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Summary: Food allergy is related to increasing risk of the development of allergic asthma, but the precise interplay between sensitization to different allergens in different compartments of the body is not fully understood. The aim of this study was to develop a novel humanized murine model of mixed food and respiratory allergy that recapitulates the human anaphylactic response and to more clearly understand the impact of food allergies on asthma. Immunodeficient mice transferred with peripheral blood mononuclear cells (PBMCs) from donors with peanut and house dust mite (HDM) allergy were exposed and challenged to peanut. Between peanut exposure and challenge, mice were intranasally treated to HDM. Allergic parameters were analyzed. Allergen‐specific immunoglobulin (Ig)E in sera could only be measured in mice treated with peripheral blood mononuclear cells (PBMCs) plus allergen. A preceding peanut exposure increased IgE levels, histamine release, bronchial hyper‐responsiveness and lung inflammation. Recruitment of inflammatory cells to the airways was aggravated associated with an enhanced T helper type 2 (Th2)/Th17 cytokine secretion when the two allergies were present. A preceding peanut exposure amplifies allergic asthma in this humanized model, which may contribute to the understanding of underlying immunological mechanism of polysensitization occurring in allergic individuals and evaluation of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Summary: Although the pathogenesis of acute myeloid leukemia (AML) is still unknown, accumulating evidence has revealed that immune response plays a vital part in the pathogenesis. Here, we investigated the involvement of 21 single nucleotide polymorphisms (SNPs) of immunorelated genes, including cytokines [interleukin (IL)‐2, IL‐4, IL‐9, IL‐12A, IL‐22, interferon (IFN‐α) and transforming growth factor (TGF)‐β1], transcriptional regulatory genes (TBX21, STAT1, STAT3, STAT5B, STAT6, GATA3, FOXP3 and IRF4) and others (IL2RA, IL6R, NFKBIA) in 269 AML in‐patients and 200 healthy controls. Furthermore, we analyzed the relationship between the SNPs and clinical characteristics. Immunorelated SNP genotyping was performed on the Sequenom MassARRAY iPLEX platform. All the SNPs in healthy controls were consistent with Hardy–Weinberg equilibrium. All final P‐values were adjusted by Bonferroni multiple testing. Our results showed that IL‐22 (rs2227491) was significantly associated with the white blood cell (WBC) counts. Signal transducer and activator of transcription 5B (STAT‐5B) (rs6503691) showed a close relationship with the recurrent genetic abnormalities in patients with AML. We verified the negatively independent effect of age and risk of cytogenetics on overall survival (OS). More importantly, the GG genotype of IL‐12A (rs6887695) showed a negative impact on AML prognosis independently. Furthermore, the relative expression of IL‐12 was decreased in GG genotype, no matter under a co‐dominant or recessive model. However, no correlation was observed between the SNPs mentioned above and disease susceptibility, risk stratification and survival. Our findings suggest that immunorelated gene polymorphisms are associated with prognosis in AML, which may perform as novel inspection targets for AML patients. [ABSTRACT FROM AUTHOR]

Summary: Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK) acts through its receptor fibroblast growth factor inducible 14 (Fn14), and participates in skin inflammation. Both TWEAK and Fn14 are highly expressed in skin lesions of patients with atopic dermatitis. The purpose of this study was to further explore the effect of Fn14 inhibition on experimental atopic dermatitis. Experimental atopic dermatitis was induced in the wild‐type and Fn14 knock‐out BALB/c mice. The effect of TWEAK/Fn14 interaction on keratinocytes was studied in an in‐vitro model of atopic dermatitis. Fn14 deficiency ameliorates skin lesions in the mice model, accompanied by less infiltration of inflammatory cells and lower local levels of proinflammatory cytokines, including TWEAK, TNF‐α and interleukin (IL)‐17. Fn14 deficiency also attenuates the up‐regulation of TNFR1 in skin lesions of atopic dermatitis. Moreover, topical TWEAK exacerbates skin lesion in the wild‐type but not in the Fn14 knock‐out mice. In vitro, TWEAK enhances the expressions of IL‐17, IL‐18 and IFN‐γ in keratinocytes under atopic dermatitis‐like inflammation. These results suggest that Fn14 deficiency protects mice from experimental atopic dermatitis, involving the attenuation of inflammatory responses and keratinocyte apoptosis. In the context of atopic dermatitis‐like inflammation, TWEAK modulates keratinocytes via a TNFR1‐mediated pathway. [ABSTRACT FROM AUTHOR]

MicroRNA-155 (mi R155) is required for antibody production after vaccination with attenuated Salmonella. mi R155-deficient B cells generated reduced germinal centre responses and failed to produce high-affinity immunoglobulin ( Ig)G1 antibodies. In this study, we observed up-regulation of mi R155 in the peripheral blood mononuclear cells ( PBMCs) of patients with myasthenia gravis ( MG), and mi R155 was also up-regulated in torpedo acetylcholine receptor ( T- AChR)-stimulated B cells. We used an inhibitor of mi R155 conjugated to anti- CD20 single-chain antibody to treat both the cultured B cells and the experimental autoimmune MG ( EAMG) mice. Our results demonstrated that silencing of mi R155 by its inhibitor impaired the B cell-activating factor ( BAFF)- R-related signalling pathway and reduced the translocation of nuclear factor ( NF)-κ B into the nucleus. Additionally, AChR-specific autoantibodies were reduced, which may be related to the altered amounts of marginal zone B cells and memory B cells in the spleens of EAMG mice. Our study suggests that mi R155 may be a promising target for the clinical therapy of MG. [ABSTRACT FROM AUTHOR]

S100 A9 belongs to the S100 family of calcium-binding proteins and plays a key role in many inflammatory conditions. Recent studies have found that S100 A9 was elevated significantly in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients, and might be a biomarker for fibrotic interstitial lung diseases. However, the exact function of S100 A9 in pulmonary fibrosis needs further studies. We performed this study to investigate the effect of S100 A9 on human embryo lung fibroblast ( HLF) proliferation and production of cytokines and collagen, providing new insights into the possible mechanism. S100 A9 promoted proliferation of fibroblasts and up-regulated expression of both proinflammatory cytokines interleukin ( IL)-6, IL-8, IL-1β and collagen type III. S100 A9 also induced HLF cells to produce α-smooth muscle actin (α- SMA) and receptor for advanced glycation end-product ( RAGE). In addition, S100 A9 caused a significant increase in extracellular-regulated kinase ( ERK)1/2 mitogen-activated protein kinase ( MAPK) phosphorylation, while the status of p38 and c-Jun N-terminal kinase ( JNK) phosphorylation remained unchanged. Treatment of cells with S100 A9 also enhanced nuclear factor kappa B ( NF-κ B) activation. RAGE blocking antibody pretreatment inhibited the S100 A9-induced cell proliferation, cytokine production and pathway phosphorylation. S100 A9-mediated cell activation was suppressed significantly by ERK1/2 MAPK inhibitor and NF-κ B inhibitor. In conclusion, S100 A9 promoted HLF cell growth and induced cells to secret proinflammatory cytokines and collagen through RAGE signalling and activation of ERK1/2 MAPK and NF-κ B pathways. [ABSTRACT FROM AUTHOR]

HBs antigen (HBsAg)183–191 (FLLTRILTI, R187 peptide) is a dominant human leucocyte antigen-A2 (HLA-A2)-restricted epitope associated with hepatitis B virus (HBV) infection in Caucasian populations. However, its prevalence is poorly understood in China, where there is a high incidence of HBV infection. In this report, we sequenced the region of HBsAg derived from 103 Chinese patients. Approximately 16·5% of the patients bore a mutant HBsAg183–191 epitope in which the original arginine (R187) was substituted with a lysine (K187 mutant peptide). Importantly, K187 still bound to HLA-A2 with high affinity, and elicited specific cytotoxic T lymphocyte (CTL) responses in HLA-A2/Kb transgenic mice. K187-specific CTLs were also generated successfully in acute hepatitis B (AHB) patients, indicating that this mutant epitope is processed and presented effectively. Our findings show that R187-specific CTLs can cross-react with the K187 peptide. These findings reveal that K187 still has the property of an HLA-A2 restricted epitope, and elicits a protective anti-HBV CTL response in humans. [ABSTRACT FROM AUTHOR]

The interaction of T cell CD28/CTLA-4 receptors with B7 on antigen-presenting cells (APCs) represents an important co-stimulatory pathway in T cell activation or anergy. Our previous study indicated that recipients immunized with allogenic donor immature dendritic cells (DCs) or resting B cells could induce specific immune tolerance and prolong allograft survival. A possible mechanism for this observation is that the expression of B7 molecules is either at a low level or lacking on these cells. The present study investigates whether blockade of B7 molecules on donor splenocytes with a B7 antisense peptide (B7AP), i.e. a peptide analogue of the CD28-binding region, could induce specific immune tolerance and prolong allograft survival in the recipients. Both the lymphocyte proliferation reaction and the mice pinna cardiac allograft experiment were performed to evaluate the role of B7AP in inducing specific immune tolerance in recipientsin vitroandin vivo. The results showed that 56·65% and 20·52% of C57BL/6 splenocytes expressed B7.1 and B7.2 molecules, respectively, on their cell surface. There were no significant changes of the B7 expression on such splenocytes after being treated by the B7AP (53·28% and 19·06%, respectively). B7AP inhibited the mixed lymphocyte reaction by up to 38·4% and a dose-response correlation was observed for inhibition. The recipients (BALB/c) immunized with B7AP-pretreated C57BL/6 splenocytes induced a specific immune hypo-response (43%versuscontrol) and notably prolonged survival of the C57BL/6 cardiac allograft by up to 20·3 days. In contrast to the normal saline group (average: 8·6 days) and FTD10 control peptide group (<4 days), the cardiac allograft survival of the test group was extended for an additional 11·7 days. These results strongly support the notion that immunization with donor splenocytes, which had been pretreated with B7AP, induced specific immune tolerance and prolonged allograft survival in the recipients. [ABSTRACT FROM AUTHOR]