Role of CXCL13 in Cigarette Smoke–induced Lymphoid Follicle Formation and Chronic Obstructive Pulmonary Disease

Bracke, Ken R.; Verhamme, Fien; Seys, Leen; Bantsimba-Malanda, Claudie; Cunoosamy, Danen; Herbst, Ronald; Hammad, Hamida; Lambrecht, Bart N.; Joos, Guy; Brusselle, Guy

doi:10.1164/rccm.201211-2055oc

Cited by 87 publications

(102 citation statements)

References 36 publications

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“…Additional studies showed that macrophage lineage cells (CD68 1 ) were the predominant source of the CXCL13 within the IPF B-cell aggregates (see Figure E2). Immunohistochemical studies in COPD lungs have been recently detailed elsewhere (43,44).…”

Section: Intrapulmonary Cxcl13mentioning

confidence: 99%

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Vuga¹,

Tedrow²,

Pandit³

et al. 2014

Am J Respir Crit Care Med

164

115

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Rationale: C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis.Objectives: To determine if CXCL13 is associated with IPF progression.Methods: CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA.Measurements and Main Results: CXCL13 mRNA was threefold and eightfold greater in IPF lungs (n = 92) compared with chronic obstructive pulmonary disease (COPD) (n = 191) and normal (n = 108) specimens, respectively (P , 0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 patients with IPF (94 6 8) than in 128 subjects with COPD (53 6 9) and 57 normal subjects (35 6 3) (P , 0.0001). Circulating CXCL13 levels were highest in patients with IPF with pulmonary artery hypertension (P = 0.01) or acute exacerbations (P = 0.002). Six-month survival of patients with IPF in the highest quartile of plasma CXCL13 was 65 6 10% versus 93 6 10% in the others (hazard ratio, 5.5; 95% confidence interval, 1.8-16.9; P = 0.0008). CXCL13 increases by more than 50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (hazard ratio, 7.2; 95% confidence interval, 1.3-40.0; P = 0.008). In contrast, CXCL13 clinical associations in subjects with COPD were limited to modest correlations with FEV 1 (P = 0.05) and progression of radiographic emphysema (P = 0.05).Conclusions: CXCL13 is increased and is a prognostic biomarker in patients with IPF, and more so than in patients with COPD. This contrast indicates CXCL13 overexpressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B cells in IPF pathogenesis, and support considerations for trials of specific B-cell-targeted therapies in patients with this intractable disease.

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Section: Intrapulmonary Cxcl13mentioning

confidence: 99%

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Vuga¹,

Tedrow²,

Pandit³

et al. 2014

Am J Respir Crit Care Med

164

115

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“…Perhaps most significantly, neutrophilic inflammation is a common feature of diseases in which iBALTs are prevalent, including COPD, rheumatoid arthritis, asthma, idiopathic pulmonary fibrosis, tuberculosis, and hypersensitivity pneumonitis. Whether neutrophils contribute to the inception and maintenance of iBALT in these diseases will be an important area of research, especially if iBALT contribute to pathogenesis by providing a niche for autoreactive T and B cells, as has recently been described in experimental models of COPD and multiple sclerosis (49,50).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, it has been reported that specialized subsets of neutrophils exist, with the type 2 B cell-helper neutrophil population more able to produce APRIL, BAFF, IL-21, and IL-6 (33). Of note, APRIL promotes B cell class switching to IgA (52), which is increased in the presence of iBALT (40,49), and is known to contribute to protective immunity. In human MALT, APRIL-secreting neutrophils can promote the survival of plasma cells (53), whereas antagonism of APRIL in human synovial tissue reduces the size of germinal centers and decreases the follicular dendritic cell network (49).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, APRIL promotes B cell class switching to IgA (52), which is increased in the presence of iBALT (40,49), and is known to contribute to protective immunity. In human MALT, APRIL-secreting neutrophils can promote the survival of plasma cells (53), whereas antagonism of APRIL in human synovial tissue reduces the size of germinal centers and decreases the follicular dendritic cell network (49). In our study, APRIL expression was greater in neonatal than weanling mice, and reduced in neonates following neutrophil depletion.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

Foo

Zhang

Lalwani

et al. 2015

The Journal of Immunology

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Inducible BALT (iBALT) can amplify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.

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“…It has been shown that the B-cell chemokine CXCL13 is upregulated in COPD and pulmonary hypertension, as well as in smoking mice [5,11], presumably produced by stromal fibroblasts and attracting (in areas with abundant reticular fibres and collagen IV) mature B-cells and a subset of follicular T-helper cells which express high levels of its receptor CXCR5. Importantly, CXCL13 is probably induced following lymphotoxin-β receptor activation and early upregulation of the IL-1α pathway, as recently shown following influenza infection of mice [12].…”

mentioning

confidence: 99%

Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?

2017

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Role of CXCL13 in Cigarette Smoke–induced Lymphoid Follicle Formation and Chronic Obstructive Pulmonary Disease

Abstract: CXCL13 is produced within lymphoid follicles of patients with COPD and is crucial for the formation of TLOs. Neutralization of CXCL13 partially protects mice against CS-induced inflammation in bronchoalveolar lavage and alveolar wall destruction.

Cited by 87 publications

References 36 publications

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?

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