Current concepts of immune dysregulation in cystic fibrosis

doi:10.1016/j.biocel.2014.01.017

The International Journal of Biochemistry & Cell Biology

Volume 52, July 2014, Pages 108-112

https://doi.org/10.1016/j.biocel.2014.01.017 Get rights and content

Abstract

Cystic fibrosis (CF) lung disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene and is characterized by a perpetuated feedback loop of bacterial infection and inflammation. Both intrinsic (CFTR-dependent) and extrinsic (CFTR-independent) mechanisms contribute to the inflammatory phenotype of CF lung disease. Innate immune cells, initially recruited to combat bacterial pathogens, are acting in a dysregulated and non-resolving fashion in CF airways and cause harm to the host by releasing proteases and oxidants. Targeting harmful immune pathways, while preserving protective ones, remains the challenge for the future. This review highlights current concepts of innate immune dysregulation in CF lung disease.

This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.

Section snippets

Immunity in cystic fibrosis: more questions than answers

Cystic fibrosis (CF) lung disease is characterized by a chronic and non-resolving activation of the innate immune system with release of chemokines and an infiltration of neutrophils into the airways. Neutrophil-derived oxidants and proteases cause harm to multiple cellular and humoral factors and have recently been shown to impair Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) functionality itself (Le Gars et al., 2013). Beyond neutrophils, the immune response in CF lungs is

CFTR in myeloid cells

Previous studies provided convincing evidence that human neutrophils express the CFTR protein, localized in the membrane of secretory vesicles (Painter et al., 2006). Optimal microbicidal activity of neutrophils relies on the generation of toxic agents such as hypochlorous acid (HOCl) within phagosomes (Hampton et al., 1998). HOCl formation, in turn, requires chloride ion transported from the cytoplasm into phagosomes mediated by chloride channels (Nauseef, 2007). Studies demonstrated that

Immunity in cystic fibrosis: future directions

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Functional role of CFTR in myeloid cells: As several myeloid cells have been demonstrated to express CFTR protein (macrophages, neutrophils, and dendritic cells) and CFTR modulators are used nowadays for the treatment of CF patients with G551D mutations (Hoffman and Ramsey, 2013), their effect, particularly of the CFTR potentiator Ivacaftor (Kalydeco), on the homeostasis and functionality of myeloid cells remains to be defined.
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Homologies between the porcine and human immune system: The more

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Frequencies of pathogenic CFTR variants in Greek cystic fibrosis patients with allergic bronchopulmonary aspergillosis and Aspergillus fumigatus chronic colonization: A retrospective cohort study
2023, Journal of Medical Mycology
Citation Excerpt :
However, the relationship between CFTR genotype and the clinical spectrum of A. fumigatus in CF has not been fully clarified yet. It is well known that CFTR is expressed in cells of both the innate and adaptive immune system and seems to play a critical role in their function [5]. According to Chaudhary et al., epithelial cells in CFTR/murine models expressed defective clearance of A. fumigatus conidia and increased susceptibility to apoptosis [6].
The clinical spectrum of Aspergillus fumigatus diseases in cystic fibrosis (CF) patients, including allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus chronic colonization, has recently gained attention due to its association with the progression of lung disease. Our aim was to examine whether there is a difference on pathogenic variant frequencies of the CFTR gene between CF patients with ABPA and those with A. fumigatus chronic colonization.
Greek CF patients diagnosed with ABPA and/or A. fumigatus chronic colonization were grouped according to their CFTR genotype. Patients with “minimal” CFTR function were defined as carrying a combination of class I or II pathogenic variants, while patients with “residual” function as carrying at least one class III, IV, V or VI pathogenic variant.
Fifty-four CF patients were included and all except one were defined as having “minimal” CFTR function. Among the 108 CFTR alleles, 69 (63.9%) of pathogenic variants belonged to class II, and 32 (29.6%) to class I. Five patients had a history of both ABPA and A. fumigatus chronic colonization. No significant difference was detected among patients diagnosed only with ABPA (n = 29) and those who had only a positive history of A. fumigatus chronic colonization (n = 20). The median age of ABPA diagnosis was significantly lower than the median age of A. fumigatus chronic colonization (P = 0.011), while no significant difference was detected on median FEV₁% predicted.
No significant differences were detected in the type of CFTR pathogenic variants among patients with ABPA and those with A. fumigatus colonization. Similar studies should be performed in larger CF populations of different ethnic origin to further confirm our results.
The effect of the cystic fibrosis care center on outcomes after lung transplantation for cystic fibrosis
2022, Journal of Heart and Lung Transplantation
Citation Excerpt :
Accreditation as a CFCC is based on the determination by the CFF that a center is able to provide specialized care for CF patients, and meets published best practices including structures of care for frequent complications and comorbidities of CF. For example, there are guidelines for pulmonary care and infection control as well as requirements for colorectal cancer screening and nutritional support given the wide array of gastrointestinal manifestations of CF.3 The CFF performs routine site visits of CFCCs in order for centers to maintain accreditation. These requirements for comprehensive care that extend well beyond pulmonary medicine are especially important in CF as it is a chronic systemic disease with broad extra-pulmonary manifestations, with particular gastrointestinal, endocrine and infectious complications.2,4,26,30-33 Lung transplantation serves as a therapy for pulmonary failure in CF but does not address the systemic manifestations.
The purpose of this study was to evaluate outcomes in people with cystic fibrosis (CF) who underwent lung transplant (LT) at a transplant center with an accredited Cystic Fibrosis Care Center (CFCC) in the United States.
We reviewed the Scientific Registry of Transplant Recipients for all adult patients with CF who received a first-time LT from 2005 to 2018. The primary outcome was graft failure. Unadjusted Kaplan-Meier analysis and adjusted multilevel Cox proportional hazards models were used to evaluate outcomes in CF patients undergoing lung transplantation at a CFCC.
2,573 patients with CF underwent a first time LT during the study period. Of the 68 lung transplantation centers, 50 were CFCCs (73.5%). After adjustment for potential confounders, patients who underwent lung transplantation at a hospital with an accredited CFCC had a 33% reduction in risk of death or re-transplantation compared to those transplanted at a hospital without an accredited CFCC (HR: 0.67, 95% CI: 0.56-0.82, p < 0.001).
People with CF who undergo LT at a transplant center with a CFCC have improved graft survival and decreased need for re-transplantation compared to those who undergo LT at a non-CFCC, independent of volume.
Therapeutic potential for coxibs-nitric oxide releasing hybrids in cystic fibrosis
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
It was recently shown, how the reduction of COX protein levels (mainly COX-2) had a positive effect on all analysed clinical parameters. This suggests an important role of the inhibition of arachidonic acid conversion into prostaglandins which, by reducing the inflammatory process, acts as protective modifier of pulmonary disease in CF patients [17,18]. With the recognition that airway inflammation plays a significant pathogenic role in CF, modulation of the inflammatory response has become a significant therapeutic target and drugs that target inflammation have been shown to slow the decline in lung function and improve survival [19,20].
This review discusses the rational for further studies of COX-2 inhibitors-NO releaser hybrids (NO-Coxibs) in the pharmacological treatment of the airway inflammation in Cystic Fibrosis (CF). Our research group developed several classes of NO-Coxibs for the pharmacological treatment of arthritis, and among them several compounds showed an outstanding in vivo efficacy and good pharmacokinetic properties. The good antiinflammatory properties displayed by these compounds during the previous screening could, by itself, suggest appropriate candidates for further testing in CF.
Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota
2019, Cellular and Molecular Gastroenterology and Hepatology
Cystic fibrosis (CF) is a monogenic disease caused by mutation of Cftr. CF-associated liver disease (CFLD) is a common nonpulmonary cause of mortality in CF and accounts for approximately 2.5%–5% of overall CF mortality. The peak of the disease is in the pediatric population, but a second wave of liver disease in CF adults has been reported in the past decade in association with an increase in the life expectancy of these patients. New drugs are available to correct the basic defect in CF but their efficacy in CFLD is not known. The cystic fibrosis transmembrane conductance regulator, expressed in the apical membrane of cholangiocytes, is a major determinant for bile secretion and CFLD classically has been considered a channelopathy. However, the recent findings of the cystic fibrosis transmembrane conductance regulator as a regulator of epithelial innate immunity and the possible influence of the intestinal disease with an altered microbiota on the liver complication have opened new mechanistic insights on the pathogenesis of CFLD. This review provides an overview of the current understanding of the pathophysiology of the disease and discusses a potential target for intervention.
Aspergillus infections in cystic fibrosis
2016, Journal of Infection
Citation Excerpt :
The pathophysiology of Aspergillus infections in the CF-lung, except for ABPA,48 is not known and the consequences of the absence of a functional CFTR protein on the specific host–fungus interaction is not understood. CFTR protein has been found in cells of both the innate and adaptive immune system49,50 and has shown to play a critical role for their normal function.51 Cystic fibrosis lung disease is characterized by early, non-resolving activation of the innate immune system, with excessive neutrophil recruitment followed by excessive expansion of lymphocyte populations and failure of normal counter-regulatory mechanisms.5,52
Patients with cystic fibrosis (CF) suffer from chronic lung infection and airway inflammation. Respiratory failure secondary to chronic or recurrent infection remains the commonest cause of death and accounts for over 90% of mortality. Bacteria as Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia complex have been regarded the main CF pathogens and their role in progressive lung decline has been studied extensively. Little attention has been paid to the role of Aspergillus spp. and other filamentous fungi in the pathogenesis of non-ABPA (allergic bronchopulmonary aspergillosis) respiratory disease in CF, despite their frequent recovery in respiratory samples. It has become more apparent however, that Aspergillus spp. may play an important role in chronic lung disease in CF. Research delineating the underlying mechanisms of Aspergillus persistence and infection in the CF lung and its link to lung deterioration is lacking. This review summarizes the Aspergillus disease phenotypes observed in CF, discusses the role of CFTR (cystic fibrosis transmembrane conductance regulator)-protein in innate immune responses and new treatment modalities.
Modeling immunity in microphysiological systems
2023, Experimental Biology and Medicine

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^☆: This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.

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Current concepts of immune dysregulation in cystic fibrosis☆

Abstract

Section snippets

Immunity in cystic fibrosis: more questions than answers

CFTR in myeloid cells

Immunity in cystic fibrosis: future directions

Free Radical Biology & Medicine

Immunity

Blood

Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society

Chest

Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society

TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis

Journal of Immunology

Innate immunity mediated by TLR5 as a novel anti-inflammatory target for cystic fibrosis lung disease

Journal of Immunology

Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection

Journal of Leukocyte Biology

Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis

Journal of Immunology

Asialo GM1 is a receptor for Pseudomonas aeruginosa adherence to regenerating respiratory epithelial cells

Infection and Immunity

Toll-like receptor 5 (TLR5), IL-1 beta secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing

Proceedings of the National Academy of Sciences of the United States of America

IL-17 in cystic fibrosis: more than just Th17 cells

American Journal of Respiratory and Critical Care Medicine

Is cystic fibrosis a TH17 disease?

Inflammation Research

Myeloid-derived suppressor cells as regulators of the immune system

Nature Reviews Immunology

The role of matrix metalloproteinases in cystic fibrosis lung disease

The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology

Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial

American Journal of Respiratory and Critical Care Medicine

Inhibition of airway proteases in cystic fibrosis lung disease

The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology

Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity

Embo Journal

TLR-4-mediated innate immunity is reduced in cystic fibrosis airway cells

American Journal of Respiratory Cell and Molecular Biology