Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by production of autoantibodies against nuclear autoantigens. Almost all the organs can be affected in patients with SLE. A wide range of molecules are involved

in SLE; therefore, the pathogenesis of the disease is complex and still unclear. The receptor for advanced glycation end products (RAGE) is a multi-ligand member belonging to the immunoglobulin superfamily. RAGE is expressed by many types of immune cells, including macrophages, neutrophils and T cells and interacts with a diverse class of ligands [1, 2]. Up to now selleck screening library identified RAGE ligands include high mobility group box-1 (HMGB1) protein, advanced glycation end products (AGEs), members of the S100/calgranulin family. AGEs is a class of compounds resulting from glycation of proteins, lipids or nucleic acids under conditions of oxidative stress and hyperglycaemia [3]. The

stimulation of RAGE through PD-0332991 nmr AGEs may contribute to certain disease state such as diabetes and Alzheimer’s disease, in which the accumulation of AGE has been demonstrated [4, 5]. In addition, as a family of over 20 related calcium-binding proteins that exclusively expressed in vertebrates, S100s modulate an array of intracellular functions [6, 7]. S100s released from different cell types during inflammation serve as useful markers of disease activity [8, 9]. It has been demonstrated that increased serum levels of S100A8/A9 correlated to disease activity index in SLE, indicating S100A8/A9 as a more relevant marker of infection in patients with SLE [10]. Besides that, HMGB1 is a ubiquitously expressed

evolutionary conserved chromosomal protein. Intracellular HMGB1 participates in transcriptional regulation [11]. Extracellular HMGB1 binds to cell surface receptors including RAGE, toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4). Studies indicate that interaction between HMGB1 and RAGE results in the production of type I interferon, which plays key role in the pathogenesis of SLE [12–14]. In addition, TNF-α and IL-6, which are implicated in association buy Pembrolizumab with disease activity or involvement of some organs in SLE [15, 16], can be induced by extracellular HMGB1 [17]. It has been documented that RAGE seemed to involve in all responses that depend on HMGB1 [18]. Notably, previous studies showed that increased serum level of HMGB1 was associated with lupus disease activity [19, 20]. All these results imply that HMGB1-RAGE pathway may participate in the pathogenesis of SLE. The RAGE protein consists of an N-terminal signal peptide, a V-type immunoglobulin-like domain, two tandem C-type immunoglobulin-like domains, a single transmembrane domain and a short C-terminal intracellular cytoplasmic tail [21].

Samples (n = 10 mice from each group) were tested in triplicate.

At the end of the incubation, the plates were washed five times with PBS and alkaline phosphatase-conjugated antibodies (goat anti-mouse IgG and goat anti-mouse IgM, dilution 1:2000, 100 μl per well) were added. The plates were incubated for 2 h at room temperature, after than washed with PBS. For detection of spots, 100 μl of BCIP/NBT find more substrate was added to each well. Following washing, the plates were left at room temperature to dry. The plates were examined for spots counts using an Axio Imager A1 microscope (Zeiss, Germany). Quantitative evaluation of spots and enumeration of Ig-producing cells was performed via KS ELISPOT 4.10 running under AxioVision software (Zeiss, Germany). Data were evaluated for statistical significance of differences by one-way ANOVA followed by Bonferroni’s multiple comparison tests and Spearman’s rank correlation www.selleckchem.com/products/PD-0332991.html test.

All data were expressed as mean ± SD. To evaluate the ability of antibodies induced by immunization with M5-BSA and M6-BSA conjugates to react with mannan structure, the specific serum antibodies levels against acid-stable mannan moiety of both C. albicans serotypes and C. guilliermondii after each injection of conjugates were determined (Fig. 2). Detected acid-stable mannan-specific antibodies levels in immune sera were compared with the controls (sera obtained after immunization with saline). M5-BSA conjugate immunization induced increase in mannan-specific IgM levels with maximal peak after the secondary sc booster injection (3rd lambrolizumab sc) for mannan C. albicans serotype A. Immunization with M5-BSA conjugate induced slight statistically significant increase in mannan-specific IgG for mannan C. albicans serotype A and mannan C. guilliermondii. Nevertheless, mannan-specific IgG levels induced by M5-BSA conjugate immunization did not exceed the levels of mannan-specific IgM levels (Fig. 2). For mannan-specific

IgA levels, we observed no increase using mannan C. albicans serotype A and slight statistically significant increase using mannans of C. albicans serotype B and C. guilliermondii as target antigen. In comparison with M5-BSA conjugate, structurally similar M6-BSA conjugate induced different kinetics of mannan-specific antibodies levels throughout the immunization (Fig. 2). We observed a marked increase in mannan C. albicans serotype A-specific IgM levels after the primary injection (1st) and the primary sc booster injection (2nd) of M6-BSA conjugate followed by significant decrease after the secondary booster injections (both, 3rd sc and 3rd ip administration). Mannan C. albicans serotype B and mannan C.

It is unclear if these CD8+ T cells

are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multiparameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen specific CD8+ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8+ CD45RA+CD27- T cell subset increases significantly during ageing and this is exaggerated in CMV immune responsive subjects. However these end-stage cells do not have the shortest telomeres implicating additional non-telomere related mechanisms in inducing

their senescence. The telomere lengths in total and CMV(NLV)-specific FK506 cost CD8+ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared to young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple -cytokine producing cells are found in CD8+ T cells at all stages of differentiation in both age groups. Furthermore, these multifunctional cells had intermediate telomere lengths compared to cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific PCI 32765 CD8+ T cells that secrete IFNγ, IL-2 and TNFα are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion. This article is protected by copyright. All rights reserved. “
“Statins are widely used drugs for the treatment of hypercholesterolaemia. A number of recent studies

have suggested that statins also have pleiotropic effects on immune responses and statins have proven to be effective in the treatment of autoimmune diseases in animal models. Foxp3+ T regulatory cells are a unique subset of CD4+ T cells that mediate immunosuppression. Foxp3+ T cells develop in the thymus, but can also be induced in peripheral sites in the presence of transforming growth factor-β (TGF-β). We demonstrate here that simvastatin blockade of the mevalonate pathway can mediate induction Epothilone B (EPO906, Patupilone) of mouse Foxp3+ T cells and that simvastatin can synergize with low levels of TGF-β to induce Foxp3+ T cells. The effects of simvastatin are secondary to a blockade of protein geranylgeranylation, are mediated at late time-points after T-cell activation, and are associated with demethylation of the Foxp3 promoter. One major effect of simvastatin was inhibition of the induction of Smad6 and Smad7, inhibitory Smads that inhibit TGF-β signalling. Our results suggest that one mechanism responsible for the immunosuppressive effects of statins is the ability to promote the generation of Foxp3+ T regulatory cells.

Additional studies on the role of platelets and IL-1 family members may be important to fully understand their roles in DENV pathogenesis. In summary, strategies that may

limit CT99021 molecular weight IL-1 and IL-17 production at local sites of inflammation and viral replication during DENV might represent a step forward in the attenuation of severe manifestations of the disease such as DHF/DSS. In addition, any eventual strategy that allows local release of IL-22 or enhances IL-22 production to counterbalance the up-regulation of IL-17 would also bring a beneficial impact to limit tissue damage and hepatic dysfunction during DHF/DSS. However, further experimental studies are necessary to understand the complex interactions of the virus with the host

cells and the regulation of cytokines, chemokines and other mediators of inflammation including complement, tissue homeostasis and metabolism at large. This is a comprehensive review of DENV biology and research, especially of the different mouse models used to study the pathogenesis of DENV infection. Overall, each mouse model has its advantages and disadvantages and the researcher must carefully select the optimal model to investigate dengue immunopathogenesis and pre-clinical testing of antiviral drugs and vaccines. With a focus on the immune competent mouse model of DENV-2 infection, we described important molecular and cellular mechanisms underlying the exacerbated inflammatory response triggered by uncontrolled viral

replication in mice (Fig. 1). These studies will help to define new potential targets to attenuate disease severity and outcome in patients. Although the P23085 ABT 737 adapted strain represents progress, further studies are required to define how the altered sequence by this adapted strain influence host–pathogen interactions and to scrutinize the phenotype against the known clinical aspects of DHF/DSS in humans. We acknowledge Dr Mauro all M. Teixeira (UFMG, Brazil) and Dr François Trottein (INSERM, Lille, France) for their mentorship and support. Our work was supported by research grants from The Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), the French National Research Agency (ANR), Fondation pour la Recherche Médicale (FRM), Fond Européen de Développement Régional (FEDER) and the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil). The research on DENV-2 experimental infection was developed and performed under the auspices of the programme INCT em Dengue (Brazil). The authors declare that they have no financial or commercial conflict of interests. “
“Autoimmune diseases are characterized by the body’s ability to mount immune attacks on self. This results from recognition of self-proteins and leads to organ damage due to increased production of pathogenic inflammatory molecules and autoantibodies.

This thin layer of fluid covers all luminal surfaces and contains multiple antimicrobial factors secreted by epithelial cells and immune cells strategically distributed throughout the

FRT. These secretions contribute in a number of ways to the defense of the FRT CCI-779 against bacterial, viral and fungal pathogens. In addition to physically protecting columnar and squamous epithelial cells that line the FRT, secretions promote ciliary clearance and contain mucus that serves both as a physical barrier and as a trap for bacteria and viruses. FRT secretions contain surfactant proteins that enhance phagocytosis of bacteria, immunoglobulins that bind bacteria, and lactoferrin that deprives bacteria of iron. Also present are antimicrobials that contribute to the protective shield against potential pathogens. As presented in this review, FRT secretions contain a spectrum of antimicrobials totaling more that 20 molecules that are able to kill or inhibit bacteria, viruses, and fungi without

inducing inflammation. Because survival depends on protection against pathogens, antimicrobial redundancy and MI-503 price synergism have evolved to provide a spectrum of protection greater than that present with a single factor.5 Less well recognized is the realization that antimicrobials in FRT tissues and secretions are under hormonal control. As a result, some antimicrobials are enhanced while others are suppressed in response to estradiol and/or progesterone. These changes lead to protection against STI at times during the menstrual cycle when aspects of the adaptive immune system are suppressed.6 Our goal in this review is to identify the innate immune cells at different sites in the FRT that provide antimicrobial protection, characterize the antimicrobials present in FRT secretions of the upper and lower FRT, and examine the changes in antimicrobials expression that occurs during the menstrual cycle, pregnancy, and following menopause. Important biologic

factors are presented under the broad headings of epithelial cells and immune cells in the FRT; antimicrobials in the upper and lower FRT; endocrine regulation of antimicrobial Progesterone protection; and relationship of antimicrobials to STI. Leukocytes in the FRT play a central role in providing cellular, humoral, and innate immune protection against bacterial and viral invasion. Using human reproductive tract tissues dispersed by enzymatic digestion prior to quantitative flow cytometry, Givan et al.7 demonstrated that CD3+ T lymphocytes were present in substantial numbers, not only in the uterine endometrium, but throughout the FRT, including the ovary, Fallopian tube, uterine endometrium, endocervix, ectocervix, and vagina.

Previous study has shown that cross-linking of FcεRI activates PI3K signalling

pathway, leading to intracellular ROS production [25]. To explore whether OVA challenge–induced ROS production and subsequent activation of SOCs are related to PI3K activation, we explored the effect of PI3K inhibitor Wortmannin on ROS production and Ca2+ signalling in OVA-activated mast cells. The results demonstrated that Wortmannin (100 nm, 15 min) pretreatment significantly decreased Y-27632 cell line intracellular ROS production by ~30%. Mast cell activation–induced histamine release was similarly reduced (~30%) by inhibiting PI3K pathway. With the reduction of ROS, Ca2+ increase through SOCs in OVA-activated mast cells was diminished by ~30% (Fig. 6A,B). Consistently, the protein expressions of Orai1 and STIM1 were attenuated by ~40% and ~30%, respectively (Fig. 6C,D). We also found that inhibition of PI3K pathway reduced mast cell activation–induced histamine release (~30%) and intracellular ROS find more production (~30%). The results indicate that PI3K-mediated ROS generation is involved in the regulation of SOCs activity and mast cell activation under food-allergic condition (Fig. 6E,F). Previous studies have demonstrated that mast cells play a critical role in allergic diseases. Using OVA-stimulated food-allergic rat model, we revealed that

mast cells were recruited and activated in the damaged intestinal tissues and peritoneal lavage, and Th2 cytokines and IgE were significantly increased, confirming

the notion that mast cells contribute to the pathogenesis of food allergy. In this study, we demonstrated that the underlying mechanism for mast cell activation 4-Aminobutyrate aminotransferase in the food-allergic mouse model is related to increased Ca2+ entry through SOCs. Furthermore, we found that OVA stimulation increased intracellular ROS production in mast cells through activation of phosphoinositide 3-kinase (PI3K) pathway, which results in upregulation of the expression levels of the major subunits of SOC, Orai1 and STIM1, leading to the enhancement of SOC activity and subsequent mast cell activation. Food allergy is one type of adverse reactions to non-toxic food that involves an abnormal immunological response to specific protein(s) in food. Allergens from egg seem to be one of the most frequent causes of food-allergic reaction as reported [26]. In the present study, we use OVA, which comprise 50% of the protein in egg white, to induce food allergy as previously reported [17, 27, 28]. According to our results, the food-allergic model in Brown-Norway rats has been successfully re-established. The OVA-challenged rat showed typical allergic appearances, including puffiness and redness around the eyes and mouth, diarrhoea, pilar erecti, reduced activity and/or decreased activity with increased respiratory rate and cyanosis around the mouth and tail.

The effectiveness of this method was demonstrated in a multi-centre randomized controlled trial in which 39 haemodialysis patients prone to intradialytic hypotension were treated using both fixed dialysate conductivity and PI3K inhibitor a dialysate conductivity derived from the conductivity kinetic model. There was a significant reduction in the intradialytic fall in systolic blood pressure (BP) when patients were dialysed using the conductivity kinetic model, with a trend towards better cardiovascular stability. Current evidence suggests that sodium modelling should be considered in patients prone to

intradialytic hypotension and those troubled by disequilibrium symptoms. Ultrafiltration refers to removal of water and constituent solutes, which thereby reduces plasma and extracellular fluid volume. It is accepted practice to perform a period of isolated UF before dialysis to improve tolerance of fluid removal in an overloaded patient. There have been few studies examining modelled UF alone, as it is usually examined www.selleckchem.com/products/XL184.html in conjunction with sodium modelling. In

the aforementioned study by Zhou et al.,5 modelled UF with standard dialysate sodium resulted in a non-significant increase in intradialytic hypotensive episodes. Donauer et al.8 trialled 53 patients on 6 regimens of UF including constant, linear reduction, stepwise reduction and intermittent high UF rate interrupted by UF pauses, while simultaneously measuring Chlormezanone relative blood volume. Linear modelled UF was

associated with an apparent reduction in hypotensive episodes, but this was not statistically significant. Stepwise and intermittent high UF models were associated with a significant increase in the frequency of symptomatic hypotension. Poor compliance with fluid restriction necessitates a higher rate of UF, and thereby increased risk of intradialytic hypotension. The level of patient compliance with fluid restriction has not been documented in the aforementioned studies. The absence of this information further limits any interpretation and recommendations that arise from these studies. Based on this limited evidence, nonlinear UF modelling alone may not be tolerated by some patients, and is best avoided in those prone to intradialytic hypotension. There are limited data to support linear modelling of UF as a method of avoiding intradialytic hypotension. Potassium is central to cardiac pacemaker rhythmicity, neuromuscular excitability and maintenance of resting cell membrane potential. Both hypokalaemia and hyperkalaemia predispose to cardiac arrhythmias.9 A higher dialysate potassium concentration is recommended for patients on digitalis therapy. Hyperkalaemia in the dialysis population is independently associated with higher all-cause and cardiovascular mortality.9 Both the rapid fall in serum potassium early in dialysis and hypokalaemia late in dialysis are arrhythmogenic.

We isolated splenic naive CD4 T cells from C57BL/6 mice and stimulated them in vitro in either Th1 or Cell Cycle inhibitor Th2 polarizing conditions. Cells were cross-linked and sonicated, and the chromatin was immunoprecipitated with either an anti-GATA-3 or anti-MTA-2 antibody. GATA-3

bound to Th2 LCR (RHS4, RHS5, RHS6, and RHS7), the promoters of il4, il5 and il13 genes, and enhancers (CNS-1 and CNS-2/HSV) in a Th2-specific manner (Fig. 2). This result shows that GATA-3 binds to the Th2 cytokine locus globally and to Th2 specifically. The MTA-2 also bound to Th2 LCR (RHS4, RHS5, RHS6, and RHS7) and promoters of Th2 cytokine genes, and enhancers (CNS-1/HSS, CNS-2/HSV) (Fig. 2). However, in contrast to GATA-3, MTA-2 bound to these regions in a Th1-specific manner (Fig. 2). Therefore, the overall binding of MTA-2 and GATA-3 on the Th2 cytokine GS-1101 nmr locus was mutually exclusive (Fig. 2). Interestingly, both GATA-3 and MTA-2 bound to the promoter of the ifng gene in Th2 cells (Fig. 2). The simultaneous binding of GATA-3 and MTA-2 on the ifng promoter was confirmed by a double-chromatin immunoprecipitation experiment. Chromatin from Th1 or Th2 cells was first immunoprecipitated with an anti-GATA-3 antibody, and the bound antibody was detached from the chromatin by treating with DTT. The eluted chromatin was then immunoprecipitated with the anti-MTA-2 antibody. The result confirms that GATA-3 and MTA-2 bound to the ifng promoter simultaneously

in Th2 cells (Fig. 3). Next, we examined whether the binding of MTA-2 to ifng promoter is dependent on GATA-3. For this purpose, we used siRNA-mediated reduction (knockdown) of GATA-3 protein in EL4 cells. We transfected gata3 siRNA into EL4 cells and measured the protein level of GATA-3 by immunoblotting (Fig. 4a).

Treatment with gata3 siRNA led to a significant reduction of GATA-3 protein level in EL4 cells (Fig. 4a). The expression of ifng gene was increased by treatment with gata3 siRNA (Fig. 4b), consistent with the previous reports.13,14 Interestingly, the binding of MTA-2 to ifng promoter was abolished by gata3 siRNA (Fig. 4c). However, the binding of MTA-2 to myc promoter, which has been shown previously24,25 but has not been GBA3 shown to have any relevance to GATA-3, was not affected by gata3 siRNA (Fig. 4c). These results strongly suggest that the binding of MTA-2 to ifng promoter is specifically dependent on GATA-3. We also examined whether MTA-2 affects the functional activity of GATA-3. The GATA-3 expression vector was transfected with reporter constructs that contain IL4P-luciferase (IL4P) or RHS7-IL4P-luciferase (IL4P-RHS7).9 Introduction of GATA-3 transactivated the transcription of the reporter gene about two-fold in IL4P and about three-fold in RHS7-IL4P constructs after treatment with PMA + ionomycin (Fig. 5). These results suggest that the il4 promoter and RHS7 are GATA-3 responsible elements, and are consistent with the ChIP data indicating that GATA-3 bound to these regions (Fig. 2).

Therefore, the following monoclonal mouse antibodies were applied: IC16 ([30], raised against Aβ1–16; 1:2000), AT8; Thermofisher, Bonn, Germany; 1:1000), MC-1 ([31]; 1:50), CP13 ([32]; 1:500), β-actin (Sigma; 1:5000) selleck chemicals llc and β3-tubulin (Millipore, Schwalbach, Germany; 1:2000). In addition, we applied rabbit antisera directed against human tau (Dakocytomation, Hamburg; 1:1000), anti-pS199

(BioSource, 1: 500), anti-pS422 ( [33]; 1:500) and anti-glial fibrillary acidic protein (GFAP; Synaptic Systems, Göttingen, Germany; 1:4000). Following overnight incubation, membranes were washed in TBST two times for 10 min. Secondary anti-rabbit or anti-mouse conjugates of horseradish peroxidase (Dianova, Hamburg, Germany) were applied for 2 h. Membranes were Napabucasin rinsed two times in TBST, and blots were developed using enhanced chemiluminescence,

followed by scanning of X-ray films (Hyperfilm EC, Amersham Biosciences, Freiburg, Germany). For quantification of relative protein amounts, protein levels were determined via ImageJ software (1.46r, National Institutes of Health, USA) by measuring band intensity in densitometric analyses normalized to β-actin or β3-tubulin levels, respectively. Sections containing hippocampi from several animals of all animal groups were pre-treated for 10 min with concentrated formic acid (98–100%, Merck) and routinely used for sensitive 4G8 staining Ribonucleotide reductase (see below). These and all other free-floating sections were extensively rinsed with TBS followed by blocking of non-specific binding sites for subsequently applied immunoreagents with 5% normal donkey serum in TBS containing

0.3% Triton X-100 (NDS-TBS-T). For the analysis of cholinergic markers, forebrain sections were either applied to affinity-purified goat-anti-ChAT (AB144P, Millipore; 1:50 in NDS-TBS-T) or rabbit-anti-p75 (G323A, Promega, Mannheim, Germany; 1:100 in NDS-TBS-T), followed by several rinses with TBS and incubation for 1 h with Cy3-conjugated donkey antibodies recognizing goat or rabbit (both from Dianova, 20 μg/ml TBS containing 2% bovine serum albumin = TBS-BSA), respectively. Markers applied for double labelling of β-amyloidosis and tauopathy in hippocampal sections are summarized in Table 1. For triple fluorescence labelling of Aβ deposits, astrocytes and microglia, sections were first incubated overnight in a mixture of biotinylated mouse antibody 4G8 ([34]; Covance, 1:500 in NDS-TBS-T), Cy3-conjugated-mouse-anti-GFAP IgG (Sigma; 1:250) and rabbit-anti-ionized calcium binding adapter molecule 1 (Iba; Wako, Neuss, Germany; 1:200). Following several rinses with TBS, immunoreactivities were visualized by incubating sections for 1 h in a mixture of Cy3-streptavidin and Cy5-tagged donkey-anti-rabbit IgG (both at 20 μg/ml TBS-BSA and from Dianova).

Testing whether type I IFNs drive this STAT4 pathway Tamoxifen cell line was one motivation for these

investigations. In our current studies, IFN-α/βR KO mice had an early defect in IFN-γ production in response to L. mexicana antigens. We found that at 4 weeks of infection, the already weak IFN-γ response seen in WT mice is further diminished when IFN-α/β signalling is lacking. This indicates that IFN-α/β does have a role in promoting Th1 development and could act through STAT4 in this process. However, later in infection, there is no lasting effect on IFN-γ (perhaps because the WT mice have decreased IFN-γ) and the overall course of lesion progression, parasite burdens, and nitric oxide production were not different in IFN-α/βR KO and WT mice. This transient importance of IFN-α/β has several potential mechanisms. Others have found that Type I IFNs can induce STAT4 phosphorylation in mice but that it is less sustained than from IL-12 stimulation, and thus does not, in and of itself, induce Th1 development. In addition, IFN-α can increase IFN-γ synergistically with IL-18 from Th1 cells (21). This less sustained nature of STAT4 signalling may contribute HDAC inhibitor review to a lack of sustained effects on IFN-γ. IFN-α/β has been shown to decrease IL-12 strongly (18,19) and thus decrease Th1 development and IFN-γ from CD4+ T cells, as well as from NK cells. Therefore, IFN-α/βR KO mice may have increased IL-12-induced STAT4 activation offsetting the lack of the IFN-α/β-driven

IL-12-independent STAT4 pathway. However, we did not see higher IL-12 levels in the serum of L. mexicana-infected ADP ribosylation factor mice making this hypothesis less likely. Later, in infection, serum IgG1, which has a delayed kinetics, is present and is able to induce IL-10 through FcγR (22) suppressing the development of a Th1 response. An early worsening of disease caused by L. major was seen in a strain of mice that is naturally

a low IFN-α/β producer (10). As in our studies, the final disease outcome was not changed by a decrease in type I IFNs indicating that there is redundancy and that type I IFNs do not drive the dominant pathway. We also found that IFN-α/βR KO mice have a defect in IL-10 production from draining lymph node cells. The ELISA data were corroborated by a decrease in IL-10 mean fluorescence intensity in CD25+CD4+ T cells, the main CD4+ T cell population that produces IL-10, and possibly a decrease in the percentage of IL-10 producing cells. There is some earlier evidence that IFN-α/β can induce IL-10, at least in humans (23,24). Our current data support the idea that mice also have this mechanism of IFN-α/β induction of IL-10. Thus, type I IFNs could work towards increased susceptibility through IL-10 stimulation, thus blunting some of the protective effects of IFN-α/β signalling through STAT4. We found that IFN-α/βR KO mice had an early increase in parasite-specific IgG1 and IgG2a and yet had less LN T cell IL-10 throughout the infection.