s maneuver learn more if required. The pelvic floor strengthening exercises were started in the preoperative period and continued thereafter. Pelvic floor rehabilitation was initiated just before removal of catheter. Data were analyzed using statistical package for social science (SPSS, version 17, Chicago, IL, USA). Normality of data were checked using one sample Kolmogorov–Smirnov test. The before-and-after comparisons were made using paired t-test (parametric), Wilcoxon signed rank test (non-parametric) or McNemar test (dichotomous categorical).

Correlations between clinical/QOL and urodynamic parameters were made using Pearson’s correlation (parametric) or Spearman’s rank correlation (non-parametric). Factors predicting continence status were examined using Mann–Whitney U-test (non-parametric dataset). Binominal logistic regression and stepwise linear regression analyses were conducted as appropriate. Total 17 patients with mean age 52.7 ± 11.3 years and body mass index 22.7 ± 3.3 kg/m2 were evaluated. All patients underwent cystoprostatectomy (radical in 16 patients with Aprepitant bladder cancer and simple in one patient with genitourinary tuberculosis) and construction of orthotopic neobladder (ONB) with ileum of mean length 48 ± 7 cm (range 40–60 cm). Three patients of bladder cancer developed recurrence; one in corpus cavernosus of penis, one in the pelvis and one in both. All were treated with systemic chemotherapy and the latter two with pelvic radiotherapy in addition. The former patient had a complete remission of disease; the latter two succumbed to progressive disease and hence were excluded.

81 mL/sec) and low voided volume (141.2 mL) compared to patients with normal (8.77 mL/sec, 202.0 mL) or strong (8.97

mL/sec, 178.3 mL) detrusor contractility. Twenty-six of 74 weak detrusor patients underwent prostate NVP-AUY922 clinical trial operation. The operated group had high obstruction grade (3.35, P < 0.001), but a low rate of detrusor overactivity (19.2%, P < 0.05), compared to the non-operated group (2.16, 41.7%). The operated group also had high urinary retention rate (38.5%) compared to the non-operation group (18.8%). Conclusion: We performed prostate surgery in patients who had episodes of urinary retention, with outlet obstruction, and with no detrusor overactivity, even in those with weak detrusor contractility. The operation may not be contraindicated for these patients. Pressure-flow study is an important tool to ensure adequate find more informed consent. “
“Objectives: To evaluate the effects of propiverine and its active metabolites (M-1 and M-2) on bladder function through modulation of afferent activity in rats. Methods: Cystometry was performed in urethane anesthetized female rats. We examined the effects of intravesical administration of propiverine, M-1 and M-2 on

bladder overactivity induced by oxotremorine-M (Oxo-M; non-selective mAChR agonist). Results: Intravesical administration of Oxo-M (200 µM) elicited bladder overactivity as evidenced by decreased intercontraction interval (ICI) and pressure threshold (PT) without changing maximum voiding pressure or baseline pressure. These effects were blocked by intravesical administration of propiverine (30 µM) or

M-2 (300 µM). Intravesical administration of M-1 (30 µM) alone increased ICI and PT, but did not prevent Oxo-M-induced decreases in ICI and PT. Conclusion: These results suggest that propiverine and M-2 have anticholinergic effects on bladder afferent activity and that M-1 has an inhibitory effect through the mechanism other than muscarinic receptor modulation. Thus, clinical benefits of propiverine in patients with overactive bladder could be mediated by multiple actions of propiverine and its active metabolites. “
“Objectives: Eviprostat is an anti-oxidant, Oxymatrine anti-inflammatory phytotherapeutic agent that is commonly used to treat lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia in Japan and Germany. Prostate cancer patients treated with brachytherapy generally have complaints of LUTS for several months postoperatively. Methods: We investigated the protective effects of Eviprostat against the development of LUTS in 37 patients, who had received 125I prostate brachytherapy as monotherapy. These patients were divided into two groups, an Eviprostat-treated group (n = 18) and an untreated control (n = 19), whose background had no significant difference. The group treated with Eviprostat was prophylactically medicated from 3 weeks preoperatively until 3 months postoperatively.

There were no statistically significant differences in demographics between the three Braak stage groups, although the Braak stage 0-I-II (non-AD) group trended toward younger age (P = 0.013 by Kruskal-Wallis,

no differences were detected with Dunn’s multiple comparison test). UBL immunoreactivity had distinct patterns in the three Braak stage groups DAPT mw (described below), and localization was almost exclusively neuronal in all groups, with only in 2/11 cases (one Braak stage VI, one Braak stage IV with family history of AD) exhibiting UBL immunoreactivity in cells with the morphological appearance of microglia and oligodendrocytes, and located throughout the gray and white matter, respectively (not shown). In Braak stage 0-I-II cases (NFT absent or confined to the selleck compound entorhinal cortex), UBL immunoreactivity was observed in the neuropil in the stratum pyramidale

of the Ammon’s horn (CA) and molecular layer of the dentate gyrus (DG). UBL immunoreactivity was also detected in neuronal soma, dendrites and in the nucleoplasm in hippocampal neurons, including pyramidal and multipolar neurons in the CA fields, and DG granular neurons. In the majority of neurons, UBL immunoreactivity intensity was higher in the nucleoplasm compared to the cytoplasm (Fig. 1; Table 2). UBL immunoreactivity in the nucleoplasm appeared punctuate/vesicular (Fig. 1 inset a; Fig. 4A) and was most prominent in the CA2/3 field (Table 2). In Braak stage III-IV cases (NFT involving the entorhinal cortex and hippocampus but not neocortex), UBL immunoreactivity in the neuropil was reduced in the CA1 and CA2/3 regions, and was unchanged in the CA4 and DG, compared to Braak stage 0-I-II cases. The majority of CA1 neurons exhibited reduced cytoplasmic and nucleoplasmic labelling; however, a subset of CA1 pyramidal neurons had prominent UBL immunoreactivity in the nucleoplasm (Fig. 1B). The intensity of UBL immunoreactivity in the nucleoplasm increased markedly in the

majority of CA2/3 pyramidal Flavopiridol (Alvocidib) neurons, CA4 multipolar neurons and DG granular neurons (Figs 1E, 2H,K; Table 2). We also observed UBL immunoreactivity in fibers in the CA2/3 radiatum/moleculare and DG molecular layer in three of the Braak stage III-IV cases (Braak III: 1; Braak IV: 2; not shown). In Braak stage V-VI cases, UBL immunoreactivity was less intense in the CA1 field, both in the neuropil and in pyramidal neurons, except those with the morphological appearance of extracellular NFT (eNFT), where UBL immunoreactivity was prominent (Fig. 1C. inset c). In contrast, UBL immunoreactivity in neuropil and neuronal cytoplasm in CA2/3, CA4 and DG was similar to the pattern observed in Braak stage III–IV cases, albeit with a less prominent increase in nucleoplasmic UBL immunoreactivity (Fig. 1F,I,L; Table 2). Analysis of UBL immunoreactivity optical density confirmed a significant increase (P < 0.

We thank Professor Caroline Sabin and Doctor Pedro Coutinho for support in statistical analysis. We are also grateful to all the blood donors who took part Selleckchem BIBW2992 in this study. The authors declare no financial conflicts of interest. Figure S1. High frequency

of cytomegalovirus (CMV) – specific CD4+ T cells. Peripheral blood mononuclear cells were stimulated with CMV, Epstein–Barr virus (EBV), herpes simplex virus (HSV), varicella zoster virus (VZV) or purified protein derivative (PPD) lysate and the percentage of interferon-γ (IFN-γ) secreting antigen-specific CD4+ T cells was assessed by flow cytometry (a). The frequency of CD4+ T cells that were specific for CMV, EBV, HSV, VZV or PPD was determined in individuals who were seropositive for these agents (b). Only responses >0.02% above background (unstimulated cells) were considered positive. Horizontal lines depict median values. Significantly increased frequency of CMV specific CD4+ T cells relative to the other antigens is indicated (Wilcoxon rank test, GraphPad Prism). Figure S2. Multiparameter flow cytometric analysis. DAPT mouse Representative dot plots from

one donor show the distribution of stimulated CD4 T cells within each CD45RA/CD27 subset. Panels show CD4 plotted against: CD40 ligand (CD40L; upper right), interferon-γ (IFN-γ; upper left), interleukin-2 (IL-2; lower right) and tumour necrosis factor-α (TNF-α; lower left), each for unstimulated and anti-CD3 stimulated T cells. Figure S3. Cell recovery. Purified CD45RA/CD27 CD4+ T-cell subsets were activated with anti-CD3

and irradiated antigen-presenting cells and irradiated antigen-presenting cells. At the indicated time-points, the cell number was determined on a haemocytometer. Results are expressed as a percentage of the initial number of cells placed in culture; results for one donor are shown. (b,c) Apoptosis was assessed by Annexin V staining and propidium iodide (PI) incorporation. The percentage of early apoptotic (Annexin V+ PI–) and late apoptotic/necrotic (Annexin V+ PI+) cells was assessed in the indicated days. Representative pseudocolour plots are Plasmin shown (b). Figure S4. CD4+ CD45RA– CD27+ cells were purified by FACS sorting and analysed for the expression of CD45RA and CD45RO before culture. Cells were stimulated with interleukin-2 (IL-2) or IL-15 and CD45RA/CD45RO expression was assessed by flow cytometry at the indicated time-points. The results shown are representative of four experiments. Figure S5. CD4+ CD45RA– CD27– cells were purified by FACS sorting and analysed for the expression of CD45RA and CD45RO before culture. Cells were stimulated with interleukin-7 (IL-7), IL-2 or IL-15 and CD45RA/CD45RO expression was assessed by flow cytometry at the indicated time-points. The results shown are representative of three experiments. Figure S6. CD4+ CD45RA– CD27+ cells were purified by FACS sorting.

1,2 This specific protein–protein interaction needs at least 10 seconds to trigger TCR-dependent intracellular signalling pathways.3 To produce an effective TCR response, an additional interaction of the CD4 or CD8 co-receptors with invariant parts of the MHC–peptide complex is required to stabilize the TCR-agonist peptide–MHC complex. Upon TCR activation, the Src kinases Fyn and Lck phosphorylate the tyrosine residues in their immune-receptor tyrosine-based activation motifs (ITAMs), which allow activation

of the ζ-chain-associated protein of molecular weight 70 000 (ZAP-70).4,5 ZAP-70 phosphorylates the adaptor proteins LAT and SLP76, which activate phospholipase Cγ (PLCγ) through the Src-like tyrosine kinase Tec.3 The PLCγ cleaves phosphatidylinositol 4,5 bisphosphate and generates the second messengers inositol 1,4,5,-trisphosphate (InsP3) and diacylglycerol.5–8

TSA HDAC order The InsP3 binds to the InsP3 receptor in the membrane of the endoplasmic reticulum, which is the main Ca2+ store, and initiates the release of its stored Ca2+.6–9 Depletion of Ca2+ from the endoplasmic reticulum induces stromal interaction molecule (STIM1)-dependent activation of store-operated calcium release-activated Ca2+ (CRAC) channels in the plasma membrane.6–11 ORAI (also called www.selleckchem.com/products/ABT-263.html CRACM) proteins have been shown to form the pore of the CRAC channel complex.12–15 STIM1 has been shown to activate CRAC/ORAI channels.16–18 The function of its close relative STIM2 is not as well understood.19–21 Analysis of STIM1- and STIM2-deficient mouse T cells revealed that they are

both important for Ca2+ influx, T-cell activation and the development and function of regulatory T cells, with STIM2 being less important than STIM1.22 Parvez et al.21 demonstrated that STIM2 activates CRAC channels but that Phloretin this activation is much more complicated because it involves store-dependent and store-independent processes. Influx of Ca2+ through STIM-activated CRAC/ORAI channels elevates the intracellular calcium concentration [Ca2+]i in T cells for times lasting from minutes up to hours.23 A rise of [Ca2+]i as the result of Ca2+ release and Ca2+ influx through store-operated CRAC channels is critically involved in the regulation of the three most important transcription factor families controlling transcriptional activity and T-cell proliferation.5,9,24,25 It is remarkable that 75% of all activation-regulated genes are dependent on Ca2+ influx through the plasma membrane via CRAC channels.26 Decreasing [Ca2+]i leads to inhibition or reduction of T-cell activation and proliferation,23,27–29 highlighting the great influence of [Ca2+]i on T-cell-based immune responses. While TCR stimulation alone activates many signalling cascades, including Ca2+ signalling, it is not sufficient for optimal T-cell activation in most circumstances and a costimulatory signal is required for adequate activation.

[48] Combining calcineurin inhibitors with corticosteroids as induction immunosuppression was associated with clinically acceptable response rates in Czech, Chinese and Japanese patients.[46, 49-51] Triple immunosuppression with corticosteroids, tacrolimus and MMF has been reported to result in a higher complete remission rate (65% versus 15%) compared with

corticosteroids and intravenous CYC in Chinese patients.[10] There is also preliminary data on the efficacy of mizoribine in Japanese patients, and that of leflunomide in Chinese patients, but detailed comparison with standard therapies is lacking.[52, 53] Although the reported incidence of hepatitis was ∼7%, the liver toxicity of leflunomide is a valid concern and needs to be carefully monitored.[53] In view of the MK-2206 ic50 data from retrospective analysis which showed that

anti-malarial treatment was associated with reduced incidence of flares (including renal flares) and less dyslipidaemia, the ACR and EULAR guidelines recommend that all LN patients be treated with a background of hydroxychloroquine unless there is contraindication.[17, 18] There is little data on the impact of hydroxychloroquine treatment in Asian patients. selleck screening library The KDIGO guidelines recommend that patients with Class V LN, normal renal function, and non-nephrotic proteinuria be treated with anti-proteinuric and anti-hypertensive agents, and corticosteroids or immunosuppressive agents be considered only when there are severe extra-renal manifestations.[16] Both the ACR and EULAR recommend that patients with pure membranous LN and nephrotic range proteinuria be treated with corticosteroids plus MMF (2–3 g/day),[17, 18] based on subgroup analysis of ALMS data which showed similar response rates to MMF or intravenous CYC at 6 months.[54] Meta-analysis of 34 studies (which included 174 Asian patients and 332 non-Asian patients) and data from an NIH controlled trial both showed that prednisone alone was inferior to dual immunosuppression with prednisone and a cytotoxic agent

or a calcineurin inhibitor.[55, 56] Relapses were more common following discontinuation of cyclosporin A compared with CYC. The EULAR guidelines do not recommend the Euro-Lupus regimen since it has not been tested in class V LN.[17] Data from Isotretinoin Asian patients has demonstrated efficacy of combined immunosuppression with prednisolone and sequential CYC-AZA, AZA, tacrolimus, or MMF.[57, 58] Socio-economic factors have a significant impact on the management of lupus nephritis in Asia. Factors such as financial limitations, education level and compliance of patients, the organization of healthcare structure and delivery, and the infection risks imposed by environment and climate, which vary markedly between different parts of Asia, can be strong determinants on the access to evidence-based standard-of-care and treatment decisions.

Using OVA peptide variants with different affinity for the OVA-specific OT-I TCR, it was shown that peptides with high affinity induce high amounts of IRF4 [22, 25], whereas peptides with intermediate or low affinity provoke intermediate or low quantities of IRF4, respectively. This dependency of IRF4 expression amounts on the peptide affinity for OT-I TCR was demonstrated in vitro and also in vivo during infection with recombinant Listeria monocytogenes that expressed the respective peptide variants [22]. At the molecular level, IRF4 expression levels seem to depend on the activity of mammalian target of rapamycin (mTOR). Thus, high IRF4 expression following strong TCR stimulation by high-affinity

ligands correlated with elevated activity of mTOR, whereas inhibition of the mTOR pathway caused downregulation of IRF4 [25]. As recently shown, IRF4 expression is also dependent on the activity of IL-2-inducible T-cell kinase (ITK) [26]. Using inhibitors for both OSI-906 ic50 ITK and mTOR, it was demonstrated that these two signaling pathways cooperate for IRF4 induction [25]. Earlier studies had already concluded that the transcription factor C-REL, a member of the NF-κB family, is also crucial for the induction of IRF4 in response to TCR

stimulation [27]. Moreover, treatment with cyclosporine Selleck GSI-IX A blocked upregulation of IRF4, suggesting that NFAT signaling also contributes to this process [3]. Finally, FOXP3 regulates IRF4 expression in regulatory T (Treg) cells [19], as do STAT3 in T helper 17 (Th17) cells [28] and STAT6 in Th9 cells [29], whereas T-BET directly represses IRF4 expression in Th1 and Th17 cells [30]. In response to signals induced by antigen recognition

and cytokines, naïve CD4+ T cells differentiate into distinct subpopulations that are characterized by specific effector functions and cytokine profiles. This subdivision is based on the expression of lineage-specific transcription factors, which function as “master regulators” for specific Th-subset properties (Fig. 1). IL-12 drives the differentiation of Th1 cells, which produce IFN-γ, express the transcription factor T-BET (encoded by T-box 21), and clear intracellular Interleukin-3 receptor pathogens. Th2 cells are induced by IL-4, secrete IL-4, IL-5, and IL-13, and express the master regulator GATA-binding protein 3 (GATA3). IL-4 in combination with transforming growth factor-β (TGF-β) induces the differentiation of Th9 cells, which produce high levels of IL-9 and IL-10. The lineage-specifying transcription factor for Th9 cells was suggested to be PU.1, which however was previously considered by the same group to characterize an IL-4 low producing subset of Th2 cells [31]. Although Th2 and Th9 cell subsets both contribute to immunity against helminths, Th9 cells are additionally involved in antitumor immunity. The cytokines IL-6 or IL-21 can act alone to induce T follicular helper (Tfh) cells, which express the master regulator BCL-6.