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 TGFbeta, 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. Consistent with their allergic tendencies, LDS patients had significantly elevated peripheral eosinophil counts and total IgE levels, higher plasma levels of the Th2 cytokines IL-5 and IL-13, as well as increased MCP-1, a chemokine important in recruiting inflammatory cells and promoting degranulation of mast cells and basophils. We also found significant elevations in IL-1Ralpha, which promotes differentiation of Th helper 17 (Th17) cells, GM-CSF which promotes bone marrow production of eosinophils and basophils, and a trend toward increased IL-17. This link between Th2 and Th17-mediated inflammation in LDS supports recent evidence that Th17 cells can upregulate Th2-mediated eosinophilic airway inflammation. We also found that Foxp3+ T regulatory cells (Tregs), which normally induce tolerance to self and innocuous antigens (including food proteins), secrete Th2 effector cytokines and promote rather than inhibit allergic inflammation in LDS patients. Remarkably, we found the same Treg defect in children with food allergy who did not have LDS. LDS mutations also conferred nave CD4+ lymphocytes with an inherent propensity to acquire Th2 effector functions in a cell-autonomous manner. We have recently demonstrated that knock-in mice carrying heterozygous LDS mutations (TgfbrIM318R/+ and TgfbrIIG372W/+) in the endogenous genomic locus also develop an allergic phenotype, including spontaneous development of eosinophilic inflammation in the lungs and esophagus, elevated IgE levels and Th2 responses, and a greater susceptibility to anaphylaxis. Taken together, these data clearly suggest that mutations in TGFbeta receptors predispose to an allergic phenotype.
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