FcαRI-mediated inhibition of IL-12 production and priming by IFN-γ of human monocytes and dendritic cells

We showed that IgA induces IL-10 in monocytes and dendritic cells. Because reciprocal inhibition exists between IL-10 and IL-12, we explored whether IgA could regulate this other immunoregulatory cytokine. In human monocytes and monocyte-derived dendritic cells preincubated with IFN-γ before stimulation by LPS, suppression of p40 and IL-12p70 production was observed upon IgA treatment during IFN-γ priming. Washout experiments and inhibition of IFN-γ-induced CXCL10 (IP-10) and FcgRI (CD64) indicated that inhibition by IgA occurred at both the LPS and IFN-γ levels. Inhibition was not affected by blockade of IL-10 or MAPK but involved FcaRI/CD89-mediated suppression of STAT1 phosphorylation. These data indicate that FcaRI ligation on human monocytes and dendritic cells inhibits IL-12 expression and type 1 activation by interfering with STAT1 activation. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved

A novel IgA/Delta-like 4/Notch axis induces immunosuppressive activity in human dendritic cells.

We aimed to study whether IgA or IgG could modulate dendritic cells through the Notch pathway. Blood myeloid DC were isolated from controls or patients with allergic rhinitis (sensitized to house dust mite, Dermatophagoides pteronyssinus, Der p) and assayed for Notch ligand, Delta-Like 4 (DLL4) expression and co-cultured with allogeneic CD4 + T cells. An upregulation of DLL4 was observed in IgA-treated, but not IgG-treated DCs. In co-culture of DCs and T cells, pulsing DCs with IgA downregulated IL-13, IL-5 and IFN-γ responses, but upregulated IL-10. The suppressive effect of IgA was mediated by DLL4 not by IL-10. In contrast, IL-10 was required for the inhibition by IgG-DCs. Altogether, IgA imprints myeloid DCs with suppressive effects on CD4 + T cell responses to Th2 and Th1 antigens through activation of DLL4/Notch pathway, whereas IgG does not induce DLL4 expression, its inhibitory effects mainly relying on IL-10

Respiratory epithelium from COPD patients: In vitro memory and plasticity.

Introduction: La bronchopneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique majeure qui représentera probablement la troisième cause de mortalité en 2030. La muqueuse respiratoire normale est tapissée d’un épithélium pseudo-stratifié muco-ciliaire qui constitue une barrière de première ligne face aux agents nocifs inhalés, notamment grâce aux jonctions serrées et à la sécrétion d’IgA et de peptides anti-microbiens. Il reste inconnu si les anomalies épithéliales observées dans la BPCO sont dues à une programmation intrinsèquement, (épi)génétiquement, anormale ou si elles sont la conséquence de l’inflammation locale. Méthodes : Le tissu broncho-pulmonaire d’une large série de patients BPCO et contrôles (opérés pour tumeur) et l’épithélium bronchique (proximal) reconstitué in vitro en interface air-liquide (pendant 2 à 5 semaines) à partir des mêmes patients ont été évalués par immunomarquage (et RT-qPCR) pour l’expression du récepteur aux immunoglobulines polymériques (pIgR, transportant l’IgA) et les marqueurs de transition épithélio-mésenchymateuse (EMT) et de typage cellulaire. Résultats : L’expression du pIgR était diminuée dans l’épithélium bronchique des patients BPCO par comparaison aux patients contrôles (fumeurs ou non-fumeurs), de manière corrélée à la sévérité de l’obstruction bronchique. L’expression du pIgR était également diminuée dans l’épithélium cultivé in vitro (2 semaines) de patients BPCO (1). Dans l’épithélium bronchique BPCO, l’expression des marqueurs épithéliaux (zonula occludens-1 et E-cadhérine) était diminuée, alors que l’expression de vimentine (marqueur mésenchymateux) était augmentée, tant in situ (dans le tissu bronchique) que dans l’épithélium cultivé in vitro (2). En parallèle, cet épithélium BPCO montrait une augmentation des cellules à mucus (MUC5AC) et une diminution des cellules ciliées (β-tubuline IV), sans changement des cellules basales (p63) (non publié). Enfin, le phénotype épithélial anormal observé in vitro à 2 semaines de culture apparaissait partiellement réversible, avec notamment perte de vimentine, après culture prolongée (3-5 semaines) (2). Discussion : le modèle de culture épithéliale en interface air-liquide permet de récapituler certaines anomalies de l’épithélium bronchique BPCO, indiquant une mémoire de sa programmation, mais montre également une réversibilité partielle du phénotype suggérant une plasticité cellulaire dont les déterminants restent à explorer

Downregulation of pIgR expression in patients with chronic rhinosinusitis

IgA represents a frontline defense factor in the airways, which is transported across the surface epithelium after binding to the polymeric immunoglobulin receptor (pIgR). We observed that pIgR immunostaining is reduced in patients with severe COPD (Pilette, 2001) and correlated to reduced lung function and neutrophilic infiltration. Whether mechanisms of IgA secretion are affected in chronic rhinosinusitis (CRS) remains poorly known

Features of mesenchymal transition in the airway epithelium from chronic rhinosinusitis

Background: Chronic rhinosinusitis (CRS) defines a group of disorders characterized by persistent inflammation of the sinonasal tract. Epithelial changes and structural remodelling are present, but whether epithelial differentiation is altered remains uncertain. Methods: To evaluate the differentiation state of the sinonasal epithelium in CRS, sinonasal biopsies from patients with CRS with (CRSwNP) or without polyps (CRSsNP), or with allergic rhinitis (AR), as compared to controls, were processed by immunohistochemistry and RT-qPCR for terminal differentiation (E-cadherin, high molecular weight cytokeratins (Hmw CK) and CK5, vimentin) and lineage differentiation (ß-tubulin IV+ ciliated cells, MUC5AC+ goblet cells, p63+ basal cells). Findings were correlated to subepithelial fibrosis and clinical CT score. Results: Expression of E-cadherin was decreased at protein and mRNA levels in CRSwNP and CRSsNP, as compared to controls. Staining for Hmw CKs was also reduced in CRSwNP and CRSsNP, and CK5 mRNA was decreased in CRSwNP. These features were not due to changes in lineage specification, but associated with increases in vimentin-expressing epithelial cells. In addition, vimentin expression correlated with the basement membrane thickening and with CT score, as well as with tissue eosinophils. Conclusion: Features of epithelial de-differentiation towards a mesenchymal phenotype are observed in CRSwNP and CRsNP, and correlate with airway fibrosis and inflammation

Immune Defence Mechanisms: Comparing Upper and Lower Airways in Chronic Airway Diseases

Several epidemiological, pathophysiologic and clinical data demonstrate the interrelationship between upper and lower airways, and common features between inflammatory pathways and disorders of the nasal and bronchial mucosa have been emphasized both in the clinic (ARIA guidelines [1]) and in basic science, and reflected by numerous reviews on this topic. In contrast, detailed comparative analysis of basic defence mechanisms in upper versus lower airways and its clinical relevance is lacking. It is becoming increasingly clear that airway epithelium plays a key role in driving key initiating steps of immune defence (either protective or deleterious) against inhaled antigens and particles. Epithelial cells respond to changes in the external environment by secreting a large array of antimicrobial host defence molecules, cytokines and chemokines following exposure to and activation by pathogen molecular patterns, and link in concert with dendritic cells innate to antigen-specific adaptive immunity. However, the type of epithelial response to `pathogens' and danger signals may differ between upper and lower airways, as well as according to genetic background. This review provides an updated, extensive and comparative review of immune defence mechanisms of the respiratory tract, in upper versus lower airways, including most relevant changes observed during chronic airway diseases and how these may translate into different clinical features

Polymeric immunoglobulin receptor expression is downregulated in severe COPD: role of TGF-1

POLYMERIC IMMUNOGLOBULIN RECEPTOR EXPRESSION IS DOWNREGULATED IN SEVERE COPD: ROLE OF TGF-1 Gohy S, Detry B, Bouzin C, Weynand B, Lecocq M, Sibille Y and Pilette C. Objectives The generation of protective secretory IgA relies on the epithelial polymeric immunoglobulin receptor (pIgR). pIgR expression is reduced in COPD, but correlation to disease severity and underlying mechanisms remain unknown. Materials and methods Surgical lung tissue and primary bronchial epithelium (cultured in air-liquid interface, ALI) obtained from a large series of patients (n=55) undergoing lung surgery for a solitary tumor were studied for pIgR expression (by immunochemistry, RT-qPCR and Elisa) and for IgA transcytosis. Statistics included non-parametric Mann-Whitney U test, following Kruskal-Wallis test for multiple comparisons, and Spearman’s correlation test. Results pIgR immunostaining was decreased in the bronchial epithelium from severe COPD (p=0.04, 1 to 15% of positive area) compared to controls (5 to 26% of positive area), while pIgR transcription was upregulated in smokers and mild-to-moderate COPD compared to controls (p=0.008 and p<0.0001 respectively). In ALI conditions, the release of free secretory component (SC) was strongly induced ( 50 fold increase, as compared to submerged cultures) and pIgR expression increased progressively from 1 to 5 weeks of culture. pIgR immunostaining was decreased in ALI-HBEC from moderate COPD patients (p=0.04, 10 to 25 of positive area) compared to controls (12 to 37% of positive area). In addition, the IgA-transcytosis capacity was decreased in COPD ALI-HBEC as compared to control smokers and mild COPD. COPD cultures released more TGF-1, reflecting increased epithelial immunostaining in COPD lung tissue. Finally, exogenous TGF-1 was able to dose-dependently inhibit pIgR transcription and IgA transcytosis, in parallel to induction of EMT. Conclusion pIgR downregulation in COPD is correlated to disease severity, and the bronchial epithelium reconstituted in vitro from these patients retains its aberrant imprinting for pIgR expression. This study also links pIgR downregulation to TGF--driven (re)programming of the bronchial epithelium, which results in impaired secretory IgA immunity in patients with severe COPD