MiR-1165-3p downregulated in Th2 cells inhibits Th2 differentiation in allergic asthma by targeting PPM1A

2019 ◽  
Author(s):  
Zhengxia Wang ◽  
Mao Huang ◽  
Ningfei Ji ◽  
Mingshun Zhang
Keyword(s):  
Allergic Asthma ◽  
Th2 Cells ◽  
Th2 Differentiation

scholarly journals Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism

2015 ◽  
Vol 309 (10) ◽  
pp. L1208-L1218 ◽  
Author(s):  
Timothy P. Moran ◽  
Keiko Nakano ◽  
Gregory S. Whitehead ◽  
Seddon Y. Thomas ◽  
Donald N. Cook ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Allergic Asthma ◽  
House Dust ◽  
Lavage Fluid ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cell Responses ◽  
Th2 Responses ◽  
Th2 Differentiation

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

scholarly journals SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuqing Mo ◽  
Ling Ye ◽  
Hui Cai ◽  
Guiping Zhu ◽  
Jian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Asthma ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Allergic Inflammation ◽  
Specific Ige ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Th1 And Th2

Abstract Background Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. Methods Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. Results Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. Conclusion Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

scholarly journals Potential of Immunoglobulin A to Prevent Allergic Asthma

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Anouk K. Gloudemans ◽  
Bart N. Lambrecht ◽  
Hermelijn H. Smits
Keyword(s):  
Allergic Asthma ◽  
Immunoglobulin A ◽  
Bronchial Hyperresponsiveness ◽  
Airway Disease ◽  
Epidemiological Studies ◽  
Allergic Airway Disease ◽  
Secretory Iga ◽  
Th2 Cells ◽  
Lower Airway

Allergic asthma is characterized by bronchial hyperresponsiveness, a defective barrier function, and eosinophilic lower airway inflammation in response to allergens. The inflammation is dominated by Th2 cells and IgE molecules and supplemented with Th17 cells in severe asthma. In contrast, in healthy individuals, allergen-specific IgA and IgG4 molecules are found but no IgE, and their T cells fail to proliferate in response to allergens, probably because of the development of regulatory processes that actively suppress responses to allergens. The presence of allergen-specific secretory IgA has drawn little attention so far, although a few epidemiological studies point at a reverse association between IgA levels and the incidence of allergic airway disease. This review highlights the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) dendritic cells in this process. Finally, we discuss how this information can be used to translate into the development of new therapies for allergic diseases based on, or supplemented with, IgA boosting strategies.

scholarly journals The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Masahiro Kiuchi ◽  
Atsushi Onodera ◽  
Kota Kokubo ◽  
Tomomi Ichikawa ◽  
Yuki Morimoto ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Allergic Airway Inflammation ◽  
T Cell Differentiation ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Th2 Differentiation ◽  
Later Phase ◽  
Th1 And Th2

Different dynamics of gene expression are observed during cell differentiation. In T cells, genes that are turned on early or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that the Cxxc1 subunit of the Trithorax complex directs transcription of genes initially down-regulated by TCR stimulation but up-regulated again in a later phase. The late up-regulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1 deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T cell immune system via epigenetic control of a specific set of genes.

scholarly journals IgM regulates airway hyperresponsiveness via modulation of actin associated genes.

2021 ◽  
Author(s):  
SABELO HADEBE ◽  
Anca Flavia Savulescu ◽  
Jermaine Khumalo ◽  
Katelyn Jones ◽  
Sandisiwe Mangali ◽  
...  
Keyword(s):  
B Cells ◽  
Allergic Asthma ◽  
Airway Hyperresponsiveness ◽  
Angiogenesis Inhibitor ◽  
Erythroid Differentiation ◽  
Immunoglobulin M ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Current Therapies ◽  
Cell Force

Abstract Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model by sensitising wild type (WT) and IgM-deficient (IgM-/-) mice with HDM. We validated our findings using CRISPR and single cell force cytometry in human ASM. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and erythroid differentiation regulator 1 (Erdr1). Deletion of BAIAP2L1 and ERDR1 reduced human ASM contraction when stimulated with TNF-α. These are unprecedented findings and have implications in future treatment of asthma beyond current therapies.

scholarly journals Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease

2020 ◽  
Author(s):  
Rod A. Rahimi ◽  
Keshav Nepal ◽  
Murat Cetinbas ◽  
Ruslan I. Sadreyev ◽  
Andrew D. Luster
Keyword(s):  
Allergic Asthma ◽  
Allergic Airway Inflammation ◽  
Lung Parenchyma ◽  
Airway Disease ◽  
Gene Signature ◽  
Allergic Airway Disease ◽  
Transcriptional Analysis ◽  
Th2 Cells ◽  
Redundant Functions

ABSTRACTMemory CD4+ T helper type 2 (Th2) cells are critical in driving allergic asthma pathogenesis, yet the mechanisms whereby tissue-resident memory Th2 cells (Th2 Trm) and circulating memory Th2 cells collaborate in vivo remain unclear. Here, using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm and circulating memory Th2 cells perform non-redundant functions in vivo. Upon HDM re-challenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+ T cell recruitment. In contrast, Th2 Trm proliferated near airways and promoted mucus metaplasia, airway hyper-responsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm and circulating memory Th2 cells share a core Th2 gene signature, but also exhibit distinct transcriptional profiles. Specifically, Th2 Trm express a tissue adaptation signature, including genes involved in regulating and interacting with extracellular matrix. Our findings demonstrate that Th2 Trm and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.SUMMARYHow memory Th2 cell subsets orchestrate allergic airway inflammation remains unclear. Rahimi et al. use a murine model of allergic asthma and parabiosis to demonstrate that tissue-resident and circulating memory Th2 cells are functionally distinct subsets with unique roles in promoting allergic airway disease.

scholarly journals T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription

2006 ◽  
Vol 203 (3) ◽  
pp. 755-766 ◽  
Author(s):  
Takashi Usui ◽  
Jan C. Preiss ◽  
Yuka Kanno ◽  
Zheng Ju Yao ◽  
Jay H. Bream ◽  
...  
Keyword(s):  
Early Stage ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Down Regulation ◽  
Ifng Gene ◽  
Deoxyribonuclease I ◽  
Negative Effect ◽  
Th2 Differentiation

T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT)4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet−/− mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti–interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet−/− mice manifest IFNG promotor accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet−/− cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed. Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/IL-12Rβ2 chain unless GATA-3 levels or function is regulated by T-bet. Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene.

scholarly journals TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis

2009 ◽  
Vol 206 (10) ◽  
pp. 2111-2119 ◽  
Author(s):  
Ning Lu ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Kazuhiko Arima ◽  
Shino Hanabuchi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Th2 Differentiation

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis.

scholarly journals Biologic targeted therapy in allergic asthma

2019 ◽  
Vol 2 (1) ◽  
pp. 24-34
Author(s):  
Kevin Kron ◽  
Mason J. Crow ◽  
Ali Olyaei ◽  
Anthony Montanaro
Keyword(s):  
Clinical Trials ◽  
Allergic Asthma ◽  
Immunoglobulin E ◽  
Treatment Options ◽  
Signs And Symptoms ◽  
Biologic Agents ◽  
Clinical Severity ◽  
Th2 Cells ◽  
Dosing Regimens

Background: Asthma is a heterogeneous inflammatory disease of the airway, characterized by airway hyperresponsiveness, airway obstruction, mucus hyperproduction, and airway-wall remodeling. Management of this disease involves the use of several types of therapeutic agents, each with unique indications based on the underlying cause of inflammation, clinical severity, and patient phenotype and/or endotype. Objective: A review of the function, clinical utility, and safety of biologic agents in the management of allergic asthma. This particular asthma phenotype involves multiple cytokines in its pathogenesis, specifically those secreted by T-helper type 2 cells. Methods: Medical literature was obtained from online biomedical archive searches from July 2018 to May 2019. An emphasis was placed on clinical trials that discussed biologic agents that target immunoglobulin E, interleukin (IL) 5, IL-4/IL-13, and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) pathways involved in the expression of allergic asthma. Results: The treatment options reviewed in this article were shown to be effective in targeting these pathways associated with allergic asthma. However, because these biologic agents are commonly prescribed in the treatment of severe asthma, many patients continue to experience asthma signs and symptoms. Conclusion: Future clinical trials that study these agents should focus on ideal patient selection, dosing regimens, and cost-effectiveness in the management of asthma. Ideally, comparative trials should be undertaken to assist the clinician in choosing the optimal agent.

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