The prevalence of food allergy and other allergic diseases is rising globally. 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 have demonstrated that patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding the receptor for TGFb, 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. Mice harboring a knock-in mutation (TgfbrIM318R/+) known to cause severe disease in humans also develop an allergic phenotype, including the spontaneous development of EoE with 100% penetrance. However, how impaired TGFb signaling leads to tissue-specific allergic inflammation is not clear. In FY19, we examined the role of hematopoietic and nonhematopoietic compartments in the development of EoE by generating bone marrow chimeric mice. These experiments demonstrated that nonhematopoietic cells are both necessary and sufficient to drive the development of EoE in LDS mice. Most mutations that cause LDS are in the kinase domain of the receptor and are therefore expected to result in a loss-of-function. However, expression levels of pSmad2/3, downstream signaling molecules in the TGFb pathway, are paradoxically increased in vivo in certain tissues. In collaboration with Hal Dietzs group at John Hopkins, we found that the effects of LDS mutations can be different in different cell types, depending on where the cells originate. While TGFb signaling is preserved and even increased in certain cells in the vasculature, we found that the activity of this pathway is impaired in lymphocytes, suggesting that reduced TGFb signaling likely contributes to the immune phenotypes seen in LDS.
| Carter, Cristina A; Frischmeyer-Guerrerio, Pamela A (2018) The Genetics of Food Allergy. Curr Allergy Asthma Rep 18:2 |
| Lyons, J J; Liu, Y; Ma, C A et al. (2017) Correction: ERBIN deficiency links STAT3 and TGF-? pathway defects with atopy in humans. J Exp Med 214:1201 |
| Lyons, J J; Liu, Y; Ma, C A et al. (2017) ERBIN deficiency links STAT3 and TGF-? pathway defects with atopy in humans. J Exp Med 214:669-680 |
| Guerrerio, Anthony L; Frischmeyer-Guerrerio, Pamela A; Huang, Chengrui et al. (2016) Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGF?. Inflamm Bowel Dis 22:2058-2062 |
