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Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box–binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2–XBP1–TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2–XBP1–SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell–dependent inflammation or allergic diseases. Editor's summary: T helper 2 (TH2) cells mediate allergic responses, and their development depends on dendritic cells (DCs) expressing the receptor TIM4. Yang et al. found that the transcription factor XBP1 induced expression of the gene encoding TIM4 in DCs. Production of the cytokine IL-2 in the airways of allergen-exposed mice induced expression of XBP1 and then TIM4 in DCs through a pathway involving the GEF Sos1 and the GTPase Ras. Targeting this pathway in DCs reduced the severity of experimentally induced allergic airway responses in mice, suggesting that these factors could be therapeutic targets for treating TH2 cell–dependent inflammatory or allergic diseases. —John F. Foley [ABSTRACT FROM AUTHOR]

The mechanism of generation of regulatory T cells (Treg) remains incompletely understood. Recent studies show that CD83 has immune regulatory functions. This study aims to investigate the role of epithelial cell‐derived CD83 in the restoration of immune tolerance in the airway mucosa by inducing the Treg differentiation. In this study, CD83 and ovalbumin (OVA)‐carrying exosomes were generated from airway epithelial cells. An airway allergy mouse model was developed to test the role of CD83/OVA‐carrying exosomes in the suppression of airway allergy by inducing Treg generation. We observed that mouse airway epithelial cells expressed CD83 that could be up‐regulated by CD40 ligand. The CD83 deficiency in epithelial cells retarded the Treg generation in the airway mucosa. CD83 up‐regulated transforming growth factor‐β‐inducible early gene 1 expression in CD4+ T cells to promote Foxp3 expression. Exposure of primed CD4+ T cells to CD83/OVA‐carrying exosomes promoted antigen‐specific Treg generation. Administration of CD83/OVA‐carrying exosomes inhibited experimental airway allergic response. In summary, airway epithelial cells express CD83 that is required in the Treg differentiation in the airway mucosa. Administration of CD83/OVA‐carrying exosomes can inhibit airway allergy that has the translation potential in the treatment of airway allergic disorders. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a disease that frequently relapses and affects more than 0.1% general population; the underlying mechanism is poorly understood. Published data show that polymorphonuclear neutrophils (PMN) contribute to the pathogenesis of UC. This study aims to identify antigen (Ag)‐specific PMNs and investigate their role in UC relapse. In this study, the correlation between PMN activities and UC relapse was assessed in a group of UC patients. A UC mouse model was developed to expand the findings of UC patient study. The results showed that a positive correlation was detected between the high PMN activities and the food Ag‐specific IgG amounts in colon biopsies of UC patients. UC patient‐derived Ag‐specific PMNs could be activated upon exposure to food specific Ag. The Ag/FcγRI complexes were detected on the surface of PMNs in UC patients. Re‐exposure of sensitized PMNs to specific Ag triggered PMN activation and induced UC‐like inflammation in the mouse colon. We conclude that FcγRI plays a critical role in UC relapse. Inhibition of FcγRI can efficiently inhibits experimental UC. [ABSTRACT FROM AUTHOR]

Background: The eosinophil (Eo) activation is a crucial factor evoking allergic rhinitis (AR) attacks; factors; the mechanism of triggering Eo activation remains to be further investigated. The interaction of antigen (Ag) and antibody plays a critical role in evoking allergy attacks. This study aims to elucidate the role of FcγRI, the high affinity receptor of IgG, in the Ag-mediated Eo activation. Methods: Nasal lavage fluids (NLF) were collected from AR patients and healthy control (HC) subjects. Eos were isolated by flow cytometry cell sorting and analyzed by pertinent immunological approaches. Results: Eos composed more than 60% of the cellular components in AR NLF. Exposure to specific Ags (sAgs) in the culture triggered Eos to release inflammatory mediators. High levels of FcγRI were detected on the surface of AR NLF Eos. Exposure to lipopolysaccharide markedly increased the FcγRI expression in naive Eos, which could be bound by Ag-specific IgG (sIgG) to form complexes on the surface of Eos; this made Eos at the sensitized status. Eos bore with the sIgG/FcγRI complexes could be activated upon exposure to sIgG in the culture; these Eos can be designated as Ag-specific Eos. Passive transfer of Ag-specific Eos resulted in profound AR response in mice upon sAg challenge. Depletion of FcγRI on Eos efficiently abolished AR response in mice. Conclusions: AR Eos express high levels FcγRI, that can be bound by sIgG to make Eos sensitized. Re-exposure to specific Ags can activate the sensitized Eos. [ABSTRACT FROM AUTHOR]

Background: The eosinophilic inflammation plays a critical role in myocarditis (Mcd); its underlying mechanism remains to be further elucidated. This study aims to investigate the role of Bcl2-like protein 12 (Bcl2L12) in inducing the defects of apoptosis in eosinophils (Eos) of the heart tissues. Methods: Human explant heart samples were collected. Eosinophilia and myocarditis (Mcd)-like inflammation were induced in the mouse heart by immunizing with murine cardiac α-myosin heavy chain (MyHCα) peptides. Results: Markedly more Eos were observed in heart tissues from patients with Mcd than those from patients with dilated cardiomyopathy. Eos isolated from Mcd hearts showed the signs of apoptosis defects. The Eo counts in the Mcd heart tissues were positively correlated with the Bcl2L12 expression in Eos isolated from the heart tissues. Exposure to interleukin 5 in the culture induced the expression of Bcl2L12 in Eos. Bcl2L12 bound c-Myc, the transcription factor of Fas ligand (FasL), to prevent c-Myc from binding to the FasL promoter, to restrict the FasL gene transcription in Eos. Inhibition of Bcl2L12 prevented the induction of eosinophilia and Mcd-like inflammation in the mouse heart. Conclusions: The Bcl2L12 expression contributes to apoptosis defects in Eos of the Mcd heart. Blocking Bcl2L12 prevents the eosinophilia induction and alleviates Mcd-like inflammation in mice. [ABSTRACT FROM AUTHOR]

The therapies for food allergy (FA) need to be improved. The generation of inducible regulatory T cells (Tregs) can support immune tolerance in the body. This study aims to suppress experimental FA by inducing Tregs through the employment of modified exosomes (mExosomes). In this study, mExosomes were prepared by incubating dendritic cells with interleukin (IL)‐2 and ovalbumin (OVA, used as a specific antigen) in the culture. Exosomes were purified from culture supernatant and used as the mExosomes. A murine FA model was developed to test the effects of mExosomes on the generation of Tregs in the mouse intestinal tissues and inhibiting FA. The results showed that mExosomes, which carried IL‐2 and a complex of OVA peptide–major histocompatibility complex class II on the surface of exosomes, bound to OVA‐specific CD4+ T cells and induced CD4+ T cells to differentiate into Tregs. In the FA mouse intestinal tissues, we found low IL‐2 levels that were positively correlated with the number of Tregs. Depletion of IL‐2 in mice prevented the generation of Tregs. The levels of peroxisome proliferator‐activated receptor‐γ were increased in the FA intestinal tissues with inhibited IL‐2 production. Administration of mExosomes induced Tregs in the intestinal tissues and efficiently suppressed FA in mice. We conclude that the mExosomes can suppress FA in mice through inducing Tregs. The data suggest that the mExosomes have translational potential in the treatment of FA and other allergic disorders. [ABSTRACT FROM AUTHOR]

Background: Skewed T helper (Th)2 response plays a crucial role in the pathogenesis of allergic diseases. The therapeutic efficacy for allergic diseases is unsatisfactory currently. This study aims to regulate the skewed Th2 response with CARsomes. Methods: The CARsome consisted of an epitope of Dermatophagoides farina‐1 (Derf1), a segment of the anti‐DEC205 antibody, the scFv, and an open reading frame of perforin. This fusion protein binds to DEC205 molecule on the surface of exosomes derived from dendritic cells (DC). The effects of CARsome on inducing antigen (Ag)‐specific Th2 cell apoptosis were assessed both in vivo and in vitro. Results: Exposure to CARsomes in the culture induced Ag‐specific Th2 cell apoptosis. Injection of CARsomes through the vein puncture also induced Ag‐specific Th2 cell apoptosis in the lungs of sensitized mice. CARsomes could induce Ag‐specific regulatory T cells. Administration of CARsomes efficiently inhibited experimental allergic airway inflammation. Conclusions: The CARsomes can inhibit allergic airway inflammation by inducing Ag‐specific Th2 cell apoptosis and induce Ag‐specific regulatory T cells. The data suggest that CARsomes have the translational potential to be used to treat allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Background and aims: Radiotherapy is one of the major remedies for the treatment of cancer, including nasopharyngeal carcinoma (NPC). Radioresistance occurs very often in target cells that is a large drawback in cancer treated with radiotherapy. Livin involves the over-growth of cancer cells. This study aims to investigate the role of livin in the radioresistance formation in NPC cells. Methods: NPC cell lines were exposed to small doses of irradiation to establish a cell model of radioresistance, in which the role of livin in the development of radioresistance was evaluated. Results: The expression of livin was observed in NPC cells, which was significantly increased after exposing to small doses of irradiation. A negative correlation was detected between livin and Fas expression in NPC cells. Livin formed a complex with heat shock factor-1 (HSF1, the transcription factor of Fas) in NPC cells after irradiation, which sped up ubiquitination of HSF1. Livin was involved in suppressing Fas expression in NPC cells with radioresistance. Exposure to livin inhibitors prevented radioresistance development and overcame the established radioresistance in NPC cells. Conclusions: Livin expression in NPC cells plays a critical role in the development of radioresistance. Depletion of livin increases the sensitiveness of NPC cells to irradiation. Target therapy against livin may have the translational potential for the treatment of NPC. [ABSTRACT FROM AUTHOR]

Background: The on‐purpose‐modulated dendritic cells (DCs) have shown charming effects on restoring immune regulatory functions in subjects with immune diseases. Objective: This study aims to construct DCs carrying chimerical antigen (Ag) peptides (CAP‐DCs) to induce interleukin (IL)‐17+ inducible Tregs (iTregs) to alleviate food allergy (FA) in a murine model. Methods: In this study, we constructed CAP‐DCs. The CAP is a fusion protein, consisting of a segment of recombinant scFv of anti‐DEC205 antibody and an ovalbumin (OVA) epitope (IC). A murine OVA‐FA model was developed to test the effects of CAP‐DCs on suppressing the allergic response in the intestine. Results: The CAP‐DCs are characterized as that a complex of scFv‐IC is presented on the surface of the cells, moderately express CD80 and CD86 as well as IL‐6, IL‐23, transforming growth factor (TGF)‐β and CCR9. After being passively transferred with CAP‐DCs or injection of scFv‐IC, Ag‐specific IL‐17+ Foxp3+ iTregs were induced in the intestinal lamina propria of FA mice. The iTregs showed immune suppressive effects on Ag‐specific Th2 response. FA mice were adoptively transferred with the CAP‐DCs or scFv‐IC injection, which resulted in a significant decrease in the number of Ag‐specific Th2 cells and suppression of FA response in an Ag‐specific manner. Conclusions and Clinical Relevance: CAP‐DCs can ameliorate FA response by inducing Ag‐specific IL‐17+ Foxp3+ iTregs and suppressing Ag‐specific Th2 response. To generate CAP‐DCs has the translational potential in the treatment of FA. [ABSTRACT FROM AUTHOR]

Survivin is an anti-apoptosis protein that may be associated with the development of eosinophilia; the latter is associated with the pathogenesis of many immune disorders. Here we report that less apoptotic eosinophils (Eos) were induced in those isolated from mice suffering from food allergy (FA) than those from naive mice after treating with cisplatin in vitro. Exposure to cisplatin induced more Fas ligand (FasL) expression in Eos isolated from naive mice than in those of FA mouse. Survivin was detected in the intestinal tissue extracts in much higher amounts in the FA group than in the naive group. Immunohistochemistry showed that epithelial cells were the major source of survivin in the intestine. Exposure to IL-4 or IL-13 up-regulated the expression of survivin in intestinal epithelial cells. Survivin interfered with the expression of FasL in Eos. Inhibition of survivin attenuated the eosinophilia-related inflammation in the intestine. In conclusion, intestinal epithelial cell-produced survivin induced defects in apoptosis in Eos to contribute to eosinophilia in the intestine. Inhibition of survivin can suppress the eosinophilia-related intestinal inflammation. The data suggest that survivin may be a novel target for the treatment of FA. [ABSTRACT FROM AUTHOR]

T helper (Th)2 polarization plays an important role in the pathogenesis of allergic diseases; the underlying mechanism remains to be further investigated. B cell lymphoma protein‐2 like protein‐12 (Bcl2L12) has the anti‐apoptotic function. This study aims to elucidate the contribution of Bcl2L12 to Th2 polarization in patients with allergic rhinitis (AR). In this study, human CD4+ T cells were isolated from blood samples collected from AR patients and healthy control (HC) subjects. The immune response profiles of CD4+ T cells were analyzed by immunologic approaches. The results showed that AR CD4+ T cells (CD4+ T cells collected from AR patients) showed defects of apoptosis. The expression of FasL in AR CD4+ T cells was lower than that of HC CD4+ T cells. Serum IL‐5 levels were negatively correlated with the expression of FasL in AR CD4+ T cells. Exposure of CD4+ T cells to IL‐5 in the culture suppressed the expression of FasL and increased the expression of Bcl2L12. IL‐5 increased the levels of Bcl2L12 in CD4+ T cells, the latter bound to the FasL promoter to prevent FasL gene transcription. Inhibition of Bcl2L12 restored the apoptosis machinery in AR CD4+ T cells. In conclusion, overexpression of Bcl2L12 in CD4+ T cells compromises the apoptosis machinery; the latter can be restored by inhibition of Bcl2L12. BcL2L12 in CD4+ T cells may be a novel target for the treatment of AR and other allergic disorders. CD4+ T cells express Bcl2L12, which restricts FasL expression and induces apoptotic defects in CD4+ T cells. [ABSTRACT FROM AUTHOR]

The article offers a study of 3‐methyl‐4‐nitrophenol (MNP), one of the components of diesel‐exhaust particles which l facilitates development of intestinal allergy Topics include exposure of mice fed with MNP and OVA daily showing that exposure to MNP increased absorption of FITC‐ dextran and induced intestinal epithelial barrier dysfunction and facilitated the development of intestinal allergy and suggests that environmental pollution may contribute to the development of allergic disease.

Interleukin (IL)-10-expressing B cells play a critical role in the immune homeostasis in the body; its regulation has not been fully understood. Micro-RNA (miR)-17-92 cluster has strong regulation in the immunity. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells. In this study, peripheral B cells were collected from patients with allergic rhinitis (AR). The B cells were treated with specific allergens, dust mite extracts, in the culture. The expressions of miR-17-92 cluster and IL-10 in the culture were assessed by real-time quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that the levels of miR-19a, but not the rest of the 5 members (miR-17, miR-18a, miR-19b, miR-20a, and miR-92a), were significantly higher in peripheral B cells from AR patients as than in B cells from healthy participants. Exposure of B cells from AR patients to specific allergen, dust mite extracts, significantly increased the levels if miR-19a and suppressed the expression of IL-10 in B cells. The levels of histone deacetylase 11 and acetylated H3K9 were higher, and the RNA polymerase II and c-Maf (the IL-10 transcription factor) were lower, at the IL-10 promoter locus. In conclusion, miR-19a mediates the allergen-specific immune response-decreased IL-10 expression in B cells. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to assess the value of early abdominal non-enhanced computed tomography (NECT) in developing strategies for treating acute gallstone pancreatitis (AGP).Methods: AGP patients underwent NECT within 48 h after symptom onset to determine the presence of peripancreatic fluid collection, gallstones, and common bile duct stones. Patients with mild AGP who had neither organ failure by clinical data nor peripancreatic fluid collection by NECT (classified as grade A, B, or C based on the Balthazar CT grading system) were randomized to undergo an early laparoscopic cholecystomy (ELC; LC performed within 7 days after a pancreatitis attack, without waiting for symptom resolution) or late laparoscopic cholecystomy (LLC; LC performed ≥ 7 days following an attack, with the patient being completely free of AGP symptoms).Results: The study enrolled 102 patients with mild AGP defined by clinical data and NECT. NECT was 89.2 % and 87.8 % accurate in detecting gallbladder stones and CBD stones, respectively. Totals of 49 and 53 patients were assigned to an ELC and LLC group, respectively. All patients in both groups were cured, no LC-related complications occurred, and no case of AGP increased in severity following LC. The mean lengths of hospital stay and LC operation time were significantly shorter in the ELC group than the LLC group (P < 0.05).Conclusions: NECT can accurately detect peripancreatic fluid collection and biliary obstructions; thus, early abdominal NECT is valuable when developing strategies for treating AGP. Patients with mild AGP without organ failure or peripancreatic fluid collection can safely undergo ELC without waiting for complete resolution of their pancreatitis. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

The abnormality of immune regulation plays a critical role in the pathogenesis of cancer; the underlying mechanism has not been fully understood yet. This study aims to investigate the role of cancer specific T helper (Th)2 response in the inhibition of colon cancer (Cca) cell growth. The results showed that with Cca cell (CT26 cell) extracts as an antigen, the Cca-extract specific Th2 response was induced in the Cca-bearing mice. The Cca mass size was significantly reduced, or radically disappeared (5 out of 10; or 50%); the survival rate was markedly improved in mice immunized with Cca-extract, but not in those immunized with another tumor cell (U87 cell) extracts or to bovine serum albumin. The immunization with Cca-extract also induced Cca cell apoptosis and converted the intra-Cca Tregs to T helper (Th) 9 cells. In conclusion, Cca-specific Th2 responses inhibit Cca growth in a mouse model via inducing Cca cell apoptosis and converting intra-Cca Tregs to Th9 cells. [ABSTRACT FROM AUTHOR]

Epithelial barrier integrity is critical to maintain the homeostasis in the body. The regulatory mechanism of the epithelial barrier function has not been fully understood. This study aims to elucidate the role of the TWIK-related potassium channel-1 (Trek1) in the regulation of the epithelial barrier function of the nasal mucosa. In this study, the levels of Trek1 were assessed by real time RT-PCR and Western blotting. The epithelial barrier function of the rat nasal epithelia was evaluated by the Ussing chamber system. The results showed that Trek1 was detected in the human and rat nasal epithelia, which were significantly lower in patients and rats with allergic rhinitis than that in healthy controls. Exposure to the signature T helper 2 cytokine, interleukin (IL)-4, markedly suppressed the expression of Trek1 in the nasal mucosa via up regulating the expression of the histone deacetylase (HDAC)1. The IL-4-induced rat nasal epithelial barrier dysfunction could be blocked by HDAC1 inhibitor (Trichostatin A), or sodium butyrate, or administration of Clostridium Butyricum. We conclude that Trek1 is critical to maintain the nasal epithelial barrier function. [ABSTRACT FROM AUTHOR]

The pathogenesis of some chronic inflammation such as inflammatory bowel disease is unclear. Insulin-like growth factor-1 (IGF1) has active immune regulatory capability. This study aims to investigate into the mechanism by which IGF1 modulates the monocyte (Mo) properties to inhibit immune inflammation in the intestine. In this study, the production of IGF1 by intestinal epithelial cells was evaluated by real time RT-PCR and Western blotting. Mos were analyzed by flow cytometry. A mouse colitis model was created with trinitrobenzene sulfonic acid. The results showed that mouse IECs produced IGF1, which could be up regulated by exposure to CpG-ODN (CpG-oligodeoxynueleotides) in the culture. Culture the CpG-ODN-primed IEC cells and Mos or exposure of Mos to IGF1 in the culture induced the Mos to express IL-10. The IGF1-primed Mos showed the immune suppressive effect on inhibiting the immune inflammation in the mouse colon. In conclusion, the IGF1-primed Mos are capable of suppressing immune inflammation in the intestine. [ABSTRACT FROM AUTHOR]