Emerging Roles of T Helper Subsets in the Pathogenesis of Asthma

Durrant, Douglas M.; Metzger, Dennis W.

doi:10.3109/08820131003615498

Cited by 109 publications

(93 citation statements)

References 135 publications

(152 reference statements)

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“…Each of these cell types has defined roles in asthma (17)(18)(19)(20). To determine whether Ova treatment of Mfge8 −/− mice affected T-cell differentiation, we isolated lymphocytes from the lung and measured cytokine production (or expression of FoxP3 for Treg cells).…”

Section: Resultsmentioning

confidence: 99%

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Kudo

Soltani

Sakuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8 −/− ) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8 −/− ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.calcium sensitivity | lactadherin

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Section: Resultsmentioning

confidence: 99%

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Kudo

Soltani

Sakuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Patients with asthma typically suffer from chronic bronchial hyperresponsiveness, overproduction of mucus, allergen-specific IgE expression, and airway remodeling (2,3). Allergic airway inflammation is characterized by an infiltrate of eosinophils, neutrophils, and Th2 and Th17 lymphocytes expressing interleukin-4 (IL-4), IL-5 IL-13, and IL-17 (4).…”

mentioning

confidence: 99%

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Furuya

Roberts

Hurteau

et al. 2014

J Virol

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Asthma was the most common comorbidity observed among patients hospitalized with influenza A virus during the 2009 pandemic. However, little remains known about how the asthmatic phenotype influences protective immune responses against respiratory viral pathogens. Using the ovalbumin-induced allergic lung inflammation model, we found that asthmatic mice, unlike nonasthmatic mice, were highly susceptible to secondary heterologous virus challenge. While primary virus infection generated protective memory immune responses against homologous secondary virus challenge in both asthmatic and nonasthmatic mice, full protection against heterologous A/California/04/2009 (CA04) viral infection was observed only in nonasthmatic mice. Significant reductions in CA04-specific IgA, IgG, and IgM levels and in CA04-neutralizing activity of bronchoalveolar lavage fluid (BALF) was observed following secondary CA04 challenge of PR8-immunized asthmatic mice. Furthermore, transfer of immune BALF obtained from nonasthmatic, but not asthmatic, donors following secondary viral infection generated protection against CA04 in naive recipients. Nonspecific B-cell activation by CpG inoculation restored protection in PR8-immunized, CA04-challenged asthmatic mice. These results demonstrate a causal link between defective mucosal antibody responses and the heightened susceptibility of asthmatic mice to influenza infection and provide a mechanistic explanation for the observation that asthma was a major risk factor during the 2009 influenza pandemic. IMPORTANCEThe prevalence of asthma worldwide is increasing each year. Unfortunately, there is no cure for asthma. Asthmatic individuals not only suffer from consistent wheezing and coughing but are also believed to be more prone to serious lung infections that result in bronchitis and pneumonia. However, little is known about the influence of asthma on host mucosal immunity. Here we show that antibody responses during secondary heterologous influenza infections are suboptimal and that this is responsible for the increased mortality in asthmatic mice from viral infections. Understanding the mechanism of increased susceptibility will aid in developing new antiviral therapies for asthmatic patients.

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“…1 T helper cells play a pivotal role in the pathogenesis of asthma (1)(2)(3)(4). CD4 1 T helper cell subsets, which include T helper cell type 1 (Th1), Th2, and Th17 cells, are key components of the adaptive immune response in rodents and humans (1,(5)(6)(7).…”

mentioning

confidence: 99%

“…CD4 1 T helper cell subsets, which include T helper cell type 1 (Th1), Th2, and Th17 cells, are key components of the adaptive immune response in rodents and humans (1,(5)(6)(7). Allergic responses in the lung are traditionally thought of as being Th2 mediated; however, recent studies have shown that IL-9 contributes to allergic responses by promoting mast cell expansion and production of IL-13, which stimulates the release of mucus and contributes to airway hyperresponsiveness (1,5,8,9). Serum IL-9 levels, which correlate with symptom severity in patients with allergic rhinitis, depend on exposure to a causal allergen (10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB

Li¹,

Edin²,

Bradbury³

et al. 2013

Am J Respir Crit Care Med

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Rationale: HelperCD41 T cell subsets, includingIL-9-and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation. Objectives: To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation., COX-2 2/2 , and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. Measurements and Main Results: Experimental endpoints were not different between COX-1 2/2 and WT mice; however, the percentage of IL-9 1 CD4 1 T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2 2/2 mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2 2/2 mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD 2 and PGE 2 , which also reduced Th9 cell differentiation of murine and human naive CD4 1 T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4 1 T cells isolated from WT mice in vitro. Conclusions: COX-2-derived PGD 2 and PGE 2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.

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Emerging Roles of T Helper Subsets in the Pathogenesis of Asthma

Cited by 109 publications

References 135 publications

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB

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