Biomedical subjects

Elizabeth Forbes

Publications and source records attributed to Elizabeth Forbes.

5 recordsLinked to original sources

PubMed2006

ICAM-1-dependent pathways regulate colonic eosinophilic inflammation.

Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal (EGID) diseases. Central to eosinophil migration into the gastrointestinal tract are the integrin-mediated interactions with adhesion molecules. Although the mechanisms regulating eosinophil homing into the small intestine have begun to be elucidated, the adhesion pathways responsible for eosinophil trafficking into the large intestine are unknown. We investigated the role of adhesion pathways in eosinophil recruitment into the large intestine during homeostasis and disease. First, using a hapten-induced colonic injury model, we demonstrate that in contrast to the small intestine, eosinophil recruitment into the colon is regulated by a beta7 -integrin addressin cell adhesion molecule-1-independent pathway. Characterization of integrin expression on colonic eosinophils by flow cytometry analysis revealed that colonic CC chemokine receptor 3+ eosinophils express the intercellular adhesion molecule-1 (ICAM-1) counter-receptor integrins alphaL, alphaM, and beta2. Using ICAM-1-deficient mice and anti-ICAM-1 neutralizing antibodies, we show that hapten-induced colonic eosinophilic inflammation is critically dependent on ICAM-1. These studies demonstrate that beta2 -integrin/ICAM-1-dependent pathways are integral to eosinophil recruitment into the colon during GI inflammation associated with colonic injury.

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PubMed2006

Mechanistic analysis of experimental food allergen-induced cutaneous reactions.

Individuals with food allergy often present with uritcaria and atopic dermatitis. Indeed, susceptibility to food allergy may predispose to the development of these cutaneous allergic disorders. Recently, we developed a model of food allergy, whereby oral consumption of food [pea Pisum sativum L.; expressing alpha-amylase inhibitor-1 (alphaAI) from the common bean Phaseolus vulgaris L. cv Tendergreen (pea-alphaAI)] promotes a T helper cell type 2 (Th2) inflammatory response and predisposes to cutaneous allergic reactions following subsequent food allergen (alphaAI) exposure. To delineate the kinetics of food allergen-induced cutaneous reactions and examine the inflammatory mechanisms involved in this allergic reaction, we used interleukin (IL)-13-, IL-4 receptor alpha-, and eotaxin-1-deficient mice and performed serum transfer and CD4+ T cell depletion studies. We demonstrate that consumption of pea-alphaAI promotes an alphaAI-specific immunoglobulin G1 (IgG1) and IgE antibody response. Furthermore, we show that subsequent food allergen (alphaAI) challenge in the skin induced an early (3 h)- and late-phase (24 h) cutaneous allergic reaction. The early-phase response was associated with mast cell degranulation and the presence of Ig, whereas the late-phase response was characterized by a lymphoid and eosinophilic infiltrate, which was critically regulated by CD4+ T cells, IL-13, and eotaxin-1. Collectively, these studies demonstrate that food allergy can predispose to cutaneous inflammatory reactions, and these processes are critically regulated by Th2 immune factors.

Allergens↗

PubMed2004

Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase.

The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.

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PubMed2004

Chemokines in eosinophil-associated gastrointestinal disorders.

Eosinophil-associated gastrointestinal disorders (EGDs) are characterized by a pronounced cellular inflammation. Recent clinical and experimental investigations have implicated a family of molecules known as chemokines in the regulation of leukocyte recruitment in these diseases. The underlying cellular and molecular mechanisms involved in chemokine-mediated cellular infiltration are largely unknown. In this review, we describe the role of CD4+ T cells and eosinophils in the clinical manifestations of EGDs and discuss the current understanding of the role of chemokines in the recruitment of these cells in the expression of diseases.

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PubMed2004

T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice.

BACKGROUND & AIMS: Eosinophil-associated gastrointestinal diseases are frequently associated with extraintestinal features, including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness in eosinophil-associated gastrointestinal diseases are unknown. To elucidate the mechanistic link between eosinophil-associated gastrointestinal diseases and bronchial hyperresponsiveness, we used murine models of eosinophil-associated gastrointestinal diseases and eotaxin-1/transgene-induced eosinophil-associated gastrointestinal diseases. METHODS: Mice were sensitized and orally challenged with ovalbumin-coated encapsulated particles to induce eosinophil-associated gastrointestinal disease, and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness. RESULTS: The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness. The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness. Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13. It is interesting to note that transgenic expression of eotaxin was linked with enhanced T helper 2 lymphocyte/cytokine synthesis (interleukin-4, -5, and -13) and the production of mucosal immunoglobulin G1 in the gastrointestinal lumen. We also showed that eotaxin treatment of CD4(+) T cells enhanced interleukin-13 production in vitro. CONCLUSIONS: These studies suggest that increased expression of eotaxin in the gastrointestinal compartment can lead to increased CD4(+) T cell-derived T helper 2 lymphocyte-cytokine production that drives aberrant immunophysiological responses in distant noninflamed mucosal tissue (the lung). These results provide a possible explanation for the altered lung function seen in some patients with inflammatory gastrointestinal disorders.

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