CFTR regulates B cell activation and lymphoid follicle development

Polverino, Francesca; Liu, Bao; Quintero, Joselyn Rojas; Vargas, Sara O.; Patel, Avignat S.; Owen, Caroline A.; Gerard, Norma P.; Gérard, Craig; Cernadas, Manuela

doi:10.1186/s12931-019-1103-1

Cited by 26 publications

(24 citation statements)

References 41 publications

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“…The model of chronic Pa lung infection favours the retention of the bacteria in the airways and reproduces some features of the CF lung disease such as strong neutrophilic inflammation and peribronchial lymphoid aggregates [ 47 , 48 ]. Only a slight increased inflammatory score in FVB F508del mice was demonstrated, in contrast with C57BL/6J CFTR-KO mice showing some lymphoid aggregates [ 49 , 50 ]. When compared with the same genetic background, CFTR-KO and F508del mice display the same phenotype and, until now, no diseased lung phenotype related to CFTR misfolding has been observed in F508del mice [51] .…”

Section: Discussionmentioning

confidence: 99%

Lung immunoglobulin A immunity dysregulation in cystic fibrosis

et al. 2020

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Background In cystic fibrosis (CF), recurrent infections suggest impaired mucosal immunity but whether production of secretory immunoglobulin A (S-IgA) is impaired remains elusive. S-IgA is generated following polymeric immunoglobulin receptor (pIgR)-mediated transepithelial transport of dimeric (d-)IgA and represents a major defence through neutralisation of inhaled pathogens like Pseudomonas aeruginosa ( Pa ). Methods Human lung tissue (n = 74), human sputum (n = 118), primary human bronchial epithelial cells (HBEC) (cultured in air-liquid interface) (n = 19) and mouse lung tissue and bronchoalveolar lavage were studied for pIgR expression, IgA secretion and regulation. Findings Increased epithelial pIgR immunostaining was observed in CF lung explants, associated with more IgA-producing plasma cells, sputum and serum IgA, especially Pa -specific IgA. In contrast, pIgR and IgA transport were downregulated in F508del mice, CFTR-inhibited HBEC, and CF HBEC. Moreover, the unfolded protein response (UPR) due to F508del mutation, inhibited IgA transport in Calu-3 cells. Conversely, pIgR expression and IgA secretion were strongly upregulated following Pa lung infection in control and F508del mice, through an inflammatory host response involving interleukin-17. Interpretation A complex regulation of IgA secretion occurs in the CF lung, UPR induced by CFTR mutation/dysfunction inhibiting d-IgA transcytosis, and Pa infection unexpectedly unleashing this secretory defence mechanism. Funding This work was supported by the Forton's grant of the King Baudouin's Foundation, Belgium, the Fondazione Ricerca Fibrosi Cistica, Italy, and the Fonds National de la Recherche Scientifique, Belgium.

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Section: Discussionmentioning

confidence: 99%

Lung immunoglobulin A immunity dysregulation in cystic fibrosis

et al. 2020

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“…Autoimmune responses, in contrast, are directed against self-antigens and are characterised by the presence of autoreactive T cells and B cell-mediated autoantibodies [ 34 ]. Only a limited number of studies have reported the involvement of adaptive immune cells, such as T and B cells, affected by CFTR mutations in CF pathology [ 36 – 39 ]. Therefore, this review will explore existing reports in the literature detailing several mechanistic signalling pathways dysregulated in innate immune cells harbouring CFTR mutations.…”

Section: Introduction: An Overview Of Cystic Fibrosismentioning

confidence: 99%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

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Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

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“…Studies in Cftr -/mice suggest that CFTR mutations directly affect B lymphocyte function. Uninfected Cftr -/mice have higher levels of the B cell survival factor, B cell-activating factor (BAFF), a member of TNF cytokine family, as well as an increased number of lung lymphoid follicles compared to control mice (141). Increased levels of BAFF and lymphoid follicles were also observed in CF patients (141).…”

Section: Possible Contribution Of Immune Cells In Progression To Cfrd In Cf Patientsmentioning

confidence: 99%

“…Uninfected Cftr -/mice have higher levels of the B cell survival factor, B cell-activating factor (BAFF), a member of TNF cytokine family, as well as an increased number of lung lymphoid follicles compared to control mice (141). Increased levels of BAFF and lymphoid follicles were also observed in CF patients (141). Moreover, the pancreas of newborn CFTR -/pigs present with a higher proportion of activated B lymphocytes, likely producing antibodies.…”

Section: Possible Contribution Of Immune Cells In Progression To Cfrd In Cf Patientsmentioning

confidence: 99%

The Potential Causes of Cystic Fibrosis-Related Diabetes

et al. 2021

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Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.

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CFTR regulates B cell activation and lymphoid follicle development

Cited by 26 publications

References 41 publications

Lung immunoglobulin A immunity dysregulation in cystic fibrosis

Lung immunoglobulin A immunity dysregulation in cystic fibrosis

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

The Potential Causes of Cystic Fibrosis-Related Diabetes

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