Background Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. Objective We sought to test the ...immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. Methods Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis–like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and TH 2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid. Results Sensitization to food allergens through an atopic dermatitis–like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific TH 2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease. Conclusion Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.
Background In steady state, hemopoietic progenitors constantly egress from the bone marrow (BM) into the blood and circulate through the peripheral tissues. In allergic diseases, the BM releases ...increased numbers of CD34+ progenitor cells that migrate to the site of allergic inflammation, where they differentiate into tissue-dwelling and classic effector cells of allergy, such as mast cells, eosinophils, and basophils. Objective To examine whether peripheral blood CD34+ cells in addition to being progenitors may also directly function as inflammatory effector cells. Methods Highly purified neonatal or adult blood CD34+ cells were examined for the expression of thymic stromal lymphopoietin (TSLP) and IL-33 receptors and for their response to these cytokines as well as to supernatants of primary small airway epithelial cells and nasal explants from rhinosinusitis and control subjects. Sputum of patients with asthma was examined before and after allergen inhalation for the presence of IL-5 and IL-13–containing CD34+ cells. Results Circulating CD34+ cells expressed receptors for TSLP and IL-33 and responded to these cytokines by rapidly releasing high levels of proinflammatory TH 2-like cytokines and chemokines. These cells were activated in a TSLP-dependent manner by the supernatant fluids from activated primary human small airway epithelial cells and from nasal explants of patients with chronic rhinosinusitis. Moreover, activated CD34+ cells containing IL-5 and IL-13 could be detected in the sputum of individuals with allergic asthma, with numbers increasing in response to specific allergen inhalation challenge. Conclusion Blood CD34+ cells, in addition to being progenitors, may act as proinflammatory effector cells by themselves and directly contribute to the allergic inflammation.
Because the in vitro response of MCs to TSLP requires the presence of IL-1, we next show that the carryover of IL-1 in the BSM supernatant has a permissive role on the MC response to TSLP released by ...BSM cells (see Fig E2 in this article's Online Repository at www.jacionline.org).
TSLPR mRNA has been detected in tissues from heart, skeletal muscle, kidney, and liver on many immune cell types, including dendritic cells, T cells, B cells, MCs, and hemopoietic CD34+ progenitors.1 ...Although the biology of TSLP is well documented, little is known about the regulation of TSLPR, except TSLPR regulation on dendritic cells via Fc receptor ligation.4 Here we have analyzed the expression profile and the regulation of the TSLPR on MCs and their precursor CD34+ cells.
Background Airway epithelial cells are important regulators of innate and adaptive immunity. Although mast cells are known to play a central role in manifestations of allergic inflammation and are ...found in the epithelium in patients with TH 2-related diseases, their role is incompletely understood. Objectives The objective of this study was to investigate the role of airway epithelial cells in the production of TH 2 cytokines in mast cells. Methods Normal human bronchial epithelial (NHBE) cells were stimulated with TNF, IL-4, IFN-γ, IL-17A, and double-stranded RNA (dsRNA) alone or in combination. Human mast cells were stimulated with epithelial cell–derived supernatants or cocultured with NHBE cells. TH 2 cytokine responses were blocked with neutralizing antibodies. Results Supernatants from IL-4– and dsRNA-stimulated NHBE cells significantly enhanced TH 2 cytokine production from mast cells. The combination of IL-4 and dsRNA itself or supernatants from NHBE cells stimulated with other cytokines did not activate mast cells, suggesting that mast cell responses were induced by epithelial cell factors that were only induced by IL-4 and dsRNA. Epithelial supernatant-dependent TH 2 cytokine production in mast cells was suppressed by anti–IL-1 and anti– thymic stromal lymphopoietin (TSLP) and was enhanced by anti–IL-1 receptor antagonist. Similar results were observed in coculture experiments. Finally, we found dsRNA-dependent production of IL-1, TSLP, and IL-1 receptor antagonist in NHBE cells was regulated by TH cytokines, and their ratio in NHBE cells correlated with TH 2 cytokine production in mast cells. Conclusions Pathogens producing dsRNA, such as respiratory viral infections, might amplify local TH 2 inflammation in asthmatic patients through the production of TSLP and IL-1 by epithelial cells and subsequent activation of TH 2 cytokine production by mast cells in the airways.
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