Bronchial Secretory Immunoglobulin A Deficiency Correlates With Airway Inflammation and Progression of Chronic Obstructive Pulmonary Disease

Polosukhin, Vasiliy V.; Cates, Justin M.; Lawson, William; Zaynagetdinov, Rinat; Milstone, Aaron P.; Massion, Pierre P.; Ocak, Sebahat; Ware, Lorraine B.; Lee, Jae Woo; Bowler, Russell P.; Кононов, А. В.; Randell, Scott H.; Blackwell, Timothy S.

doi:10.1164/rccm.201010-1629oc

Cited by 114 publications

(149 citation statements)

References 49 publications

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“…In 2001, Pilette and coworkers (13) reported that secretory component expression is reduced in airways of patients with COPD. Subsequently, we showed that pIgR expression is down-regulated in COPD and that airway surface SIgA deficiency is widespread in COPD and correlates with severity of airflow obstruction (14,15). Consistent with these observations, cultured airway epithelial cells from patients with COPD were reported to express lower levels of pIgR than airway epithelial cells from healthy control subjects (16).…”

supporting

confidence: 55%

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Polosukhin

Richmond

et al. 2017

Am J Respir Crit Care Med

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Rationale: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood.Objectives: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD).Methods: We studied 1,104 small airways (,2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-kB activation, neutrophil and macrophage infiltration, and airway wall thickness.Measurements and Main Results: Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgAdeficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-kB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall.Conclusions: Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation.

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supporting

confidence: 55%

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Polosukhin

Richmond

et al. 2017

Am J Respir Crit Care Med

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“…Diseased epithelium was unable to transport adequate amounts of secretory immunoglobulin A (SIgA), particularly in advanced disease associated with stratified squamous epithelial metaplasia. This study also found that proportion of patients with COPD harbouring latent viral agents was significantly higher than in control subjects and that 90% of virally infected airways were surface IgA deficient in COPD airways [Polosukhin et al 2011]. This highlights the possible role of mucosal pathology in contributing to the defective immunity to viruses, even in the context of an adequate systemic antibody response.…”

Section: Copd and The Immune Systemsupporting

confidence: 52%

Influenza vaccination for patients with chronic obstructive pulmonary disease: understanding immunogenicity, efficacy and effectiveness

Sanei

Wilkinson

2016

Ther Adv Respir Dis

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Influenza infection is an important cause of global mortality and morbidity with the greatest impact on older people and those with chronic disease. Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to influenza, with evidence for increased incidence and severity of infection. In this patient group influenza is associated with exacerbations and pneumonia which result in a significant healthcare burden and premature mortality. Influenza vaccination and in particular the use of the seasonal trivalent influenza vaccine (TIV) is recommended for patients with COPD. The evidence base for its effects in this population is, however, limited. Available data suggest that immunogenicity is variable in COPD but the underlying mechanisms are not completely understood. The contribution of age, disease severity, comorbidity and treatments to vaccine responses has only been investigated in a limited manner. Existing data suggest that key immune mechanisms governing T-and B-cell responses are adversely affected by these factors. The efficacy of TIV has been studied in a number of small clinical trials which form the basis of a Cochrane review. Here evidence for effect is conflicting depending on individual trial design and inclusions. Overall, TIV offers protection against influenza infection in the trial setting but further studies are required to stratify patients and enable prediction of inadequate responses. Larger-scale clinical studies have largely been observational and have often been conducted in consort with pneumonia vaccination. Overall the mortality benefit of TIV in COPD is suggested by a number studies but the impact on exacerbation prevention is less clear. Influenza vaccination currently plays an important role in disease prevention in COPD. However, we postulate that a more in-depth understanding of mechanisms of response in the context of a highly heterogeneous disease will lead to a more informed approach to vaccination and greater benefit for the individual patient.

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“…This observation is probably related to reduced pIgR-mediated transport of IgA across the epithelium, which has been reported in COPD [2,5], and may abort IgA trafficking across the respiratory mucosa and limit its role for so-called immune exclusion of inhaled pathogens. In addition, although in vitro exposure of the epithelium to cigarette smoke could upregulate IL-6 release and TACI expression, it counteracted the IgA-promoting effect of the epithelium on B cells.…”

Section: Both Maturation Of B-cells Into Cd38mentioning

confidence: 91%

“…We previously showed that patients with severe COPD display decreased bronchial pIgR expression [2], and this defect correlated with disease severity and neutrophilic inflammation [3,4]. It was also shown that this impaired transport of IgA could not only result in impaired mucosal immunity but also in the formation of immune complexes in subepithelial tissues [5].…”

Section: Introductionmentioning

confidence: 97%

Increased IgA production by B-cells in COPDvialung epithelial interleukin-6 and TACI pathways

et al. 2014

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Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD).We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured with in vitro-reconstituted airway epithelium.In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas. In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38 + plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI.These data show that in COPD, the bronchial epithelium imprints B-cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF-APRIL/TACI pathways, while cigarette smoke partly counteracts this IgApromoting effect. @ERSpublications COPD epithelium induces B-cell maturation of IgA-producing plasma cells via IL-6/IL-6R and BAFF-APRIL/TACI pathways

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Bronchial Secretory Immunoglobulin A Deficiency Correlates With Airway Inflammation and Progression of Chronic Obstructive Pulmonary Disease

Abstract: Our findings indicate that epithelial structural abnormalities lead to localized SIgA deficiency in COPD airways. Impaired mucosal immunity may contribute to persistent airway inflammation and progressive airway remodeling in COPD.

Cited by 114 publications

References 49 publications

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling

Influenza vaccination for patients with chronic obstructive pulmonary disease: understanding immunogenicity, efficacy and effectiveness

Increased IgA production by B-cells in COPDvialung epithelial interleukin-6 and TACI pathways

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