Increased IgA Expression in Lung Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease

Ladjemi, Maha Zohra; Martin, Clémence; Lecocq, Marylène; Detry, Bruno; Nana, Frank Aboubakar; Moulin, Charlotte; Weynand, Birgit; Fregimilicka, Chantal; Bouzin, Caroline; Thurion, Pascal; Carlier, François; Serré, Jef; Gayan‐Ramirez, Ghislaine; Delos, Monique; Ocak, Sebahat; Burgel, P.-R.; Pilette, Charles

doi:10.1164/rccm.201802-0352oc

Cited by 49 publications

(48 citation statements)

References 41 publications

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“…smokers, differences in smoking history may explain this observed discrepancy, which requires further studies. A more recent study showed that some of these follicles stain positively for interleukin (IL21), a cytokine that promotes B cell proliferation in the germinal centers of lymphoid follicles [21], which are almost exclusively expressed in CD3+ T cells in patients with moderate and severe COPD compared to healthy controls [22].…”

Section: Discussionmentioning

confidence: 99%

Sex differences in lymphoid follicles in COPD airways

et al. 2020

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Background: Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. Tertiary lymphoid follicles are often found in the lungs of patients with severe COPD but sex-related differences have not been previously investigated. We determined the impact of female sex hormones on chronic cigarette smoke-induced expression of lymphoid aggregates in mice with COPD-like pathologies. Methods: Lymphoid aggregate counts, total aggregate cross-sectional area and foamy macrophage counts were determined morphometrically in male, female, and ovariectomized mice exposed to air or cigarette smoke for 6 months. B-cell activating factor (BAFF) protein expression and markers of oxidative stress were evaluated in mouse lung tissues by immunofluorescence staining and gene expression analyses. Quantitative histology was performed on lung tissue sections of human COPD lungs to evaluate follicle formation. Results: Lymphoid follicle and foamy macrophage counts as well as the total follicle cross-sectional area were differentially increased in lung tissues of female mice compared to male mice, and these differences were abolished by ovariectomy. These lymphoid aggregates were positive for CD45, CD20, CD21 and BAFF expression. Differential increases in Mmp12 and Cxcl2 gene expression correlated with an increase in foamy macrophages in parenchymal tissues of female but not male mice after smoke exposure. Parenchymal tissues from female mice failed to induce antioxidant-related genes in response to smoke exposure, and this effect was restored by ovariectomy. 3nitrotyrosine, a stable marker of oxidative stress, positively correlated with Mmp12 and Cxcl2 gene expression. Hydrogen peroxide induced BAFF protein in mouse macrophage cell line. In human lung tissues, female smokers with severe COPD demonstrated increased numbers of lymphoid follicles compared with males. Conclusions: Chronic smoke exposure increases the risk of lymphoid aggregate formation in female mice compared with male mice, which is mediated female sex hormones and BAFF expression in an oxidative environment.

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Section: Discussionmentioning

confidence: 99%

Sex differences in lymphoid follicles in COPD airways

et al. 2020

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“…It is only fitting that Ladjemi and colleagues (pp. 592–602 ) contribute another in this issue of the Journal ( 16 ). Using lung tissues removed for clinical indications (subjects with COPD, n = 37; control subjects, n = 34) plus murine models of chronic Pseudomonas aeruginosa and of smoking, they assessed Ig class expression by B cells in LLFs in COPD and during chronic lung infection.…”

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confidence: 92%

“…There are multiple novel and interesting results. The first is that IgA + B cell numbers were increased in LLFs in distal lung parenchyma in subjects with COPD relative to smokers without COPD, and correlated with spirometrically defined severity ( 16 ). That was not true in proximal airways, which do not depend on sIgA transcytosis, extending previous studies ( 3 , 9 ).…”

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confidence: 99%

B Cells Caught in the Act: Class Switching to IgA in Lung Lymphoid Follicles in Chronic Obstructive Pulmonary Disease

Curtis

2019

Am J Respir Crit Care Med

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“…9,10,12 Loss of SIgA in the airways of COPD patients results from decreased pIgR expression in the airway epithelium, which prevents SIgA transcytosis despite increased numbers of IgA-producing plasma cells. [10][11][12][13] Mice lacking pIgR (pIgR −/− mice) are SIgA deficient and develop persistent inflammation in the lungs, along with progressive emphysema and small airway remodeling that resemble the pathology of patients with COPD. 14,15 Although existing data suggest that loss of the SIgA immunobarrier plays a causative role in COPD, it remains unknown whether SIgA deficiency contributes to adaptive immune activation, which is common in lungs of patients with advanced COPD.…”

Section: Introductionmentioning

confidence: 99%

Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD

et al. 2021

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Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4+ or CD8+ T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4+ and CD8+ effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.

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Increased IgA Expression in Lung Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease

Cited by 49 publications

References 41 publications

Sex differences in lymphoid follicles in COPD airways

Sex differences in lymphoid follicles in COPD airways

B Cells Caught in the Act: Class Switching to IgA in Lung Lymphoid Follicles in Chronic Obstructive Pulmonary Disease

Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD

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