The Role of Transforming Growth Factor Beta (TGFbeta) in Promoting Allergic Inflammation

National Institute Of Allergy And Infectious Diseases

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Abstract

Food allergy and other allergic conditions have become increasingly common both in the United States and in other developed countries around the world. While both genetic and environmental factors likely contribute to the development of food allergy and other allergic conditions, the complex interaction between these variables has frustrated efforts to elucidate pathogenesis and develop mechanism-targeted therapies. We recently demonstrated that patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding the receptor for TGF, TGFBRI and TGFBR2, are at significantly increased risk of developing nearly all forms of allergic disease, including food allergy, asthma, eosinophilic esophagitis (EoE), eczema and allergic rhinitis. We have now demonstrated that knock-in mice carrying heterozygous LDS mutations (TgfbrIM318R/+ and TgfbrIIG372W/+) in the endogenous genomic locus also spontaneously develop an allergic phenotype. Beginning at about 6 weeks of age, total serum IgE levels are significantly higher in LDS mice compared to their wild type (WT) littermates. These mice also spontaneously develop esophageal dilation and food impaction with a pronounced inflammatory infiltrate comprised of eosinophils, T cells and mast cells. This inflammatory signature is reminiscent of that seen in esophageal biopsies of patients with EoE. By generating bone marrow chimeric mice, we have preliminary evidence that altered TGF signaling in nonhematopoietic cells alone may be sufficient to induce the development of EoE. Transfer of LDS bone marrow into irradiated WT animals did not induce EoE, while LDS mice harboring WT bone marrow continued to develop florid EoE. Furthermore, the development of EoE is not T-cell dependent, as LDS mice continue to develop eosinophilic inflammation and food impaction in the esophagus on a Rag-deficient background. Moreover, eosinophilic inflammation in LDS mice appears to be limited to the esophagus. No significant increase in the number or percentage of eosinophils was observed in the bone marrow, spleen, lymph nodes, blood or the small and large intestine of these animals. Taken together, these data clearly suggest that mutations in TGF receptors are sufficient to predispose to an allergic phenotype including EoE, and that nonhematopoietic cells may play a central role in this process