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            17 inflammatory pathways are reciprocally regulated in asthma

Choy, David F.; Hart, Kevin M.; Borthwick, Lee A.; Shikotra, Aarti; Nagarkar, Deepti R.; Siddiqui, Salman; Jia, Guiquan; Ohri, Chandra; Doran, Emma; Vannella, Kevin M.; Butler, Claire A.; Hargadon, Beverley; Sciurba, Joshua; Gieseck, Richard L.; Thompson, Robert W.; White, Sandra; Abbas, Alexander R.; Jackman, Janet; Wu, Lawren C.; Egen, Jackson G.; Heaney, Liam G.; Ramalingam, Thirumalai R.; Arron, Joseph R.; Wynn, Thomas A.; Bradding, Peter

doi:10.1126/scitranslmed.aab3142

Cited by 404 publications

(400 citation statements)

References 62 publications

(108 reference statements)

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“…This finding suggests that Th2 activation precedes Th17 activation and not the reverse. Second, in asthma, it was recently demonstrated that there are 3 subgroups (i.e., Th2 high , Th17 high , and Th2 low /Th17 low ), but not a group with high expression of both Th2 and Th17, which shows that these cell types are mutually exclusive [47]. This result was explained by the experimental findings of Newcomb et al [45,46].…”

Section: Discussionmentioning

confidence: 91%

Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects

Pandya

Lundell

Hallström

et al. 2016

Journal of Leukocyte Biology

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The pathogenic role and frequency of T cell subtypes in early rheumatoid arthritis are still unclear. We therefore performed a comprehensive analysis of the circulating T cell subtype pattern in patients with untreated early rheumatoid arthritis compared to healthy control subjects. Peripheral blood mononuclear cells were obtained from 26 patients with untreated early rheumatoid arthritis and from with 18 age- and sex-matched healthy control subjects. T helper cell types Th0, Th1, Th2, Th17, and Th1/17 and nonclassic T helper subsets were defined by flow cytometry based on the expression of chemokine receptors CCR4, CCR6, and CXCR3. Regulatory T cells were defined by expression of CD25 CD127 and also FOXP3 CXCR5 cells among regulatory and nonregulatory T cells were defined as T follicular regulatory and T follicular helper cells, respectively. The phenotype of T cell subsets was confirmed by transcription factor and cytokine secretion analyses. Multivariate discriminant analysis showed that patients with untreated early rheumatoid arthritis were segregated from healthy control subjects based on the circulating T cell subset profile. Among the discriminator subsets, CCR4CXCR3 (Th2 and Th17), CTLA4 and FOXP3 subsets were present in significantly higher frequencies, whereas CCR4 (Th1/Th17, CCR6CCR4CXCR3, and Th1) subsets were present in lower frequencies in patients with untreated early rheumatoid arthritis compared with healthy control subjects. The proportions of Th2 and Th17 subsets associated positively with each other and negatively with the CXCR3/interferon γ-secreting subsets (Th1 and Th1/Th17) in patients with untreated rheumatoid arthritis. The proportions of Th2 cells increased with age in patients with untreated early rheumatoid arthritis and healthy control subjects. The dominance of circulating CCR4CXCR3 T helper subsets (Th2 and Th17) in untreated early rheumatoid arthritis point toward a pathogenic role of these cells in early stages of the disease.

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Section: Discussionmentioning

confidence: 91%

Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects

Pandya

Lundell

Hallström

et al. 2016

Journal of Leukocyte Biology

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“…Furthermore, CXCR2 signaling derived Th2 responses are enhanced. 118 In patients with CRS with NP IL-25 and IL-33 interact locally with IL-17RBþST2þ polyp T cells to augment Th2 responses. 115 IL-17 significantly increases MUC5B mucin expression, while IL-13 additionally induces significant goblet cell hyperplasia and MUC5AC mucin expression in CRS with NP.…”

Section: Neurogenic Inflammationmentioning

confidence: 99%

“…Neutralization of both IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population with a mixed Th2/ Th17 endotype. 118 Chitinases and chitinase-like proteins (CLPs) may be an important link between type 2 immunity and IL-17. Acting as dangerassociated molecular patterns CLPs release IL-1 with IL-17 production by innate gd T cells, which in turn drives a type 2 response.…”

Section: Neurogenic Inflammationmentioning

confidence: 99%

Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine

Agache

Akdiş

2016

Allergology International

161

140

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Discoveries from basic science research in the last decade have brought significant progress in knowledge of pathophysiologic processes of allergic diseases, with a compelling impact on understanding of the natural history, risk prediction, treatment selection or mechanism-specific prevention strategies. The view of the pathophysiology of allergic diseases developed from a mechanistic approach, with a focus on symptoms and organ function, to the recognition of a complex network of immunological pathways. Several subtypes of inflammation and complex immune-regulatory networks and the reasons for their failure are now described, that open the way for the development of new diagnostic tools and innovative targeted-treatments. An endotype is a subtype of a disease condition, which is defined by a distinct pathophysiological mechanism, whereas a disease phenotype defines any observable characteristic of a disease without any implication of a mechanism. Another key word linked to disease endotyping is biomarker that is measured and evaluated to examine any biological or pathogenic processes, including response to a therapeutic intervention. These three keywords will be discussed more and more in the future with the upcoming efforts to revolutionize patient care in the direction of precision medicine and precision health. The understanding of disease endotypes based on pathophysiological principles and their validation across clinically meaningful outcomes in asthma, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis and food allergy will be crucial for the success of precision medicine as a new approach to patient management.

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“…Imbalances of Th17/Treg cells have been demonstrated in patients with allergic asthma, and were shown to be associated with moderate to severe asthma [12, 13]. Choy et al [14] have identified Th2-high, Th17-high, and Th2/–17-low 409 clusters of patients with asthma, and combination therapies targeting both Th2 and Th7 pathways could provide additional efficacy over single inhibition. In addition, the elevated plasma IL-17 and IL-22, as well as the circulating Th17 cells are important features of allergic asthma and the Th17-driven immunity is paralleled with the severity of asthma, as indicated by Zhao et al [15].…”

Section: Introductionmentioning

confidence: 99%

Correlation of PD-1/PD-L1 Signaling Pathway with Treg/Th17 Imbalance from Asthmatic Children

Xia

Liu

Guo

2018

Int Arch Allergy Immunol

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Background: The balance between T helper 17 (Th17) and regulatory T cells (Treg) is a new paradigm in asthma pathogenesis, but no therapeutic targets could modulate the Th17/Treg balance specifically for asthma. Since previous studies have shown the programmed cell death-1(PD-1)/PD-ligand 1 (PD-L1) pathway is critical to immune homeostasis in this disease, we hypothesized that the PD-1/PD-L1 pathway might be involved in the regulation of Treg/Th17 imbalance in asthmatic children. Methods: The percentage of Treg and Th17 cells and the expression of PD-1 and PD-L1 were detected by flow cytometry in children with asthma and healthy controls. CD4⁺ T cells were stimulated with Th17 and Treg differentiating factors, and treated with anti-PD-1. Then cells were harvested and measured for Th17 and Treg percentages and Foxp3 and RORγt levels using RT-PCR. Results: We observed an inverse correlation between the percentages of Treg and Th17 cells, and the expression of PD-1 and PD-L1 in the two subsets also changed in the mild persistent and moderate to severe persistent groups compared with healthy controls. In vitro, administration of anti-PD-1 could decrease Th17 percentages and RORγt mRNA, and increase Treg percentages and Foxp3 mRNA in CD4⁺ T cells of children with asthma in the mild persistent and moderate to persistent groups. Additionally, the role played by anti-PD-1 in regulating Treg/Th17 balance was further confirmed in an asthmatic mouse model. Conclusion: Alteration of the PD-1/PD-L1 pathway can modulate Treg/Th17 balance in asthmatic children. Treatment with anti-PD-1 posed protective effects on asthma models, providing a novel theoretical target for asthma.

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T _H 2 and T _H 17 inflammatory pathways are reciprocally regulated in asthma

Abstract: Concurrent blockade of IL-13 and IL-17A may improve control of asthma.

Cited by 404 publications

References 62 publications

Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects

Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects

Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine

Correlation of PD-1/PD-L1 Signaling Pathway with Treg/Th17 Imbalance from Asthmatic Children

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T H 2 and T H 17 inflammatory pathways are reciprocally regulated in asthma

Abstract: Concurrent blockade of IL-13 and IL-17A may improve control of asthma.

Cited by 404 publications

References 62 publications

Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects

Circulating T helper and T regulatory subsets in untreated early rheumatoid arthritis and healthy control subjects

Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine

Correlation of PD-1/PD-L1 Signaling Pathway with Treg/Th17 Imbalance from Asthmatic Children

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T _H 2 and T _H 17 inflammatory pathways are reciprocally regulated in asthma