Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells

Compelling evidence suggests that the epithelial cell–derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell–mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell–mediated, TSLP-dependent activation of MCs may play a central role in “intrinsic” forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases

No evidence for IgE receptor FcεRI expression on bronchial epithelial cells of asthmatic patients

Immunoglobulin E (IgE) plays an important role in the pathogenesis of asthma and anti-IgE therapy was approved for treating patients with severe persistent allergic asthma. The exact target sites of anti-IgE therapy are not well characterized; however, it has been proposed that the therapeutic effects of anti-IgE come from its intervention in the airway remodeling process. To gain insights on how anti-IgE therapy improves asthma symptoms, we aimed to validate the expression of FcεRI on airway epithelial cells and demonstrate its role in airway remodeling. The expression of FcεRI was measured (1) in situ in bronchial biopsy tissues of asthmatic and control subjects using immunohistochemistry and (2) in vitro in primary bronchial epithelial cells obtained from asthmatic subjects, at baseline and after treatment with human IgE, using qPCR and flow cytometry. FcεRI expression in situ was detected only in a very small number of cells in the epithelium of bronchial biopsies of asthmatic and control subjects. In vitro measurement revealed no expression of the receptor both at baseline and after stimulation with IgE. The release of transforming growth factor—beta (TGF)-β and thymic stromal lymphopoietin (TSLP) were examined by ELISA in bronchial epithelial cells after crosslinking of IgE. No significant differences in TSLP and TGF-β protein levels were detected between stimulated and unstimulated cells. Hence, our data conclusively indicate that bronchial epithelial cells have negligible expression of functional high affinity receptor for IgE. Taken together, anti-IgE therapy is very likely to exert its therapeutic effects via other structural cell types

NOD2 Agonism Counter-Regulates Human Type 2 T Cell Functions in Peripheral Blood Mononuclear Cell Cultures: Implications for Atopic Dermatitis

Atopic dermatitis (AD) is known as a skin disease; however, T cell immunopathology found in blood is associated with its severity. Skin Staphylococcus aureus (S. aureus) and associated host–pathogen dynamics are important to chronic T helper 2 (Th2)-dominated inflammation in AD, yet they remain poorly understood. This study sought to investigate the effects of S. aureus-derived molecules and skin alarmins on human peripheral blood mononuclear cells, specifically testing Th2-type cells, cytokines, and chemokines known to be associated with AD. We first show that six significantly elevated Th2-related chemokine biomarkers distinguish blood from adult AD patients compared to healthy controls ex vivo; in addition, TARC/CCL17, LDH, and PDGF-AA/AB correlated significantly with disease severity. We then demonstrate that these robust AD-associated biomarkers, as well as associated type 2 T cell functions, are readily reproduced from healthy blood mononuclear cells exposed to the alarmin TSLP and the S. aureus superantigen SEB in a human in vitro model, including IL-13, IL-5, and TARC secretion as well as OX-40-expressing activated memory T cells. We further show that the agonism of nucleotide-binding oligomerization domain-containing protein (NOD)2 inhibits this IL-13 secretion and memory Th2 and Tc2 cell functional activation while inducing significantly increased pSTAT3 and IL-6, both critical for Th17 cell responses. These findings identify NOD2 as a potential regulator of type 2 immune responses in humans and highlight its role as an endogenous inhibitor of pathogenic IL-13 that may open avenues for its therapeutic targeting in AD