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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 (T H 2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the T H 2 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 T H 2 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 T H 2 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 T H 2 cell-dependent inflammation or allergic diseases.

Background: Allergen-specific immunotherapy (AIT) is the mainstay in the treatment of allergic diseases, but the therapeutic effects of AIT need to be improved. CD38 + B cells are an immune cell fraction involved in the pathogenesis of allergic diseases as well as in immune regulation., Objective: We sought to elucidate the role of antigen-specific CD38 + B cells in AIT., Methods: An analysis was carried out on AIT results of 48 patients with perennial allergic rhinitis (AR), among which peripheral blood immune cells were analyzed by flow cytometry; serum cytokine levels were determined by ELISA. An AR murine model was developed to test the role of CD38 + B cells in AIT., Results: A fraction of antigen-specific CD38 + B cell was detected in AR patients. CD38 + B-cell frequency was negatively correlated with the therapeutic effects of AIT. A negative correlation was detected between the CD38 + B-cell frequency and regulatory T-cell frequency in AR patients treated with AIT. Exposure to specific antigens induced CD38 + B cells to produce IL-6, that converted Treg cells to T H 17 cells. Coadministration of anti-CD38 antibody significantly promoted the therapeutic effects of AIT., Conclusions: Antigen-specific CD38 + B cells compromise AIT effects by producing IL-6 to convert regulatory T cells to T H 17 cells. Inhibition of CD38 + B cells promotes the effects of AIT., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

IL-10-expressing regulatory B cells (B10 cells) are dysfunctional in patients with many immune disorders. The underlying mechanism remains to be further elucidated. Glutamine is an essential nutrient for cell metabolism. This study aims to elucidate the role of glutaminolysis in maintaining the immune regulatory capacity in B10 cells. Peripheral blood samples were collected from 50 patients with allergic rhinitis and 50 healthy control subjects. B cells were isolated from blood samples by cell sorting with flow cytometry. The role of glutaminolysis in regulating B10 cell activities was assessed by immunological and biochemical approaches. The results showed that B cells from patients with allergic rhinitis expressed low levels of the transporter of glutamine and neutral amino acid. Glutaminolysis was required in the IL-10 expression in B cells. The glutamine catabolism was required in B10 cell generation. The mTOR activation mediated the glutaminolysis-associated B10 cell induction, and the suppression of the B cell glycogen synthase kinase-3 (GSK3) activation. GSK3 activation suppressed IL-10 expression in B cells. Inhibition of GSK3 enhanced IL-10 expression in B cells and alleviated experimental allergic rhinitis by generating immune competent type 1 regulatory T cells., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

The infection of coronavirus disease (COVID-19) seriously threatens human life. It is urgent to generate effective and safe specific antibodies (Abs) against the pathogenic elements of COVID-19. Mice were immunized with SARS-CoV-2 spike protein antigens: S ectodomain-1 (CoV, in short) mixed in Alum adjuvant for 2 times and boosted with CoV weekly for 6 times. A portion of mice were treated with Maotai liquor (MTL, in short) or/and heat stress (HS) together with CoV boosting. We observed that the anti-CoV Ab was successfully induced in mice that received the CoV/Alum immunization for 2 times. However, upon boosting with CoV, the CoV Ab production diminished progressively; spleen CoV Ab-producing plasma cell counts reduced, in which substantial CoV-specific Ab-producing plasma cells (sPC) were apoptotic. Apparent oxidative stress signs were observed in sPCs; the results were reproduced by exposing sPCs to CoV in the culture. The presence of MTL or/and HS prevented the CoV-induced oxidative stress in sPCs and promoted and stabilized the CoV Ab production in mice in re-exposure to CoV. In summary, CoV/Alum immunization can successfully induce CoV Ab production in mice that declines upon reexposure to CoV. Concurrent administration of MTL/HS stabilizes and promotes the CoV Ab production in mice., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Li-Hua Mo et al.)

The mechanism of antigen-specific regulatory T cell (T reg ) induction is not yet fully understood. Curcumin has an immune regulatory function. This study aims to induce antigen-specific T regs by employing extracellular vesicles (EVs) that carry two types of T cell activators. Two types of T cell activators, ovalbumin (OVA)/major histocompatibility complex-II (MHC-II) and tetramethylcurcumin (FLLL31) (a curcumin analog) were carried by dendritic cell-derived extracellular vesicles, designated OFexo. A murine model of allergic rhinitis (AR) was developed with OVA as the specific antigen. AR mice were treated with a nasal instillation containing OFexo. We observed that OFexo recognized antigen-specific T cell receptors (TCR) on CD4 + T cells and enhanced Il10 gene transcription in CD4 + T cells. Administration of the OFexo-containing nasal instillation induced antigen-specific type 1 T regs (Tr1 cells) in the mouse airway tissues. OFexo-induced Tr1 cells showed immune suppressive functions on CD4 + T cell proliferation. Administration of OFexo efficiently alleviated experimental AR in mice. In conclusion, OFexo can induce antigen-specific Tr1 cells that can efficiently alleviate experimental AR. The results suggest that OFexo has the translational potential to be employed for the treatment of AR or other allergic disorders., (© 2021 British Society for Immunology.)

The pathogenesis of recurrent tonsillitis is to be further investigated. B cell-derived interleukin (IL)-10 plays a critical role in immune regulation. Ras activation plays an important role in cancer and many immune disorders. This study aims to investigate the role of Ras activation in down regulating IL-10 expression in tonsillar B cells. Surgically removed tonsil tissues were collected from patients with recurrent acute tonsillar inflammation; B cells were isolated from the tonsillar tissues by flow cytometry sorting to be analyzed by the Ras-specific enzyme-linked immunosorbent assay and pertinent immunological approaches. We found that, compared to peripheral B cells (pBC), B cells isolated from the tonsillar tissues with recurrent inflammation (tBC) showed higher Ras activation, lower IL-10 expression and higher Bcl2L12 expression. Bcl2L12 formed a complex with GAP (GTPase activating protein) to prevent Ras from deactivating. The Ras activation triggered the MAPK/Sp1 pathway to promote the Bcl2L12 expression in B cells. Bcl2L12 prevented the IL-10 expression in tBCs, that was counteracted by inhibition of Ras or the Ras signal transduction pathway. In conclusion, Bcl2L12 interacts with Ras activation to compromise immune tolerance in the tonsils by inhibiting the IL-10 expression in tBCs. Inhibition of Bcl2L12 can restore the IL-10 expression in tBCs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2021 John Wiley & Sons Ltd.)

Rationale: Corticosteroid resistance (CR) is a serious drawback to steroid therapy in patients with ulcerative colitis (UC); the underlying mechanism is incompletely understood. Twist1 protein (TW1) is an apoptosis inhibitor and has immune regulatory functions. This study aims to elucidate the roles of TW1 in inducing and sustaining the CR status in UC. Methods: Surgically removed colon tissues of patients with ulcerative colitis (UC) were collected, from which neutrophils were isolated by flow cytometry. The inflammation-related gene activities in neutrophils were analyzed by RNA sequencing. A CR colitis mouse model was developed with the dextran sulfate sodium approach in a hypoxia environment. Results: Higher TW1 gene expression was detected in neutrophils isolated from the colon tissues of UC patients with CR and the CR mouse colon tissues. TW1 physically interacted with glucocorticoid receptor (GR)α in CR neutrophils that prevented GRα from interacting with steroids; which consequently abrogated the effects of steroids on regulating the cellular activities of neutrophils. STAT3 (Signal Transducer and Activator of Transcription-3) interacted with Ras protein activator like 1 to sustain the high TW1 expression in colon mucosal neutrophils of CR patients and CR mice. Inhibition of TW1 restored the sensitivity to corticosteroid of neutrophils in the colon tissues of a CR murine model. Conclusions: UC patients at CR status showed high TW1 expression in neutrophils. TW1 prevented steroids from regulating neutrophil activities. Inhibition of TW1 restored the sensitivity to corticosteroids in the colon tissues at the CR status., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Eosinophils (Eos) are the canonical effector cells in allergic rhinitis (AR) and many inflammatory diseases. The mechanism of eosinophilia occurring in the lesion sites is not fully understood yet. Twist1 protein (Twist, in short) is an apoptosis inhibitor that also has immune regulatory functions. This study aims to investigate the role of Twist in the pathogenesis of eosinophilia in AR. In this study, surgically removed human nasal mucosal samples were obtained from patients with chronic sinusitis and nasal polyps with AR (the AR group) or without AR (the nAR group). Eos were isolated from the samples by flow cytometry. We found that abundant Eos were obtained from the surgically removed nasal mucosa tissues of both nAR and AR groups. Significantly higher Ras activation was detected in AR Eos than that in nAR Eos. Ras activation was associated with the apoptosis resistance in AR Eos. The Twist (an apoptosis inhibitor) expression was higher in AR Eos, which was positively correlated with the Ras activation status. The sensitization to IgG induced Twist expression in Eos, in which Ras activated the MAPK-HIF-1α pathway, the latter promoted the Twist gene transcription. Twist bound Rac GTPase activating protein-1 to sustain the Ras activation in Eos. Ras activation sustained the apoptosis resistance in Eos. In conclusion, high Ras activation was detected in the AR nasal mucosal tissue-isolated Eos. IgG-sensitization induced Ras activation and Twist expression in Eos, that conferred Eos the apoptosis resistance., (Copyright © 2021. Published by Elsevier Inc.)

Rationale : Corticosteroid resistance (CR) seriously affects the therapeutic effects of steroids on many chronic inflammatory disorders, including airway allergy. The mechanism of CR development is unclear. Recent research indicates that livin, an apoptosis inhibitor, is associated with the regulation in cell activities. This study investigates the role of livin in the inducing and sustaining CR in the airway mucosa. Methods : Nasal epithelial cells (NECs) were isolated from surgically removed nasal mucosal tissues of patients with allergic rhinitis (AR) and nasal polyps with or without CR. Differentially expressed genes in NECs were analyzed by the RNA sequencing. A CR mouse model was developed to test the role of livin in CR development. Results : The results showed that NECs of AR patients with CR expressed high levels of livin, that was positively correlated with the thymic stromal lymphopoietin (TSLP) expression and the high Ras activation status in NECs. Livin and Ras activation mutually potentiating each other in the inducing and sustaining the TSLP expression in NECs. TSLP induced eosinophils and neutrophils to express glucocorticoid receptor-β (GRβ). Eosinophils and neutrophils with high CRβ expression were resistant to corticosteroids. Depletion of livin or inhibition of TSLP markedly attenuated CR and airway allergy. Conclusions : Livin facilitates CR development in the airways by promoting TSLP expression in epithelial cells and the GRβ expression in eosinophils and neutrophils. Depletion of livin or inhibiting TSLP attenuates CR development and inhibits airway allergy, this has the translational potential to be used in the treatment of airway allergy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Antigen (Ag)-specific T helper (Th)2 cells play a central role in food allergy (FA) pathogenesis. Methods can be used to eliminate Ag-specific Th2 cells that are currently lacking. This study aims to eliminate the Ag-specific Th2 cells with a novel nanoparticle, the mEV (modified extracellular vesicles, that carry a chimeric antigen peptide, MHC II and caspase 3) in a murine FA model., Methods: mEVs were generated by exposing dendritic cells (DC) to ovalbumin (OVA, a specific Ag) and recombinant caspase 3 (Casp3) in the culture overnight. Exosomes were purified from culture supernatant by the magnetic antibody approach. A murine FA model was developed with OVA as the specific Ag., Results: Purified mEVs had the molecular markers of extracellular vesicle, CD81, CD63, and CD9, cleaved Casp3 and MHC II/OVA complexes. mEVs specifically bound to the surface of Ag-specific CD4 + T cells, induced Ag-specific CD4 + T cell apoptosis both in vitro and in vivo as well as increased regulatory T cells in the intestinal tissues. Administration of mEV efficiently suppressed experimental FA., Conclusions: mEVs carry Ag/MHC II complexes and Casp3, that can induce Ag-specific Th2 cell apoptosis. Administration of mEV can efficiently suppress experimental FA. The results suggest that the mEVs have the translational potential to be used in the treatment of FA and other allergic diseases., Competing Interests: None to declare., (© 2021 The Author(s).)

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., (© 2020 Wiley-VCH GmbH.)

Background: Integrin αvβ6 can convert the transforming growth factor (TGF)-β precursor to the mature form. Resiquimod (R848) can generate TGF-β-producing regulatory T cells (Treg). Thus, to concurrent administration of specific antigen and R848 may generate antigen-specific Tregs, that is expected to restore immune tolerance in subjects with airway allergic diseases (AAD)., Methods: A bio-nanoparticle, designated Rexo, containing an antigen/MHC II complex and R848, was naturally assembled in dendritic cells, that was released as an exosome. An AAD mouse model was developed used to test the effects of Rexo on restoring the immune tolerance in the airways., Results: Exposure to R848 failed to induce Tregs in the β6-deficient mouse airway tissues, that were successfully induced in wild type mice. The results were validated inin vitro experiments. R848 activated the TLR7/MyD88/p38 signal pathway to increase the αvβ6 levels in CD4 + T cells, the αvβ6 then converted the TGF-β precursor to its mature form, and thus, induced Treg generation. Administration of Rexo restored the antigen-specific immune tolerance in the airways manifesting efficiently suppressing experimental AAD by inducing antigen-specific Tregs in the airways and inhibiting antigen-specific Th2 response., Conclusions: Rexos can inhibit experimental AAD via inducing antigen-specific Tregs to restore immune tolerance in the airway tissues, suggesting that Rexos have the translational potential to be used in the treatment of AAD., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Polymorphonuclear neutrophils (PMN) are one fraction of the major inflammatory cells in allergic asthma (asthma, in short); the role of PMN in the asthma pathogenesis is not fully understood yet. This study aims to investigate the effects of specific Ag-guiding exosomes on suppressing the neutrophil-dominant airway inflammation. In this study, BALB/c mice were immunized with ovalbumin plus complete Freund adjuvant to induce an asthma model featured with neutrophil-dominant lung inflammation. The Ag specific PMN (sPMN)-targeting exosomes (tExo), that were exosomes carrying a complex of specific Ag/anti-CD64 Ab and Fas ligand, were constructed to be used to alleviate neutrophilic asthma in mice. We found that sPMNs were the major cellular component in bronchoalveolar lavage fluid (BALF) in asthma mice, while less than 3% PMNs in naive control mice. The sPMNs expressed higher levels of CD64, which formed complexes with Ag-specific IgG (sIgG). The sIgG/CD64 complex-carrying PMNs could be activated upon exposing to specific Ags. Exposure to tExos induced Ag-specific PMNs apoptosis. Administration of tExos efficiently suppressed experimental asthma. We conclude that a fraction of sPMN was identified in the airway of asthma mice. The sPMNs could be activated upon exposure to specific Ags. tExos could induce sPMNs apoptosis, that show the translational potential in the treatment of asthma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Eosinophil (Eo) degranulation plays a central role in the initiations of allergic attacks. Flagellin (FGN), the major component of bacterial flagella, has immune regulatory functions. This study aims to investigate the role of FGN in alleviating the allergic reaction by stabilizing Eos. A toll-like receptor 5-knockout mouse strain was employed to test the role of FGN in stabilizing Eos. An airway allergy mouse model was developed to test the administration of FGN in alleviating the airway allergy by stabilizing Eos. The results showed that FGN was required in stabilizing Eos in the airway tissues. FGN prevented specific antigen-induced Eo activation. Oxidative stress was associated with the antigen-induced Eo activation that could be counteracted by the presence of FGN. The FGN levels were lower and chymase levels were higher in the airway tissues of mice with allergic inflammation. Negative correlation was detected between the data of FGN and chymase in the lung tissues. Chymase physically contacted FGN to speed up its degradation. The administration of FGN alleviated experimental allergic inflammation in the mouse airways by stabilized Eos in the lung tissues. In conclusion, FGN contributes to Eo stabilization. The administration of FGN alleviates the experimental airway allergy. The data suggest that FGN can be a candidate to be employed in the treatment of allergic disorders., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: The causative factors and pathogenesis of food allergy (FA) is not fully understood yet. Cold stress (CS) occurs frequently in human life that influences physiological activities in the body. In this study, we aimed to investigate the chronic CS (CS) effects on promoting the expression of IL-33 in intestinal epithelial cells., Methods: CS was carried out by placing mice at 4 °C for 1 h daily for 7 consecutive days. We developed a mouse model used to test the effects of CS on the FA development., Results: We found that, similar to conventional FA mouse model, CS induced the core body temperature to drop markedly in mice, increased intestinal epithelial barrier permeability and facilitated FA development. CS promoted interleukin (IL)-33 expression in intestinal epithelial cells through the adrenocorticotropic hormone (ACTH)/cortisol axis and via inducing the Il33 promoter methylation. CS facilitated the FA development in mice, that could be blocked by depletion of IL-33 expression in intestinal epithelial cells., Conclusions: CS induces IL-33 expression in intestinal epithelial cells to promote Th2 polarization in the intestinal tissues and facilitates FA development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The pathogenesis of airway allergic disorders (AAD) needs to be further investigated. Eosinophils (Eos) are the canonical effector cells in AAD attacks. Bcl2 like protein-12 (Bcl2L12) is an apoptosis inhibitor and an immune regulator. Eos have the defects of apoptosis. This study aims to investigate the role of Bcl2L12 in the AAD pathogenesis by regulating Eo activities., Methods: Human nasal lavage fluids (NLF) and mouse bronchoalveolar lavage fluids (BALF) was collected. Eos in NLF and BALF were analyzed by flow cytometry. A murine AAD model was developed with ovalbumin as a specific antigen., Results: We found that Eos isolated from NLF or BALF of AAD subjects expressed high levels of Bcl2L12 and showed defects of apoptosis. The Bcl2L12 expression in Eos was positively correlated with the AAD response. High lipopolysaccharide levels were detected in the AAD airways, that promoted the Bcl2L12 expression in Eos. Bcl2L12 mediated the LPS-induced autocrine eotaxin 1 expression in Eos through activating the MAPK p38/STAT6/NF-κB signal pathway. Depletion of Bcl2L12 in Eos suppressed experimental AAD in mice., Conclusions: AAD Eos express high levels of Bcl2L12, the latter is associated with AAD response by regulating the autocrine eotaxin 1 in Eos. Depletion of Bcl2L12 in Eos attenuates experimental AAD, suggesting that to suppress the Bcl2L12 Eos has the translational potential in the treatment of AAD., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

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., (© 2020 Australian and New Zealand Society for Immunology Inc.)

Background: It is known that the immune tolerance can be naturally established in the intestine, while the mechanism by which the immune tolerance development in the intestine is not fully understood yet. Vasoactive intestinal peptides (VIP) has the immune regulatory functions. This study aims to investigate the role of VIP in the immune tolerance development in the intestine., Methods: Intestinal epithelial cell (IEC)-derived exosomes were prepared. The exosomes carried IL-10 and antigen/MHC II complexes. VIP-deficient (VIPd) mice and wild type mice were employed to test the role of VIP in the development of immune tolerance in the intestine., Results: VIPd mice failed to induce type 1 regulatory T cells (Tr1 cells) in the intestine and retarded the establishment of antigen (Ag)-specific immune tolerance. Exposure to VIP in the culture induced IL-10 expression in intestinal epithelial cells (IECs). Exosomes derived from ovalbumin (OVA, used as a specific Ag)/VIP-primed IECs carried IL-10 and OVA/MHC II complexes; these exosomes were designated IL10CARs (IL-10/chimeric antigen receptor-carrying exosomes). IL10CARs could recognize OVA-specific CD4 + T cells and converted OVA-specific CD4 ± T cells to OVA-specific Tr1 cells. Administration of IL10CARs suppressed experimental food allergy., Conclusions: The data show that IL10CARs are capable of suppressing experimental FA by inducing antigen-specific Tr1 cells, which has the translation potential for FA treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The pathogenesis of recurrent acute tonsillitis (Rtn) is to be further investigated. Polymorphonuclear neutrophils (PMN) often associate with the pathogenesis of acute and chronic inflammation. This study aims to identify the antigen-specific PMNs (sPMNs) isolated from the tonsillar tissues with recurrent acute inflammation. In this study, CD66b + PMNs were isolated from surgically removed tonsils (40 tonsils were from 20 Rtn patients; 24 tonsils were from 12 tonsil tumour patients) by flow cytometry cell sorting. sPMNs were identified through immunological approaches. We found that compared with the control tonsil samples (from marginal non-tumour tissues of tonsil cancer), Rtn samples showed higher PMN frequency, higher levels of myeloperoxidase (MPO) and neutrophil elastase (NE), in which positive correlation was detected between the inflammatory scores in the Rtn tissues and PMN counts ( r  = .7352; p  = .0002), or MPO ( r  = .6565, p  = .0017), or NE ( r  = .6687, p  = .0013). Upon exposure to tonsillar tissue protein extracts in the culture, a portion of Rtn PMNs was activated and released inflammatory mediators. A complex of tonsillar tissue-specific IgG and FcγRI was observed on the surface of Rtn PMNs; these PMNs could specifically recognize the Rtn tissue extracts and were designated the tonsillar antigen-specific PMNs (sPMNs). A signal transduction pathway of mitogen-activated protein kinase (MAPK)-nuclear factor of T cell activation (NFAT) was activated in sPMNs after exposure to Rtn tissue extracts. In summary, a fraction of sPMN in the Rtn tonsillar tissues was identified and characterized. The sPMNs can be activated upon exposure to tonsil-specific antigens. These sPMNs may contribute to the Rtn pathogenesis.

Rationale : Inflammatory heart disorders are among the causes of human death. The causative factors of heart inflammation are to be further elucidated. House dust mite (HDM)-derived protein antigens are involved in the pathogenesis of many human diseases. This study aims to investigate the role of HDM-specific autoantibodies in the pathogenesis of heart inflammation. Methods : Human heart tissue samples were obtained from surgically removed hearts in heart transplantation. The interaction of the heart tissues with HDM-specific antibodies was assessed by pertinent immune analysis. The role of HDM-specific autoantibodies in the induction of heart inflammation was assessed with a murine model. Results : HDM-specific IgG (mIgG) was detected in the serum of patients with myocarditis (Mcd); the mIgG titers were positively correlated with the neutrophil counts in the heart tissues. The mIgG specifically bound to keratin-10 (KRT10) in heart vascular endothelial cells and the heart tissue protein extracts. The amounts of C3a, C5a and C5b-9 were increased in the mouse heart tissues after exposing to mIgG. In the presence of the complement-containing serum, mIgG bound cardiovascular epithelial monolayers to impair the barrier functions. Administration of mIgG or HDM induced the Mcd-like inflammation in the heart, in which neutrophils were the dominant cellular components in the infiltration of inflammatory cells. Conclusions : Mcd patients with neutrophilic inflammation in the heart had higher serum levels of mIgG. The mIgG bound heart endothelial cells to impair the endothelial barrier functions and induce neutrophilic inflammation in the heart., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The skewed T helper (Th) 2 response plays a critical role in the pathogenesis of allergic asthma. Regulatory T (Treg) cells and the regulatory cytokines are required in maintaining the homeostasis in the body. This study aims to determine the effects of a poly(lactic-co-glycolic) acid (PLGA)-ovalbumin (OVA)+A20 (a ubiquitin E3 ligase) nanovaccine on inhibiting allergic asthma in a murine model. In this study, A20 and OVA (a model antigen) were encapsulated into PLGA to be a nanovaccine (PLGA-OVA+A20). An allergic asthma murine model was developed with OVA as the specific antigen to test the role of PLGA-OVA+A20 nanovaccine in maintaining the immune homeostasis in the airway tissues. The results showed that PLGA-OVA+A20 nanovaccine inhibited the asthma responses in mice by suppressing Th2 inflammatory responses, promoting the generation of Treg cells in the airway tissues. We conclude that the PLGA-OVA+A20 nanovaccine has a marked inhibitory effect on the airway allergic response in sensitized mice by significantly promoting the generation of Treg cell and IL-10. The data suggest that PLGA-OVA+A20 has translational potential in the treatment of allergic asthma.

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., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background and aims : Dysfunction of the immune regulatory system plays a role in the pathogenesis of allergic rhinitis (AR). The underlying mechanism needs to be further investigated. Published data indicate that soluble CD83 (sCD83) has immune regulatory activities. This study aims to investigate the role of sCD83 in the alleviation of experimental AR. Methods : Peripheral blood samples were obtained from AR patients. Serum levels of sCD83 were determined by enzyme-linked immunosorbent assay. A murine AR model was developed to test the effects of sCD83 on suppressing experimental AR. Results : We found that serum levels of sCD83 in the AR group were lower than that in the healthy control group. A negative correlation was identified between the serum sCD83 levels and the frequency of T helper-2 (Th2) cells. The low serum sCD83 levels were also associated with the Bcl2L12 expression in antigen-specific Th2 cells. Exposure to sCD83 enhanced the responsiveness of antigen-specific Th2 cells to apoptosis inducers via suppressing the Bcl2L12 expression. Administration of sCD83 efficiently suppressed experimental AR. Conclusions : sCD83 contributes to immune homeostasis by regulating CD4 + T cell activities. Administration of sCD83 may have translational potential for the treatment of AR or other allergic diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The therapeutic efficacy of allergic rhinitis (AR) needs to be improved. Probiotics have immunoregulatory functions. In this study we evaluated the effects of protein extracts of probiotics in the amelioration of AR., Methods: Extracts of Bifidobacterium infantis (EBI) were prepared by lysing the live probiotics. AR mice were developed to be used to evaluate the therapeutic efficacy of EBI., Results: The results show that EBI induced interleukin (IL)-10-producing dendritic cells (DCs) via increasing IL-35 and signal transducer and activator of transcription 3 (STAT3) phosphorylation. IL-10-expressing DCs induced IL-10-producing B cells (B10 cells), with the latter showing immunosuppressive functions. After challenge with specific antigens, AR mice showed sneezing, nasal itch, and increases in serum-specific immunoglobulin E (IgE) and mouse mast cell protease-1; higher levels of T helper 2 (Th2) cytokines (IL-4, 67.17 ± 10.66; IL-5, 62.83 ± 9.70; IL-13, 51.00 ± 6.69, before treatment) in nasal mucosal protein extracts, which were significantly suppressed (IL-4, 27.00 ± 6.66; IL-5, 23.86 ± 4.53; IL-13, 25.67 ± 4.93, after treatment (p < 0.001) by administration with EBI nasal drops., Conclusion: EBI can suppress AR via inducing B10 cells. Thus, after carrying out required preclinical experiments and tests, EBI has the translational potential to be used in the treatment of AR and other allergic diseases., (© 2019 ARS-AAOA, LLC.)

The tolerogenic dendritic cell dysfunction is associated with the pathogenesis of immune diseases. Microbial stimulus is required in the maintenance of immune functions. This study aims to elucidate the role of Mal signal in the maintenance of DEC205 + DC (decDC) immune tolerogenic function. In this study, peripheral DCs were collected from allergic rhinitis (AR) patients and healthy control (HC) subjects to assess the functional status of decDCs. An AR murine model was developed to test the role of Mal signals in the maintenance of decDCs' functions. We observed that AR decDCs (decDCs obtained from AR patients) were incompetent in the induction of type 1 regulatory T cells (Tr1 cells). AR decDCs expressed less IL-10 than that in HC decDCs. IL-10 mRNA decayed spontaneously in AR decDCs. Tat-activating regulatory DNA-binding protein-43 (TDP43) protected IL-10 mRNA from decay. AR decDCs expressed lower levels of Mal than that in HC decDCs. Mal depletion resulted in IL-10 mRNA decay in HC decDCs. Reconstitution of Mal in AR decDCs restored the capacity of inducing Tr1 cells and attenuated experimental AR in mice. In conclusion, Mal plays a critical role in the maintenance of decDC's immune tolerogenic function. The absence or insufficient Mal signal impairs decDC's tolerogenic property. Reconstitution of Mal in AR decDCs can restore the immune tolerogenic capacity, which may have translational potential in the treatment of AR and other allergic diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rationale : Mast cells play a crucial role in allergic diseases. Yet, the regulation of mast cell bioactivities is not fully understood. This study aims to elucidate the role of B cell lymphoma 2 like protein 12 (Bcl2L12), one of the anti-apoptosis proteins, in regulating mast cell apoptosis. Methods : A food allergy (FA) mouse model was developed to establish mast cell over population in the intestinal tissue. Either compound 48/80 (C48/80) or specific antigens were used to activate mast cells in the intestinal mucosa. Results : After treating with C48/80, apoptosis was induced in mast cells of the intestine of naive control mice, but not in FA mice. The expression of Fas ligand (FasL) was lower in the mast cells of FA mice. Interleukin (IL)-5 was responsible for the suppression of FasL by upregulating the expression of Bcl2L12 in mast cells. Bcl2L12 prevented c-Myc, the major transcription factor of FasL, from binding the FasL promoter to inhibit the expression of FasL in mast cells. Inhibition of Bcl2L12 restored the apoptosis machinery of mast cells in the FA mouse intestine. Conclusions : The apoptosis machinery in mast cells is impaired in an allergic environment. Inhibition of Bcl2L12 restores the apoptosis machinery in mast cells in the FA mouse intestine., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The biased T helper 2 (Th2) responses play a critical role in the pathogenesis of allergy. The underlying mechanism is not fully understood yet. Survivin can regulate multiple cellular activities. This study aims to elucidate the role of survivin in the development and maintenance of Th2 polarization., Methods: CD4 + T cells were isolated from blood samples collected from patients with allergic asthma (AS) and HS control (HS) subjects. Mice carrying CD4 + T cells with survivin knockout (KO mice) were employed to test the role of survivin in the development of the biased Th2 responses., Results: KO mice failed to induce airway allergy. Peripheral CD4 + T cells expressed survivin, which was higher in the AS group than that in the HS group. Naive CD4 + T cells with higher expression of survivin were prone to differentiating into Th2 cells. Survivin bound to the Il4 promoter in CD4 + T cells to enhance Il4 gene transcription. The expression of Fas was lower in CD4 + T cells of the AS group than that in the HS group. Overexpression of survivin suppressed the expression of Fas and impaired the activation-induced cell death (AICD) of CD4 + T cells., Conclusion: Survivin facilitates the development of biased Th2 polarization through promoting expression of interleukin 4 (IL-4) and impairing the AICD machinery of CD4 + T cells. To modulate the expression of survivin in CD4 + T cells has the translational potential in the treatment of allergic diseases., (© 2019 ARS-AAOA, LLC.)

Dysfunction of immune regulatory cells has been recognized in a variety of immune diseases; the underlying mechanism remains to be further investigated. This study aims to investigate the critical role of Toll-like receptor (TLR) signal in the maintenance of function of regulatory T cells (Tregs). In this study, Tregs were isolated from patients with allergic rhinitis (AR) and healthy control (HC) subjects. The role of TLR signal in the maintenance of Treg's function was tested with experiments of cell culture and an AR mouse model. We observed that the immune suppressive function of AR Treg (Tregs isolated from AR patients) was impaired, although the number of peripheral AR Treg was comparable with HC Treg. Expression of transforming growth factor (TGF)-β was lower in AR Tregs than that in HC Tregs that was positively correlated with expression of Mal in Tregs; the latter was lower in AR Tregs as compared to HC Tregs. TGF-β mRNA in Tregs decayed spontaneously in the culture. Activation of Mal counteracted TGF-β decay and maintained the Treg's immune regulatory function. Mal bound Tristetraprolin (TTP) to prevent TTP from inducing TGF-β mRNA decay. Absence of TLR signals resulted in Treg dysfunctional and worsened experimental AR response in a murine model. In conclusion, TLR signal is required in the maintenance of Treg function. Absence of TLR signal may result in Treg dysfunction and immune intolerance., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

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.

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., (©2019 Society for Leukocyte Biology.)

Background: Swertia chirayita, has been commonly used under the name "Zang-yin-chen" for the treatment of liver infections, inflammation, abdominal pain, and bacterial infection in traditional Tibetan medicine. However, the bioactive components with anti-inflammatory activities and underlying mechanisms remain poorly evaluated., Study Design/methods: Repeated column chromatography yielded two main xanthones from petroleum ether (PE) and ethyl acetate fractions of whole plants of S. chirayita, and their structures were determined as bellidifolin (1) and swerchirin (2) on the basis of spectroscopic data and literature analysis. The anti-inflammatory activities and mechanisms of anti-inflammation of these two isolated xanthones were determined via enzyme-linked immunosorbent assay (ELISA) and western blot in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages in vitro., Results: Anti-inflammation assay demonstrated that 1 and 2 inhibit the production of the pro-inflammatory cytokines interleukin-6 (IL-6) and TNF-α in LPS-stimulated RAW 264.7 macrophages. Xanthone 1 also potently inhibited the production of prostaglandin E 2 (PGE 2 ) by suppressing the protein expression of cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophages. Western blot showed that the phosphorylation of c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs were remarkably attenuated by 1 in a concentration-dependent manner. Particularly, Compound 1 suppressed the phosphorylation of the inhibitor κB kinase-β (IKK-β), Akt, and p65 subunit of nuclear factor-kappaB (NF-κB)., Conclusion: The potent suppressive effects of 1 from S. chirayita on inflammatory mediators by blocking the expression of COX-2 and phosphorylation of Akt, IKK-β, MAPK and NF-κB, activation in LPS-stimulated macrophages suggest that 1 can be a preventive therapeutic candidate for the management of inflammatory-mediated immune disorders., (Copyright © 2018. Published by Elsevier GmbH.)

Ethnopharmacological Relevance: Yan-Hou-Qing (YHQ), a Chinese medicine formula containing fourteen kinds of materials, has been designed for pharyngitis and cough treatment in Oriental medicine. In the present study, the anti-allergic effects and underlying mechanisms of YHQ in inhibition of airway hyper responsiveness (AHR) was explored in an ovalbumin (OVA)-induced allergic asthma mouse model., Materials and Methods: BALB/c mice were sensitized by OVA and cholera toxin (CT) and challenged with OVA intranasally to induce allergic asthma mouse model. YHQ (200 mg/kg) was orally administered for 3 weeks from week-2 after OVA sensitization. The AHR and histological changes of lung tissues were evaluated by whole-body barometric plethysmography analysis and hematoxylin and eosin (H&E) staining, respectively. The serum concentration of OVA-specific IgE and T helper 2 (Th2) cytokines (IL-4 and IL-13) were determined by enzyme-linked immune sorbent assay (ELISA). Flow cytometry was performed to evaluate the percentage of CD4 + CD25 + Foxp3 + regulatory T cells (Treg) in the spleen., Results: The elevated AHR responses, heavier inflammatory cell infiltration and Th2 cytokines in allergic asthma group indicated Ovalbumin-induced asthmatic mouse models were built successfully. Compared to allergic asthma group, OVA-induced AHR responses and eosinophil infiltration in lung were improved significantly, and the productions of OVA-specific IgE and Th2 cytokines, IL-4 and IL-13, in the serum were also reduced dramatically after the treatment of YHQ. Moreover, YHQ treatment significantly increased the percentage of CD4 + CD25 + Foxp3 + Treg in OVA-induced allergic asthma mouse model., Conclusions: YHQ improves the allergic asthma related symptoms via promotion of CD4 + CD25 + Foxp3 + Treg and suppression of Th2 responses in mouse model, suggesting YHQ can be used as a potent agent to alleviate allergic asthma related symptoms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The interleukin (IL)-10 expression in B cells plays an important role in immune tolerance. The regulation of IL-10 expression in B cells is not fully understood yet. Tumor necrosis factor (TNF) is increased in allergic rhinitis (AR) patients. This study tests a hypothesis that TNF enhances histone deacetylase (HDAC)11 expression to inhibit the expression of IL-10 in B cells of AR patients., Methods: Peripheral B cells were collected from healthy persons and patients with AR. The B cells were analyzed by immune assay and molecular biological approaches for the expression of IL-10., Results: The expression of HDAC11 was higher in B cells of patients with AR than that in healthy persons. The expression of IL-10 in B cells was lower in AR patients than that in healthy subjects. The levels of HDAC11 in B cells were negatively correlated with the levels of IL-10. Exposure of B cells to TNF in the culture inhibited the expression of IL-10, in which HDAC11 played a critical role in the interference with the Il10 gene transcription. Inhibition of HDAC11 restored the IL-10 expression in B cells from AR patients and attenuated the experimental AR., Conclusion: TNF can suppress the expression of IL-10 in B cells via enhancing the expression of HDAC11. Inhibition of HDAC11 restores the IL-10 expression in B cells of AR subjects. HDAC11 may be a novel target for the treatment of AR., (© 2018 ARS-AAOA, LLC.)

Background and Aims: It is recognized that the air pollution is associated with the pathogenesis of airway diseases. This study aims to elucidate the role of the 3-methyl-4-nitrophenol (PNMC), one of the components of diesel-exhaust particles, in compromising the airway epithelial barrier integrity., Methods: A549 cells, an airway epithelial cell line, were cultured to monolayers to be used as an in vitro epithelial barrier model. BALB/c mice were treated with nasal drops containing PNMC to test the effects of PNMC on alternating the airway epithelial barrier functions., Results: Exposure of mice to PNMC induced nasal epithelial cell apoptosis and increased the permeability of the nasal epithelial barrier. PNMC increased casp8 and casp3 activities in nasal epithelial cells. Exposure to PNMC up regulated Fas and FasL expression in airway epithelial cells. Inhibition of caspase abolished the PNMC-induced airway epithelial barrier dysfunction., Conclusion: Exposure of airway mucosa to PNMC induces epithelial cell apoptosis and compromises the epithelial barrier function, which can be prevented by the inhibition of caspases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Allergens from dust mites play a critical role in the pathogenesis of airway allergy. The mechanism by which dust mite allergens induce allergic diseases is not fully understood yet., Objective: This study tests a hypothesis that the eighth subtypes of Dermatophagoides farina allergen (Derf8) play an important role in the induction of airway allergy., Methods: The protein of Derf8 was synthesized via molecular cloning approach. Dendritic cells (DC) were stimulated with Derf8 in the culture, and then, the expression of T cell immunoglobulin mucin domain 4 (TIM4) in dendritic cells (DC) was analysed. The role of Derf8 in the induction of airway allergy was evaluated with a mouse model., Results: Exposure to Derf8 markedly induced the TIM4 expression in DCs by modulating the chromatin at the TIM4 promoter locus. Derf8 played a critical role in the expansion of the T helper 2 response in the mouse airway via inducing DCs to produce TIM4. Administration with Derf8-depleted dust mite extracts (DME) inhibited the allergic inflammation and induced regulatory T cells in mice with airway allergy., Conclusion: Derf8 plays an important role in the initiation of dust mite allergy. Vaccination with Derf8-deficient DME is more efficient to inhibit the dust mite allergic inflammation than using wild DME., (© 2016 John Wiley & Sons Ltd.)

The pathogenesis of intestinal chronic inflammation is unclear. Food allergy plays an important role in the induction of intestinal inflammation. This study aims to test a hypothesis that food allergy initiates colitis. In this study, BALB/c mice were sensitized to a common food allergen, ovalbumin (OVA) with cholera toxin (CT) as an adjuvant. The colon epithelial barrier function was assessed with Ussing chamber technique. Expression of T cell immunoglobulin mucin domain molecule-4 (TIM4) in dendritic cells was evaluated by flow cytometry, RT-PCR and Western blotting. The results showed that allergen-related colitis was induced in mice as shown by heavy infiltration of inflammatory cells in the colon mucosa, loss of body weight of mice, increases in myeloperoxidase, tumor necrosis factor-α, interleukin-4, OVA-specific IgE in the colon tissue. The colon epithelial barrier function was markedly compromised in colitis group mice, which was mimicked by exposure the colon mucosa to CT in Ussing chamber. High frequency of TIM4(+) dendritic cells was detected in the colon mucosa of colitis mice. Exposure of dendritic cells to CT markedly increased the expression of TIM4. We conclude that IBD-like inflammation can be induced in the mouse colon by the food allergen-related immune response.

The etiology and the underlying mechanism of CD4(+) T-cell polarization are unclear. This study sought to investigate the mechanism by which interleukin (IL)-13 prevents the activation-induced apoptosis of CD4(+) T cells. Here we report that CD4(+) T cells expressed IL-13 receptor α2 in the intestine of sensitized mice. IL-13 suppressed both the activation-induced apoptosis of CD4(+) T cells and the expression of p53 and FasL. Exposure to recombinant IL-13 inhibited activation-induced cell death (AICD) along with the expression of p53, caspase 3, and tumor necrosis factor-α in CD4(+) T cells. Administration of an anti-IL-13 antibody enhanced the effect of specific immunotherapy on allergic inflammation in the mouse intestine, enforced the expression of p53 in intestinal CD4(+) T cells, and enhanced the frequency of CD4(+) T-cell apoptosis upon challenge with specific antigens. In summary, blocking IL-13 enhances the therapeutic effect of antigen-specific immunotherapy by regulating apoptosis and thereby enforcing AICD in CD4(+) T cells.

Background: Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients., Methods: Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules., Results: After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-α were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC., Conclusions: UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics.

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., (Copyright © 2016 John Wiley & Sons, Ltd.)

The initiation mechanism of IgE expression has not been fully understood. Flagellin (FGN) is an important microbial factor in the regulation of immune responses in the intestine. This study tests a hypothesis that FGN plays a crucial role in the isotype switching of IgE in B cells and the initiation of food allergy. In this study, the expression of IgE in B cells was analyzed by real time RT-PCR, Western blotting and chromatin immunoprecipitation. A mouse model was developed to assess the role of Toll like receptor-5 in the development of IgE-mediated allergic reaction in the intestinal mucosa. The results showed that exposure to FGN suppressed the expression of Bcl6 in B cells via increasing the levels of histone deacetylase (HDAC) 7; the latter up regulated the levels of methylated H3K9 and H3K27, down regulated RNA polymerase II and STAT3 (signal transducer and activator of transcription 3) at the Bcl6 promoter locus. Exposure to FGN and IL-4 markedly increased the expression of IgE in B cells via activating p300, H3K4, Pol II and STAT6 at the IgE promoter locus. As compared with the sensitized wild mice, the sensitized TLR5-deficient mice showed no detectable OVA-specific IgE in the serum; mast cells in the intestinal mucosa were not activated, no apparent allergic symptoms were evoked after the specific antigen challenge. In conclusion, FGN facilitates the initiation of food allergy in mice by triggering IgE transcription in B cells in a Th2 polarization environment via activating HDAC7 and suppressing Bcl6 expression.

The pathogenesis of allergen-related inflammation in the intestine is to be further understood. Micro RNA (miR) can regulate immune responses. This study aims to investigate the role of miR-17-92 cluster in the induction of food allergen-related inflammation in the intestine. In this study, a mouse model of food allergen-related intestinal inflammation was developed. Expression of miR-17-92 cluster in B cells of the intestinal mucosa was analyzed by real time quantitative RT-PCR. The results showed that the levels of miR-19a, one of the members of the miR-17-92 cluster, were detected in the B cells of the intestine of mice sensitized to ovalbumin, which was significantly higher than that in naïve control mice. The expression of IL-10 by B cells was significantly lower in the sensitized mice as compared with naive control mice. Exposure to IL-4 in the culture increased the expression of miR-19a as well as suppression the expression of IL-10 in B cells via remolding DNA structure at the IL-10 promoter locus. We conclude that B cells from sensitized mice show higher levels of miR-19a, which plays an important role in the suppression of IL-10 in the B cells.