The B Lymphocyte Differentiation Factor (BAFF) Is Expressed in the Airways of Children with CF and in Lungs of Mice Infected with Pseudomonas aeruginosa

Neill, Daniel R.; Saint, Gemma; Bricio-Moreno, Laura; Fothergill, Joanne L.; Southern, Kevin W; Winstanley, Craig; Christmas, Stephen E.; Slupsky, Joseph R.; McNamara, Paul; Kadioglu, Aras; Flanagan, Brian

doi:10.1371/journal.pone.0095892

Cited by 13 publications

(17 citation statements)

References 23 publications

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“…The protective antigen Apa2h1 appears to contribute to BAFF and APRIL production in A. pleuropneumoniae infection because incubation of mouse DCs with Apa2h1 upregu- Pseudomonas aeruginosa is a respiratory pathogen frequently isolated from the lungs of cystic fibrosis patients. Bronchoalveolar lavage fluids of children with cystic fibrosis contain high levels of BAFF, and increased BAFF expression levels have been measured in lung homogenates of mice infected intranasally with P. aeruginosa (145) ( Table 3 and Fig. 3).…”

Section: Bacteria Bacterial Infections Of the Respiratory Systemmentioning

confidence: 99%

The Role of BAFF System Molecules in Host Response to Pathogens

Sakai

Akkoyunlu

2017

Clin Microbiol Rev

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The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.

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Section: Bacteria Bacterial Infections Of the Respiratory Systemmentioning

confidence: 99%

The Role of BAFF System Molecules in Host Response to Pathogens

Sakai

Akkoyunlu

2017

Clin Microbiol Rev

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“…(28). B cell differentiation factor (BAFF) is high in BALF from young CF patients compared with healthy controls, suggesting involvement in early CF lung disease (46). B cell depletion is considered a potential treatment in chronic inflammatory disorders (38) and may be beneficial to CF patients as well.…”

Section: Abnormal Dendritic Cell Ratio and Myeloid Infiltration In Cfmentioning

confidence: 99%

Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931

Veltman

Stolarczyk

Radzioch

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Progressive lung disease with early onset is the main cause of mortality and morbidity in cystic fibrosis patients. Here we report a reduction of sphingosine-1-phosphate (S1P) in the lung of unchallenged Cftr F508del CFTR mutant mice. This correlates with enhanced infiltration by inducible nitric oxide synthase (iNOS)-expressing granulocytes, B cells, and T cells. Furthermore, the ratio of macrophage-derived dendritic cells (MoDC) to conventional dendritic cells (cDC) is higher in mutant mouse lung, consistent with unprovoked inflammation. Oral application of a S1P lyase inhibitor (LX2931) increases S1P levels in mutant mouse tissues. This normalizes the lung MoDC/cDC ratio and reduces B and T cell counts. Lung granulocytes are enhanced, but iNOS expression is reduced in this population. Although lung LyC6+ monocytes are enhanced by LX2931, they apparently do not differentiate to MoDC and macrophages. After challenge with bacterial toxins (LPS-fMLP) we observe enhanced levels of proinflammatory cytokines TNF-α, KC, IFNγ, and IL-12 and the inducible mucin MUC5AC in mutant mouse lung, evidence of deficient resolution of inflammation. LX2931 does not prevent transient inflammation or goblet cell hyperplasia after challenge, but it reduces MUC5AC and proinflammatory cytokine levels toward normal values. We conclude that lung pathology in homozygous mice expressing murine F508del CFTR, which represents the most frequent mutation in CF patients, is characterized by abnormal behavior of infiltrating myeloid cells and delayed resolution of induced inflammation. This phenotype can be partially corrected by a S1P lyase inhibitor, providing a rationale for therapeutic targeting of the S1P signaling pathway in CF patients.

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“…BAFF has been detected in bronchoalveolar lavage (BAL) fluid from patients with CF and was most elevated in patients infected with P. aeruginosa . BAFF was not detected in BAL fluid from healthy controls [16]. BAFF was also shown to be induced in the lungs of wild type mice infected with P. aeruginosa [16].…”

Section: Introductionmentioning

confidence: 99%

“…BAFF was not detected in BAL fluid from healthy controls [16]. BAFF was also shown to be induced in the lungs of wild type mice infected with P. aeruginosa [16].…”

Section: Introductionmentioning

confidence: 99%

“…Peribronchial lymphoid follicles (LFs) have been observed in patients with CF and developed in wild type mice in response to bacterial infection. Wild type mice infected with P. aeruginosa had elevated levels of lung tissue BAFF and B cell chemoattractants including CXCL13 [16, 17]. Lung B cell BAFF expression has also been shown to correlate with LF development in chronic obstructive pulmonary disease (COPD) [13].…”

Section: Introductionmentioning

confidence: 99%

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CFTR regulates B cell activation and lymphoid follicle development

et al. 2019

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Background Cystic fibrosis (CF) is an inherited disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that promotes persistent lung infection and inflammation and progressive loss of lung function. Patients with CF have increased lung lymphoid follicles (LFs) and B cell-activating factor of tumor necrosis factor family (BAFF) that regulates B cell survival and maturation. A direct role for CFTR in B cell activation and disease pathogenesis in CF remains unclear. Methods The number of LFs, BAFF + , TLR4 + and proliferation marker Ki67 + B cells in lung explants or resections from subjects with CF and normal controls was quantified by immunostaining. The role of CFTR in B cell activation and LF development was then examined in two independent cohorts of uninfected CFTR-deficient mice ( Cftr −/− ) and wild type controls. The number of lung LFs, B cells and BAFF + , CXCR4 + , immunoglobulin G + B cells was examined by immunostaining. Lung and splenocyte B cell activation marker and major histocompatibility complex class II (MHC class II) expression was quantified by flow cytometry. Inflammatory cytokine levels were measured in supernatants from isolated B cells from Cftr −/− and wild type mice stimulated in vitro with Pseudomonas aeruginosa lipopolysaccharide (LPS). Results There was a significant increase in well-formed LFs in subjects with CF compared to normal controls. Increased B cell activation and proliferation was observed in lung LFs from CF subjects as was quantified by a significant increase in B cell BAFF, TLR4 and Ki67 expression. Uninfected Cftr −/− mice had increased lung LFs and BAFF + and CXCR4 + B cells compared to wild type controls. Lung B cells isolated from uninfected Cftr −/− mice demonstrated increased MHC class II expression. In vitro, isolated B cells from Cftr −/− mice produced increased IL-6 when stimulated with LPS compared to wild type controls. Conclusions These data support a direct role for CFTR in B cell activation, proliferation and inflammatory cytokine production that promotes lung LF follicle development in cystic fibrosis.

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The B Lymphocyte Differentiation Factor (BAFF) Is Expressed in the Airways of Children with CF and in Lungs of Mice Infected with Pseudomonas aeruginosa

Cited by 13 publications

References 23 publications

The Role of BAFF System Molecules in Host Response to Pathogens

The Role of BAFF System Molecules in Host Response to Pathogens

Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931

CFTR regulates B cell activation and lymphoid follicle development

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