Heme oxygenase‐1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2‐mediated allergic airway inflammation

The anti‐inflammatory role of heme oxygenase‐1 (HO‐1) has been studied extensively in many disease models including asthma. Many cell types are anti‐inflammatory targets of HO‐1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO‐1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigen‐induced allergic airway inflammation, we demonstrated in this study, for the first time, that the up‐regulation of HO‐1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC‐II and activation marker CD200R on basophils, blocked DQ‐ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO‐1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO‐1. Furthermore, adoptive transfer of HO‐1‐modified basophils reduced ovalbumin‐induced allergic airway inflammation. The above effects of HO‐1 can be reversed by the HO‐1 inhibitor Sn‐protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO‐1 may involve multiple immune cells. Collectively, our findings demonstrated that HO‐1 exerted its anti‐inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.     

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

The interferon‐inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4⁺ Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild‐type (WT) CD4⁺ T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm‐family‐deficient CD4⁺ T cells had higher expression of Th1‐associated genes than WT and purified naive Ifitm‐family‐deficient CD4⁺ T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm‐family‐deficient mice, but not Ifitm3‐deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL‐27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology.     

Interleukin-9 as a T helper type 17 cytokine

The production of interleukin‐9 (IL‐9) by CD4 T cells has gathered renewed interest as the result of the observation that its expression is broader than originally thought. This includes the production of IL‐9 by a recently characterized subset of CD4 helper T (Th) cells that are termed Th9 as well as production by additional T‐cell subsets including Th17 cells. There is an incomplete understanding as to which IL‐9‐producing T‐cell subsets develop under physiological conditions. We describe the conditions used to generate IL‐9 in Th17 cells in vitro. We also summarize conditions where both IL‐9 and IL‐17 are found in vivo and propose that Th17 cells producing IL‐9 may co‐exist and interact with Th9 cells during conditions of autoimmunity, allergy and infection.     

Larval Echinococcus multilocularis infection reduces dextran sulphate sodium‐induced colitis in mice by attenuating T helper type 1/type 17‐mediated immune reactions

The tumour‐like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune‐mediated processes. Parasite‐mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine dextran sodium sulphate (DSS) ‐induced colitis. At 3 months after E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with haematoxylin & eosin for assessing inflammatory reactions. Cytokine levels were measured by flow cytometry and quantitative RT‐PCR. Colitis severity was assessed (by board‐certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semi‐quantitative score of morphological changes. The histopathological analysis of the colon showed a significant reduction of DSS‐induced gut inflammation by concomitant E. multilocularis infection, which correlated with down‐regulation of T helper type 1 (Th1)/Th17 T‐cell responses in the colon tissue. Echinococcus multilocularis infection markedly reduced the severity of DSS‐induced gut inflammation upon down‐regulation of Th1/Th17 cytokine expression and attenuation of CD11b⁺ cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS‐induced colitis in mice by attenuating Th1/Th17‐mediated immune reactions.     

Therapeutic effects of a fermented soy product on peanut hypersensitivity is associated with modulation of T‐helper type 1 and T‐helper type 2 responses

Background ImmuBalance^? is a koji fungus (Aspergillus oryzae) and lactic acid fermented soybean product. This unique production process is believed to create a food supplement that helps to induce or maintain normal immune response. Objective To assess possible therapeutic effects of ImmuBalance^? on peanut (PN) hypersensitivity using a murine model of peanut allergy (PNA). Methods PN allergic C3H/HeJ mice were fed standard mouse chow containing 0.5% or 1.0% ImmuBalance (ImmuBalance 2X), radiation‐inactivated 1.0% ImmuBalance (I‐ImmuBalance 2X), or regular diet chow (sham) for 4 weeks, beginning 10 weeks after the initial PN sensitization, and then challenged with PN. Anaphylactic symptom scores, plasma histamine, serum PN specific‐IgE levels and splenocyte cytokine profiles were determined. Results While 100% of sham‐treated PNA mice developed anaphylactic reactions with a median score of 3.3 following PN challenge, only 50% of ImmuBalance, 30% of ImmuBalance 2X and 40% of I‐ImmuBalance 2X‐treated mice developed allergic reactions with median scores of 1.0, 0.4 and 0.5 respectively, which were significantly less than that in the sham‐treated mice (P<0.05). Plasma histamine and PN specific‐IgE levels were also significantly less in all treated mice than in sham‐treated mice (P<0.05). Furthermore, IL‐4, IL‐5 and IL‐13 production by PN‐stimulated splenocytes in vitro from ImmuBalance fed mice were markedly reduced compared with sham‐treated mice, whereas IFN‐γ production was moderately increased. TGF‐β and TNF‐α production were similar. Conclusions ImmuBalance protects against PN‐induced anaphylaxis when administered as a food supplement in this model. Protection was associated with down‐regulation of Th2 responses. This supplement may provide a potential novel therapy for PNA.     

Interleukin‐4‐ and NACHT,LRR and PYD domains‐containing protein 3‐independent mechanisms of alum enhanced T helper type 2 responses on basophils

Aluminium hydroxide (alum), the most widely used adjuvant in human and animal vaccines, has long been known to promote T helper type 2 (Th2) responses and Th2‐associated humoral responses, but the mechanisms have remained poorly understood. In this study, we explored whether alum is able to directly modulate antigen‐presenting cells to enhance their potency for Th2 polarization. We found that alum treatment of dendritic cells failed to show any Th2‐promoting activities. In contrast, alum was able to enhance the capacity of basophils to induce Th2 cells. When basophils from interleukin‐4 (IL‐4) knockout mice were examined, the intrinsic Th2‐promoting activities by basophils were largely abrogated, but the alum‐enhanced Th2‐promoting activities on basophils were still detectable. More importantly, Th2‐promoting adjuvant activities by alum found in IL‐4 knockout mice were also largely reduced when basophils were depleted by antibody administration. Therefore, basophils can mediate Th2‐promoting activities by alum both in vitro and in vivo through IL‐4‐independent mechanisms. Further studies revealed that secreted soluble molecules from alum‐treated basophils were able to confer the Th2‐promoting activities, and neutralization of thymic stromal lymphopoietin or IL‐25 attenuated the IL‐4‐independent development of Th2 cells elicited by alum‐treated basophils. Finally, alum was able to activate NACHT, LRR and PYD domains‐containing protein 3 (NLRP3) inflammasome in murine basophils in the same way as alum in professional antigen‐presenting cells, but NLRP3 was not required for Th2‐promoting activities on basophils by alum in vitro. These results demonstrated that alum can enhance the capacities of basophils to polarize Th2 cells via IL‐4‐ and NLRP3‐independent pathways.     

T cells and ILC2s are major effector cells in influenza‐induced exacerbation of allergic airway inflammation in mice

Influenza virus infection is an important cause of severe asthma exacerbations, but it remains unclear how a Th1‐mediated antiviral response triggers a prototypical Th2 disease. We investigated CD4⁺ T cells and group 2 innate lymphoid cells (ILC2s) in influenza virus‐infected mice. We found that ILC2s accumulated in the lung rapidly after influenza virus infection, but the induction of IL‐5 and IL‐13 secretion was delayed and concomitant with T cell activation. In an influenza‐induced exacerbation of allergic airway inflammation model we noticed an initial reduction of ILC2 numbers and cytokine production in broncho‐alveolar lavage compared to chronic house dust mite (HDM)‐mediated airway inflammation alone. ILC2s phenotype was characterized by low T1/ST2, ICOS, KLRG1, and CD25 expression, resembling naïve ILC2s. The contribution of ILC2s to type 2 cytokine production in the early stage of the influenza‐induced exacerbation was limited. In contrast, T cells showed increased IL‐4 and IL‐5 production when exposed to both HDM and influenza virus. Upon virus clearance, ILC2s regained an activated T1/ST2^highICOS^highKLRG1^highCD25^high phenotype paired with cytokine production and were major contributors to the type 2 cytokine milieu. Collectively, our data indicate that both T cells and ILC2s contribute to influenza‐induced exacerbation of allergic airway inflammation, but with different kinetics.     

Respiratory syncytial virus protects against the subsequent development of ovalbumin‐induced allergic responses by inhibiting Th2‐type γδ T cells

Respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans still remain inconclusive. The association between RSV infection and allergic diseases may be dependent on an atopic background and previous history of RSV infection. It has been reported that RSV infection before sensitization to an allergen decreased the production of Th2‐like cytokines in the lung and the levels of allergen‐specific Th2‐type antibodies in the serum. However, the underlying mechanisms are largely unknown. In the present study, the role of pulmonary γδ T cells in RSV‐affected, allergen‐induced airway inflammation was investigated. BALB/c mice were sensitized to or challenged with ovalbumin (OVA) and infected with RSV either before or after the sensitization period. It became clear that sensitization and challenge of mice with OVA induced a large influx of γδ T cells to the lungs. However, prior RSV infection inhibited the infiltration of γδ T cells as well as activated γδ T cells, characterized by expression of CD40L or CD69 molecular in the cell surface. Moreover, prior RSV infection elevated the type 1 cytokine gene expression but suppressed type 2 cytokine expression in the lung γδ T cells. Adoptive transfer of γδ T cells from OVA‐sensitized and challenged mice increased airway inflammation, suggesting that γδ T cells may play a proinflammatory role in allergic responses. These results described here support the idea of an unknown γδ T cell‐dependent mechanism in the regulation of RSV‐affected, allergen‐induced allergic airway responses. J. Med. Virol. 85:149–156, 2012. © 2012 Wiley Periodicals, Inc.     

Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation

Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4‐mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen‐activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE‐12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE‐12 did not affect CXCL12‐mediated calcium influx, indicating that CXCR7 does not modulate CXCR4‐mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12‐mediated signalling through β‐arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.     

类风湿性关节炎患者外周血TH1/TH2细胞的研究

目的探讨CD4+TH1/TH2细胞在类风湿性关节炎(RA)发生发展过程中的作用.方法采用酶联免疫斑点法(ELISPOT)对15例RA患者和30例健康人外周血中T淋巴细胞亚群及CD4+TH1/TH2功能亚型进行检测.结果RA患者外周血中TH1细胞的百分率较正常对照组升高(P＜0.05).结论 TH1细胞介导的细胞免疫可能与RA的发生发展有关.     

Updates on T helper type 17 immunity in respiratory disease

Interleukin-17 (IL-17)-producing cells play a critical role in mucosal immunity including the respiratory tract. This review will highlight recent advances in our understanding of these cells in mucosal immunity in the lung as well as their potential pathogenic roles in respiratory diseases. The IL-17-producing cells include γδ T cells, natural killer cells, group 3 innate lymphoid cells, and T helper type 17 (Th17) cells. There have been recent advances in our understanding of these cell populations in the lung as well as emerging data on how these cells are regulated in the lung. Moreover, Th17 cells may be a key component of tissue-resident memory cells that may be acquired over time or elicited by mucosal immunization that provides the host with enhanced immunity against certain pathogens.     

Therapeutic effects of DNA vaccine on allergen-induced allergic airway inflammation in mouse model

Vaccination with DNA encoding Dermatophagoides pteronyssinus group 2 （Der p 2） allergen previously showed its effects of immunologic protection on Der p 2 allergen-induced allergic airway inflammation in mice. In present study, we investigated whether DNA vaccine encoding Der p 2 could exert therapeutic role on allergen-induced allergic airway inflammation in mouse model and explored the mechanism of DNA vaccination in asthma specific-allergen immunotherapy. After sensitized and challenged by Der p 2, the BALB/c mice were immunized with DNA vaccine. The degrees of cellular infiltration were scored. IgE levels in serum and IL-4/IL-13 levels in BALF were determined by ELISA. The lung tissues were assessed by histological examinations. Expressions of STAT6 and NF-kB in lung were determined by immunohistochemistry staining. Vaccination of mice with DNA vaccine inhibited the development of airway inflammation and the production of mucin induced by allergen, and reduced the level of Der p 2-specific IgE level. Significant reductions of eosinophil infiltration and levels of IL-4 and IL-13 in BALF were observed after vaccination. Further more, DNA vaccination inhibited STAT6 and NF-kB expression in lung tissue in Der p 2-immunized mice. These results indicated that DNA vaccine encoding Der p 2 allergen could be used for therapy of allergen-induced allergic airway inflammation in our mouse model. Cellular ＆ Molecular Immunology.