Is cystic fibrosis a TH17 disease?

Dubin, Patricia J.; McAllister, Florencia; Kolls, Jay K.

doi:10.1007/s00011-007-6187-2

Cited by 86 publications

(67 citation statements)

References 71 publications

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“…On the basis of our findings, we speculate that flagellin-induced MDSC accumulation in chronic P. aeruginosa infection in CF patients has functional immunological relevance, as ex vivo and in vitro P. aeruginosa-induced MDSCs significantly suppressed both CD4 and CD8 T cell proliferation and dampened Th17 cell responses, which play a vital role in CF lung disease (24)(25)(26)(27)(28)(29)(30)(31). Consequently, MDSCs, as key interface cells between innate and adaptive immunity, may represent a novel therapeutic target in CF and other P. aeruginosa-associated pulmonary diseases, such as chronic obstructive pulmonary disease or ventilator-associated pneumonia.…”

Section: Discussionmentioning

confidence: 67%

“…Previous studies have characterized the T cell response in human CF patients (33,34) (24,26,27,30) (35) and murine P. aeruginosa (36)(37)(38)(39)(40) or Aspergillus fumigatus infection models (41)(42)(43), providing evidence that the adaptive T cell response in CF is altered at several levels. CF T cells were found to be prone to a Th2 phenotype, with the CFTR mutation itself and/or chronic infections with P. aeruginosa as possible underlying factors (42,(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…CF T cells were found to be prone to a Th2 phenotype, with the CFTR mutation itself and/or chronic infections with P. aeruginosa as possible underlying factors (42,(44)(45)(46). Importantly, recent lines of evidence indicate that Th17 cells and the IL-17 axis-related cytokines IL-22 and IL-23 could play an essential role in recruiting neutrophils to the CF airways and thereby contributing to neutrophil-mediated tissue damage in CF lung disease, thus labeling CF as a "Th17 disease" (24)(25)(26)(27)(28)(29)(30)(31). Th17 cells secrete IL-17 that, in turn, enhances G-CSF and thereby boosts neutrophil mobilization from the bone marrow.…”

Section: Discussionmentioning

confidence: 99%

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Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

114

127

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Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

114

127

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“…101 Discovery of the T H 17 lineage has provided insight to this disease causing immune response in pioneering work performed by Jay Kolls and colleagues. 102 A mouse model of P. aeruginosa pulmonary colonization found an induction of the IL-23 and IL-17A pathway, leading to a predominantly neutrophillic infiltrate. 103 More directly, measurements of cytokine levels in the sputum of CF patients demonstrated increase levels of IL-17A, IL-17F and IL-23, 104 leading to a hypothesis that CF lung pathology is T H 17 driven.…”

Section: T H 17 Resonses In Hiv and Aidsmentioning

confidence: 99%

“…103 More directly, measurements of cytokine levels in the sputum of CF patients demonstrated increase levels of IL-17A, IL-17F and IL-23, 104 leading to a hypothesis that CF lung pathology is T H 17 driven. 102 Further research must be performed to determine the exact mechanism by which P. aeruginosa in CF patients leads to a disease causing T H 17 immune response. However, these findings can lead to significant advancements in therapies used to alleviate pulmonary disease in CF patients.…”

Section: T H 17 Resonses In Hiv and Aidsmentioning

confidence: 99%

Manipulation of T_H17 responses in pulmonary immunity and disease through vaccination

Sonnenberg

Weiner²

2009

Human Vaccines

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Since the discovery of a novel subset of CD4 + T helper cells, T H 17 cells have been implicated in a wide range of human diseases, including autoimmunity, allergic reactions and autoinflammatory diseases. Conversely, it has also been determined that T H 17 cells are required to mount a protective immune response to a number of pathogens. It has therefore been of great interest to manipulate T H 17 responses to either prevent disease or promote immunity. Vaccination is a particularly attractive approach for this manipulation. With a focus on the pulmonary mucosal environment, we herein review T H 17 responses and potential methods for manipulation.

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The cystic fibrosis gender gap: Potential roles of estrogen

Sweezey

Ratjen

2013

Pediatr Pulmonol.

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Cystic fibrosis (CF) is a complex, multi-system, autosomal recessive disease predominantly affecting Caucasians that leads to vigorous airway inflammation and chronic respiratory infection, commonly with Pseudomonas aeruginosa. A variety of factors significantly modify the progression and severity of CF lung disease and the timing of the resulting mortality. We summarize here data indicating that there is in CF a female disadvantage in survival and morbidity, called the "CF gender gap". Although controversy exists regarding the nature and relative importance of the various contributing mechanisms involved, gender affects the progression of CF disease with respect to lung infection, decline in pulmonary function and nutritional status. These interrelated factors in turn have a negative impact on survival. This review will emphasize the increasing evidence that suggest a role for the effects of gender, and particularly the female sex hormone estrogen, on infection, inflammation and transepithelial ion transport, all major determinants of CF lung disease. Future elucidation of the pathophysiology of hormonal aggravation of CF lung disease may pave the way for novel therapeutic interventions. This, combined with the magnitude of the gender gap in CF mortality, strongly suggests that further work in this field is well justified.

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Is cystic fibrosis a TH17 disease?

Cited by 86 publications

References 71 publications

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Manipulation of T_H17 responses in pulmonary immunity and disease through vaccination

The cystic fibrosis gender gap: Potential roles of estrogen

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Is cystic fibrosis a TH17 disease?

Cited by 86 publications

References 71 publications

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Manipulation of TH17 responses in pulmonary immunity and disease through vaccination

The cystic fibrosis gender gap: Potential roles of estrogen

Contact Info

Product

Resources

About

Manipulation of T_H17 responses in pulmonary immunity and disease through vaccination