114 When mice are injected with poly(I:C), abortion occurs because uterine NK cells are activated. Similarly, the human uterine NK cells can be activated towards cytotoxicity. The final activity of NK cells is governed by a balance of inhibition and activation by the trophoblast ligands/NK cell receptor interactions. El Costa et al. have shown that engagement of NKp46 receptor, but not NKp30 receptor on decidual NK cells, triggers cytotoxicity. Such cytotoxic potential is negatively controlled by NKG2A inhibitory receptor Selleck BAY 80-6946 co-engagement.115 This and other studies on NK cell KIR repertoire in spontaneous

abortions suggest that uNK cells, and in some circumstances systemically activated blood NK cells, can ‘reject the foetal allograft’ Selleckchem GSK126 as seen in break of transplantation tolerance. More partners, such as NKT cells and inhibitory NKT (iNKT) cells, are emerging in tolerance. As a recent example, alpha beta(+) CD161(+) NKT cells have been shown to reside in the decidua and may play an important role in foetal tolerance, and this is reinforced by demonstration of expression of CD1d on trophoblasts.116,117 Linking ‘tolerance’ and immunotrophism,

decidual iNKT cells are strongly polarised towards GMCSF expression, and CD1d expression is linked to trophoblast differentiation.117 Another subset certainly playing a role is Th17 cells, which can be involved in rejection. Galectin regulates this subset. Interestingly, FoxP3/IL-17 dysregulation is seen in preeclampsia, and we have obtained data linking IL-17 with implantation failure. Other cytokines important in this respect are Ebi3 (IL-27) and its derivative IL-35, an immunosuppressor expressed at interface in mice118 and

by activated T regs. Another emerging modulator is IL-22, regulator of Th17, IL-17, IL-23 also regulating in many systems G-CSF, a matter of importance in view of CSF role in Carnitine palmitoyltransferase II embryo implantation potential and foetal tolerance.119 As stated earlier, the danger theory predicted Toll-like receptors and the initial steps of pregnancy as an inflammatory, Th-1-dominated stage. This suggests that Toll-like receptors play a cardinal role in early adhesion/invasion and participate in the promotion of foeto-maternal tolerance. We will not substitute here the excellent reviews of Mor and Abraham,120 but recall in the context that the system includes regulation of Toll-like receptors by ligands as regulators of T reg function. Data suggest that a ‘break of tolerance’ can be linked to response to local danger, as strongly suggested by CBA × DBA/2 matings, with a role for MD1. Similarly, TLR9-triggered activation in IL-10 KO mice amplifies uterine neutrophil and macrophages and their migration to the placental zone, with high pregnancy losses.78 Finally, ‘priming’ for ‘tolerance’ might start before implantation.

“
“Nocturia is one of the most common urological symptoms in men and women. Its prevalence is significantly related to age, but the causes of nocturia are multifactorial, such as diabetes, obesity, and other diseases and conditions. Recently, it has been reported that metabolic syndrome (MetS) is associated with lower urinary tract symptoms, including incomplete emptying, intermittency, and nocturia.

We reviewed the relationship between MetS and its EX 527 nmr components and nocturia. The results from our epidemiological study indicate that nocturia can be a marker not only of MetS but also of the precursor of MetS. Nocturia is a common condition among men and women, especially among the elderly. Its prevalence is significantly related to age. The increasing number of publications concerning nocturia, both in terms of absolute and relative numbers of papers, indicates that interest in the condition is also increasing.1 Epidemiologic studies of nocturia are also being performed more frequently, not only in Western countries,2 but also in Asian countries.3–5

click here The result of a population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms (LUTS) in five Western countries shows that nocturia is the most prevalent LUTS among men and women.2 Similar to other countries, LUTS are highly prevalent in Japan. Nocturia was the single most distressing symptom in men. For women, nocturia and stress

incontinence were equally the two most distressing symptoms.6 Nocturia not only affects quality of life, but also increases mortality. Nocturia is associated with a 1.8-fold increased risk of hip fracture.7 Men who have nocturia (≥3 voids/night) also have a two-fold increase in mortality.8 In a population-representative study in Japan, persons aged ≥70 years with nocturia (≥2 voids/night) had a significantly increased risk of mortality when compared to the elderly without nocturia.9 In the past, nocturia has been considered as an irritative symptom of benign prostatic hyperplasia (BPH). However, among seven symptoms included in the International Prostate Symptom Score, rate of improvement was lowest for nocturia after invasive treatments for BPH.10 Many epidemiological Interleukin-3 receptor surveys have demonstrated that nocturia is equally prevalent in both genders.11 This would suggest that BPH is not a principal cause of nocturia. There are many putative causes of nocturia. Nocturia is associated conditions or circumstance, including aging, overactive bladder, BPH/LUTS, diabetes, congestive heart failure, chronic kidney disease, medication usage (including diuretics, analgesics), and sleep disturbance.1 The pathophysiological process of nocturia consists of three basic phenomena: polyuria, nocturnal polyuria, and bladder storage problems.

,

2006), while Chawla et al. (2009) have suggested preserving those tissue samples in normal saline and not in the formalin as the latter is known to cause alterations in DNA for PCR assays. The combined use of nested PCR targeting IS6110 and mycobacterial culture (both automated and conventional) for the diagnosis of osteoarticular TB has also been documented (Agashe et al., 2009). Recently, Sharma et al. (2011b) introduced a highly sensitive and specific multiplex PCR targeting IS6110 and MPB-64 protein genes in the prospective evaluation of synovial fluid and pus samples from 80 cases of osteoarticular TB. The rpoB PCR-plasmid TA cloning-sequencing method to detect M. tuberculosis in the joint tissue, synovial fluid and pus samples from osteoarticular TB has been developed by Yun et al. S1P Receptor inhibitor (2005) and their method could simultaneously determine rifampin (RIF)

susceptibility of tubercle bacilli. Fujimoto et al. (2010) also confirmed a case of TB pleuritis with knee-joint involvement by PCR analysis of the synovial fluid. Interestingly, Colmenero et al. (2010) developed a reliable and sensitive multiplex real-time PCR based on conserved region of the gene coding for an immunogenic membrane protein of 31 kDa of Brucella abortus (BCSP31) and SenX3-RegX3 (intergenic region of M. tuberculosis) gene for the rapid differential diagnosis of TB vertebral osteomyelitis and brucellar vertebral osteomyelitis. CHIR-99021 solubility dmso Genitourinary TB comprising of genital and renal TB is the second most common EPTB and contributes up to 46% cases of EPTB (Jacob et al., 2008). Renal TB occurs up to 20 times more frequently in kidney transplant recipients than in the general population (Wise, 2009). The early diagnosis of renal TB is very important in preventing progressive destruction of the kidney (Wise, Quisqualic acid 2009). Recently, Sun et al. (2010) described an early and rapid diagnosis of renal TB from renal biopsy specimens by real-time PCR using 35-

and 40-cycle threshold (CT) cut-off values. It was found that the real-time PCR (CT 40) showed better sensitivity than the real-time PCR (CT 35). Genital TB has been involved in the infertility of both men and women, and majority of such cases remain undiagnosed owing to asymptomatic presentation of the disease (Rana et al., 2011). Hence, a high index of suspicion is necessary for the diagnosis of genitourinary TB. To confirm genitourinary TB (both in men and women) in urine samples, PCR targeting MPT-64 protein gene has earlier been demonstrated to be the most sensitive indicator as compared to intravenous urography, bladder biopsy or urine culture (Hemal et al., 2000). The utility of PCR targeting IS6110 or 16S rRNA gene has also been evaluated in urine samples for the diagnosis of genitourinary TB (Moussa et al., 2000; Abbara & Davidson, 2011). High sensitivity up to 100% has been claimed by nested PCR based on MTP-40 protein gene of M. tuberculosis (Garcia-Elorriaga et al., 2009).

However, the chemotaxis of infant PMNs toward CXCL2 was still significantly lower than that of adult PMNs after the blockage of GRK2 (p < 0.05) (Fig. 3F), indicating that GRK2 is not responsible for the reduced CXCR2 and chemotaxis in infant PMNs. To further clarify the mechanism underlying the enhanced susceptibility to microbial infection and delayed bacterial clearance in infant mice, we measured

the surface expression of two phagocytic receptors, complement receptor type 3 Apoptosis inhibitor (CR3) and FcγIII/II receptor (FcγR) on macrophages from infant and adult mice. Significantly reduced constitutive expression of CR3, but not FcγR, was observed in infant macrophages (p < 0.05 versus adult macrophages) (Fig. 4A). Stimulation with LPS or BLP resulted in diminished upregulation of CR3 expression on infant macrophages compared with adult macrophages (p < 0.05) (Fig. 4A). Although both constitutive and stimulated CR3 expression was reduced on infant macrophages,

phagocytosis of either S. aureus or S. typhimurium by infant and adult macrophages was comparable (Fig. 4B). However, intracellular killing of the ingested live S. aureus and S. typhimurium by infant macrophages was markedly reduced compared with adult macrophages (p < 0.05) (Fig. 4C). Thus, infant macrophages display an impaired bactericidal activity after ingestion of Ixazomib purchase gram-positive and gram-negative bacteria. Phagosome maturation of professional phagocytes after ingestion of microbial bacteria is characterized by phagosomal acidification and phagosome/lysosome fusion [23, 25]. A significantly delayed and reduced phagosomal acidification after ingestion of S. aureus was observed in infant macrophages compared with adult macrophages (p < 0.05) (Fig. 5A). A similar defect in phagosomal acidification was also found in infant macrophages after ingestion of S. typhimurium (p < 0.05 versus adult macrophages) (Fig. 5B). PLEK2 We subsequently loaded peritoneal macrophages with LysoTracker red that

selectively labels late endosomes/lysosomes and monitored the maturation of phagosomes that have ingested S. aureus–FITC by examining their ability to colocalize with LysoTraker red over time. Almost all the ingested S. aureus-FITC were colocalized with LysoTraker red in the adult macrophage at 60 min after macrophages were chased with S. aureus-FITC, whereas most S. aureus-FITC ingested by the infant macrophage at this time point did not colocalize with LysoTraker red (Fig. 5C). A substantially reduced colocalization of Escherichia coli-FITC with LysoTraker red was also found in the infant macrophage compared with the adult macrophage (Fig. 5D). These results indicate that, in contrast to adult macrophages, infant macrophages show a defect in phagosome maturation after ingestion of microbial bacteria.

First, unlike mHFE+ skin grafts

onto DBA/2 mHfe KO mice (whether TCR-transgenic or not), with local and coinciding antigenic charge and inflammatory reaction, the anti-mHFE TCR-transgenic CD8+ T cells were i.v. injected into Rag 2 KO DBA/2 mHFE+ mice in a noninflammatory context (LPS was administered on day 12, at which time the CFSE experiment established that the injected cells had already disappeared). Second, albeit HFE is broadly expressed, its expression in antigen-presenting cells in particular dendritic cells is relatively limited [[4]] and HFE is expressed in a variety of nonantigen-presenting cells including cells of the liver, an Ensartinib datasheet organ endowed with strong tolerogenic properties [[35]]. It should however be stressed that the absence of GVHD

when HFE is the sole molecule targeted by a monoclonal CD8+ T-cell population does not exclude that in other situations (additional minor histocompatibility mismatches, polyclonality of the injected cells, etc.) an HFE mismatch would not contribute to GVH reactions, as documented for HY mismatches in human clinic [[36]]. Whereas most anti-mHFE TCR-transgenic T lymphocytes are blocked in the thymus at the CD4+ CD8+ double positive stage in DBA/2 mHFE+ mice, some cells escape deletion and are found in the periphery. These cells express a low level of the transgenic TCR, are CD4−, CD8−, CD25− and approximately 50% of them express NK-cell markers, NKp46, and DX5. These cells differ from Treg cells phenotypically (CD4−, FoxP3−) and functionally (no suppressive activity) but share similarities (co-expression of NK-cell markers, reduced amounts of TCR) with conventional NKT cells [[37]]. However, CHIR-99021 purchase unlike NKT cells, they do not express the PLZF transcription factor [[38]] and produce neither IL-4, nor IFN-γ but produce IL-6, IL-10, and hepcidin. They must therefore have been differently reprogrammed. Whether these cells are a residual and not a functional population of lymphocytes simply “parked” in the periphery or, as their production of IL-6 and hepcidin (two key regulators of iron metabolism) may suggest, contribute to iron homeostasis is an open question. From that point of view it has to be stressed that similar cytokine productions

were not observed with H-2 Db-restricted anti-HY TCR transgenic T lymphocytes from male mice that similarly downregulate their TCRs selleck screening library [[34]]. Several other observations support the notion that the immune system plays a regulatory role in iron metabolism. Iron overload in Rag/β2m double KO is more accentuated than in β2m single KO mice [[39]] and, in hemochromatosis patients, an inverse correlation has been observed between CD8+ T-cell numbers and disease severity [[40]], a possible consequence of the recently documented production of hepcidin by T lymphocytes [[41]]. Having established that mHFE is an autonomous histocompatibility antigen for mHfe KO and mHfe-C282Y mutated mice, it remains to be seen whether the same is true for hereditary hemochromatosis patients.

Thus, alternative splicing represents an effective regulatory mechanism to fine-tune an immune response. The two novel isoforms of IKKε described here differentially modulate IRF3 and NF-κB signaling pathways. Both splice variants have lost the capability to activate IRF3, whereas only IKKε-sv2 is additionally unable to activate NF-κB-driven luciferase expression. Moreover,

the splice variants have the potential to inhibit the activation of NF-κB and/or IRF3 in a dominant-negative manner. Importantly, we could demonstrate that this effect led to enhanced infection spread of VSV-GFP in cells, Fostamatinib price where IKKε-wt and one of the splice variants were coexpressed, whereas overexpression of IKKε-wt alone protected from infection. The relative abundance of the different IKKε isoforms might thus represent a novel regulatory mechanism controlling the different functions of this kinase. When analyzing expression patterns of the various IKKε isoforms,

we observed ubiquitous expression of all three variants in different human organs. Additionally, we found a remarkably high expression of IKKε-sv1 in testis and striking differences in the quantities of IKKε-sv2 expressed in PBMC from different donors. Since both variants inhibit IRF3 signaling, it would be conceivable that enhanced expression of IKKε-sv1 or IKKε-sv2 might lead to a decreased type-I IFN release and consequently to an increased susceptibility to viral infections. Since IKKε-sv1 still check details activates NF-κB, a selective upregulation of this splice variant might even contribute to the development of virus-induced inflammatory diseases, because the antiviral response would be shifted to increased NF-κB-dependent expression of proinflammatory cytokines at the expense of type I IFN release. Interestingly, we observed in the two monocytic cell lines U937 and THP1 that infection with VSV leads to such a selective upregulation of IKKε-sv1. On the contrary, TNF upregulates in monocytes both splice variants likely leading to the inhibition of both IKKε functions. In MCF7 cells, however, TNF stimulation upregulates only IKKε-sv1,

thereby preserving the activation of NF-κB by IKKε-wt, which is essential for MCF7 cell proliferation 20. Surprisingly, the in-frame deletion of only 25 amino acids near the C-terminus of IKKε led to a complete failure to activate IRF3. Similar results were published Rebamipide by Gatot et al., who reported that deletion of 30 C-terminal amino acid results in the loss of IRF3 activation most likely due to the failure of truncated IKKε to interact with TANK 23. We could extend their results by demonstrating that binding of not only TANK but also of NAP1 and SINTBAD requires residues 383–407 of human IKKε representing a putative third coiled-coil motif. The domain structure of IKKε including proposed binding sites for potential interaction partners like the three scaffold proteins required for IRF3 activation is shown in Supporting Information Fig. S4.

2b), as detected by SDS-PAGE. Strikingly, there was only minimal loss of binding of the AMCA-HA peptide to HLA-DR1 upon digestion with CatG, and this slight loss was unaffected by the CatG inhibitor (Fig. 2c). Thus, peptide-loaded HLA-DR molecules are susceptible to CatG proteolysis, and cleavage of the β chain does not disrupt the integrity of the antigen-binding groove occupied by the peptide. To determine

the exact CatG cleavage site within the HLA-DR β chain, we performed N-terminal sequencing as well as peptide mapping NVP-LDE225 of the digestion products of purified soluble HLA-DR1 (sDR1). For these experiments we used sDR1 expressed in either insect cells or E. coli. Neither of these have a transmembrane domain and E. coli purified sDR1 is not glycosylated, which led to the fragments being smaller on gels (10 and 15 kDa). sDR1 expressed in insect cells (not shown) was used for identification of the N-terminal sequence of both fragments by Edman degradation (underlined italic sequence, Fig. 3a). The first residue of the larger fragment corresponds to the glycine (G) in position 1 of the mature protein. The first residue of the smaller fragment was FK866 manufacturer identified as glutamine (Q) at position 110. In order to define the boundaries

of both fragments, we also digested sDR1 expressed in E. coli (Fig. 3a), which is not glycosylated and was therefore used for MALDI-TOF analysis. The two bands were excised from a gel and digested with trypsin, Staphylococcus aureus V8 protease, or Arg-C protease. All peptides of these digests identified by mass spectrometry are indicated in black text in Fig. 3a. The peptide SFTVQRRVEPKVTVYPSKTQPL (underlined in Fig. 3a) was identified from a V8 digest and the peptide RVEPKVTVYPSKTQPL was identified from an Arg-C digest of the larger fragment, indicating that CatG did www.selleck.co.jp/products/U0126.html not cleave after the arginine (R), but did cleave after leucine 109 (L109). Based on the masses of the two fragments and on the fact that their sequences were contiguous, these fragments appear to represent the complete β chain, which therefore has only a single CatG cleavage site. The cleavage site, between HLA-DRβ L109 and glutamine 110 (Q110,

L/Q), is located on a loop between fx1 and fx2 of the membrane-proximal, immunoglobulin-like domain, as indicated on the crystal structure of HLA-DR (Fig. 3b). To explore whether HLA-DR β chain polymorphism might influence CatG susceptibility, we first compared the amino acid sequences of several HLA-DR β chains [DRB1*0101 (DR1), DRB1*1501 (DR2b), DRB1*0301 (DR3), DRB1*0401, and DRB1*0404] and found conservation of the L/Q cleavage site (Fig. 4a). We then subjected various recombinant soluble HLA-DR allelic variants to digestion with CatG and used HLA-DR-specific rabbit serum (CHAMP) to measure residual levels of DRβ and detect the 18-kDa DRβ fragment (Fig. 4b). As predicted from sequence alignment, CatG degraded the β chain of all HLA-DR molecules tested.

The guinea-pigs were observed twice daily for 5 days, for the general activity level, consistency of stool passed into the drop pan of their DAPT chemical structure cages and the nature of blood or mucus observed in the feces. Rectal swabs were taken daily and plated onto Hektoen enteric agar (Difco) and MacConkey agar (Difco) to identify shedding of the challenge organisms. Isolated colonies were confirmed by slide agglutination with appropriate antisera (Denka Seiken Co. Ltd, Japan). Rectal temperature was measured using a mercury thermometer and the body weight was recorded using a digital balance. The animals were sacrificed by an intravenous injection of euthanasia solution

(Starfil Lab Pvt Ltd, India) and the intestinal tissues were taken for a colonization assay and histological tests. The overnight growth of S. dysenteriae 1 (NT4907) and S. flexneri 2a (B294) was scrapped off from TSA and suspended in PBS and centrifuged (10 min, 10 000 g). The resulting pellet was washed twice and resuspended in PBS. The bacterial suspension was adjusted to an OD600 nm of 1.5. Organisms were heat-killed at 100 °C for 1 h, washed twice after centrifugation and resuspended in PBS. The suspension was adjusted again to OD600 nm 1.5 and was stored at −80 °C till use for oral immunization. OD 1.5 corresponded to 107 CFU mL−1. Two groups (eight animals in each) were used for

oral immunization with heat-killed S. dysenteriae 1 and S. flexneri 2a. Oral immunization was performed according to the method of learn more Sack et al. (1988). Guinea-pigs were anesthetized using a mixture of ketamine (35 mg kg−1 of body weight) and xylazine (5 mg kg−1 of body weight). Guinea-pigs were orally immunized with 107 CFU of heat-killed Shigella strains in l mL of PBS under anesthesia. Control guinea-pigs were treated with sterile selleck chemical PBS instead of heat-killed immunogens. The immunization schedule was followed on the 0, 7th, 14th and 21st day. After four successive oral immunizations, both immunized and PBS control guinea-pigs were challenged on the 35th day with wild-type S. dysenteriae 1 (NT4907) and S. flexneri 2a (B294) strains. The challenge experiment was performed with the direct

introduction of live virulent shigellae (1 mL of 109 CFU) into the cecocolic junction after ligation of the distal cecum. The animals were observed for the development of typical shigellosis till 48 h. Blood was collected from the foot vein on days 0, 7, 14, 21, 28 and 35 and the sera were separated and stored at −80 °C. From both the groups, stool samples were collected from the drop pan two times daily for 2 consecutive days after the challenge (i.e. days 36 and 37). After 48 h of the luminal challenge of both immunized and control groups, the animals were sacrificed by an intravenous injection of euthanasia solution and the intestinal tissues were taken for colonization and histological examinations. Intestinal lavage from guinea-pigs was collected following the method of Orr et al.

Recently it has also been reported in the United States. Case: We reported one case of a hypertensive S1P Receptor inhibitor male 44 years old male after consumption of 5 pieces of java barb gallbladders. He got profuse vomiting, decreased urine output and developed edemas at both limbs and the scrotum within 3 days. He was diagnosed as prerenal acute kidney injury. Both his serum creatinine and serum ureum raised to 17,7 mg/dL to 193 mg/dL respectively. Meanwhile, he also developed ischemic acute hepatitis failure, with a ALT: 56 U/L, and AST: 536 U/L. He remained

hypertensive (170/80 mmHg). Renal ultrasound detected no evidence of abnormalities. During admission, patient has been treated conservatively with restricted fluid management, bicarbonate tablet three times a day, amlodipine 10 mg a day, pantoprazole injection 40 mg a day. The urine output is more than Epigenetics Compound Library in vitro 2000 mL/24 hours, no diuretics has been used. The patient did not require dialysis. After 10 days he was discharged from the hospital with a serum creatinine concentration 4,46 mg/dL, ureum 90 mg/dL ALT 17 U/L and AST 42 U/L. After a week discharged his serum creatinine concentration

reached 1,83 mg/dL and his ureum 38 mg/dL. Conclusion: It seems acute kidney injury and acute ischemic hepatic failure after fish gallbladder consumption has an excellent prognosis. We suggested that this is an transient AKI induced by prerenal causes and toxicity of the gall bladder. A renogram and kidney biopsy should be perform and also a toxicological study of the gallbladder should be done. 303 RIGHT INTRA-ATRIAL CATHETER PLACEMENT FOR HAEMODIALYSIS Thymidylate synthase IN THE SETTING OF LIMITED VASCULAR ACCESS M HARFIELD1,3,V MANICKAM1,3, V SRIVASTAVA1,3, G KAN1,3, S YADAV2,3, O ASHRAF2 1Department of Nephrology and 2Department of Cardiothoracic Surgery, The Townsville Hospital, Townsville, Queensland; 3The School of Medicine and Dentistry, James Cook University, Queensland, Australia Background: Intra-atrial catheters are a little known alternative for access in patients

who have limited vascular access options. Case Report: A 55 year old female had been receiving dialysis treatment since 2006 following a diagnosis of end stage renal disease secondary to IgA Nephropathy. Since commencement on dialysis she had experienced multiple vascular access issues, including central venous stenosis and thrombosis of venous catheters and multiple fistulas. She was admitted for the creation of a right brachio-basilic transposition with current access via a right internal jugular (IJ) catheter. One week post-operatively her right IJ catheter thrombosed and was unable to be accessed. Despite numerous attempts at re-wiring and repositioning catheters, establishing vascular access was unsuccessful. The radiology department was not equipped to perform a direct translumbar catheterisation of the inferior vena cava, and an attempt at cannulating the new fistula resulted in haematoma formation.

68 However, unlike IL-4-mediated Th2 development, a variety of signals can block Th17 commitment including IFN-γ, IL-4 and IL-12. Interferon-α/β was also demonstrated to negatively regulate Th17 development in mice,69 and the suppression of Th17 development by IFN-α/β has recently been extended to human Th17 cells.70 Consequently, Th17 cells represent a more flexible developmental programme that can be counter-regulated by various signals, particularly by IFN-α/β.

Given the use of IFN-β clinically for the treatment of multiple sclerosis, a disease associated with Dasatinib chemical structure increased inflammation and IL-17 levels in the central nervous system,71 the ability of IFN-α/β to limit Th17 cells may explain the effectiveness of this treatment.72 Furthermore, the ability of IFN-α/β to inhibit Th2 and Th17 cells suggests that it may play a key role in controlling allergic responses.

The importance of IFN-α/β-mediated suppression of allergic T cell subsets is underscored by studies demonstrating that pDCs from asthma patients secrete less IFN-α/β than healthy donor pDCs in response to viral Staurosporine cost infections and toll-like receptor (TLR) ligands.73–75 Likewise, Gill et al.76 compared the induction of IFN-α by influenza virus in pDCs isolated from patients with asthma or healthy subjects and found that influenza virus infection promoted significantly less IFN-α secretion by pDCs from patients with asthma patients. Considering recent observations that IFN-α blocks Th2 development and stability,63 we propose that the defect in IFN-α production in pDCs from patients with asthma may skew T-cell priming toward Th2 development. It has been suggested that the reduction in IFN-α/β secretion during upper respiratory viral infections may lead to exacerbated lung pathology in those with asthma because of the inability of innate secretion of IFN-α/β to control viral replication in the lungs.75 While this is possible, asthma

exacerbation by viruses may also be attributed to the lack of counter-regulation normally provided by IFN-α/β. Given that respiratory viral acetylcholine infections, such as RSV, have been linked to the induction of asthma, it is possible that the inflammation accompanying these infections supports priming of bystander allergen-specific Th2 cells. Furthermore, as people with asthma encounter recurrent infections, the lack of IFN-α secretion may allow additional Th2 priming. Although pDCs are a significant source of IFN-α/β secretion during viral infections, these cells also express relatively elevated levels of the high-affinity IgE receptor FcεRI. Although it is not clear what specific role pDCs may play in allergen-induced asthma via IgE-mediated activation, Liu and colleagues77 recently demonstrated a reciprocal regulation of TLR9 and FcεRI upon receptor–ligand engagement.