Maha Zohra Ladjemi

Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to-mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction. Surgical lung tissue and primary broncho-epithelial cultures (in air–liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-β1. The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-β1 during ALI differentiation prevented vimentin induction and fibronectin release. In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF-β1-driven epithelial reprogramming. The COPD airway epithelium is programmed for mesenchymal transition via a TGF-β1-dependent process http://ow.ly/LhIQb

Anti-idiotypic antibodies as cancer vaccines: achievements and future improvements

Since the discovery of tumor-associated antigens (TAAs), researchers have tried to develop immune-based anti-cancer therapies. Thanks to their specificity, monoclonal antibodies (mAbs) offer the major advantage to induce fewer side effects than those caused by non-specific conventional treatments (e.g., chemotherapy, radiotherapy). Passive immunotherapy by means of mAbs or cytokines has proved efficacy in oncology and validated the use of immune-based agents as part of anti-cancer treatment options. The next step was to try to induce an active immune protection aiming to boost own’s host immune defense against TAAs. Cancer vaccines are thus developed to specifically induce active immune protection targeting only tumor cells while preserving normal tissues from a non-specific toxicity. But, as most of TAAs are self antigens, an immune tolerance against them exists representing a barrier to effective vaccination against these oncoproteins. One promising approach to break this immune tolerance consists in the use of anti-idiotypic (anti-Id) mAbs, so called Ab2, as antigen surrogates. This vaccination strategy allows also immunization against non-proteic antigens (such as carbohydrates). In some clinical studies, anti-Id cancer vaccines indeed induced efficient humoral and/or cellular immune responses associated with clinical benefit. This review article will focus on recent achievements of anti-Id mAbs use as cancer vaccines in solid tumors.

Chronic inflammatory airway diseases: the central role of the epithelium revisited

The respiratory epithelium plays a critical role for the maintenance of airway integrity and defense against inhaled particles. Physical barrier provided by apical junctions and mucociliary clearance clears inhaled pathogens, allergens or toxics, to prevent continuous stimulation of adaptive immune responses. The “chemical barrier”, consisting of several anti‐microbial factors such as lysozyme and lactoferrin, constitutes another protective mechanism of the mucosae against external aggressions before adaptive immune response starts. The reconstruction of damaged respiratory epithelium is crucial to restore this barrier. This review examines the role of the airway epithelium through recent advances in health and chronic inflammatory diseases in the lower conducting airways (in asthma and chronic obstructive pulmonary disease). Better understanding of normal and altered epithelial functions continuously provides new insights into the physiopathology of chronic airway diseases and should help to identify new epithelial‐targeted therapies.

Increased IgA production by B-cells in COPD via lung epithelial interleukin-6 and TACI pathways

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 IgA-promoting effect. COPD epithelium induces B-cell maturation of IgA-producing plasma cells via IL-6/IL-6R and BAFF-APRIL/TACI pathways http://ow.ly/D7bR3

Mite allergen-specific IgE is detectable in bronchial secretions of patients with nonatopic asthma and correlates with mucosal expression of periostin.

IgE is synthesized locally, in the bronchial mucosa, in both atopic and non-atopic asthma. The present study of bronchial secretions from asthma patients confirms that part of this IgE is specific to house dust mite (Dermatophagoides pteronyssinus) allergens, irrespective of atopy. In addition, it reveals that this IgE response correlates with periostin, but not to eosinophils, in sputum from these patients, probably in relation to their common IL-4/IL-13 triggering pathway.

Bronchial Epithelial IgA Secretion Is Impaired in Asthma. Role of IL-4/IL-13

Rationale: Asthma is associated with increased lung IgE production, but whether the secretory IgA system is affected in this disease remains unknown. Objectives: We explored mucosal IgA transport in human asthma and its potential regulation by T‐helper cell type 2 inflammation. Methods: Bronchial biopsies from asthma and control subjects were assayed for bronchial epithelial polymeric immunoglobulin receptor (pIgR) expression and correlated to T‐helper cell type 2 biomarkers. Bronchial epithelium reconstituted in vitro from these subjects, on culture in air‐liquid interface, was assayed for pIgR expression and regulation by IL‐4/IL‐13. Measurements and Main Results: Downregulation of pIgR protein was observed in the bronchial epithelium from patients with asthma (P = 0.0002 vs. control subjects). This epithelial defect was not observed ex vivo in the cultured epithelium from patients with asthma. Exogenous IL‐13 and IL‐4 could inhibit pIgR expression and IgA transcytosis. Mechanistic experiments showed that autocrine transforming growth factor‐&bgr; mediates the IL‐4/IL‐13 effect on the pIgR, with a partial contribution of upregulated transforming growth factor‐&agr;/epidermal growth factor receptor. Conclusions: This study shows impaired bronchial epithelial pIgR expression in asthma, presumably affecting secretory IgA‐mediated frontline defense as a result of type 2 immune activation of the transforming growth factor pathway.