A Mendelian Presentation of Multiple Th2-Mediated Allergic Diseases

RationaleTransforming growth factor-beta (TGFb) is a cytokine that regulates T regulatory cell (Treg) maturation and induction of tolerance to mucosal antigens. Mutations in the TGFb receptor cause Loeys-Dietz syndrome (LDS), an autosomal dominant aortic aneurysm syndrome. In this study, we recognized and mechanistically characterized a strong predisposition to develop TH2 inflammation and allergic disease in LDS.MethodsThe occurrence of allergic phenotypes in 58 patients with LDS was determined using a detailed questionnaire, clinical examination, serologic testing, tissue biopsy and/or review of medical records. Peripheral eosinophil counts, plasma cytokine levels, levels of phosphorylated Smad2 (pSmad2) in thymic tissue and peripheral lymphocytes, naïve T cell skewing patterns, and Treg frequency and function were evaluated.ResultsAsthma was diagnosed in 45%, allergic rhinitis in 48%, eczema in 38%, food allergy in 31%, and eosinophilic gastrointestinal disease (EGID) in 10%. LDS patients had elevated IgE levels, eosinophil counts, and TH2 cytokines (IL-5, IL-13) in their serum. LDS patients demonstrated high levels of CD4+ T cells that expressed both Foxp3 and IL-13, but retained the ability to suppress effector T cell proliferation. Naive CD4+ T cells from LDS patients differentiated into TH2-cytokine producing cells in a TGFb-dependent manner in vitro. Levels of pSmad2 were elevated in thymi and peripheral CD4+lymphocytes from LDS patients.ConclusionsLDS is the first Mendelian disorder to be associated with the development of food allergy, EGID, and other allergic disease. These data will inform efforts to elucidate pathogenesis in nonsyndromic presentations of allergic disease and potentially reveal novel therapeutic strategies. RationaleTransforming growth factor-beta (TGFb) is a cytokine that regulates T regulatory cell (Treg) maturation and induction of tolerance to mucosal antigens. Mutations in the TGFb receptor cause Loeys-Dietz syndrome (LDS), an autosomal dominant aortic aneurysm syndrome. In this study, we recognized and mechanistically characterized a strong predisposition to develop TH2 inflammation and allergic disease in LDS. Transforming growth factor-beta (TGFb) is a cytokine that regulates T regulatory cell (Treg) maturation and induction of tolerance to mucosal antigens. Mutations in the TGFb receptor cause Loeys-Dietz syndrome (LDS), an autosomal dominant aortic aneurysm syndrome. In this study, we recognized and mechanistically characterized a strong predisposition to develop TH2 inflammation and allergic disease in LDS. MethodsThe occurrence of allergic phenotypes in 58 patients with LDS was determined using a detailed questionnaire, clinical examination, serologic testing, tissue biopsy and/or review of medical records. Peripheral eosinophil counts, plasma cytokine levels, levels of phosphorylated Smad2 (pSmad2) in thymic tissue and peripheral lymphocytes, naïve T cell skewing patterns, and Treg frequency and function were evaluated. The occurrence of allergic phenotypes in 58 patients with LDS was determined using a detailed questionnaire, clinical examination, serologic testing, tissue biopsy and/or review of medical records. Peripheral eosinophil counts, plasma cytokine levels, levels of phosphorylated Smad2 (pSmad2) in thymic tissue and peripheral lymphocytes, naïve T cell skewing patterns, and Treg frequency and function were evaluated. ResultsAsthma was diagnosed in 45%, allergic rhinitis in 48%, eczema in 38%, food allergy in 31%, and eosinophilic gastrointestinal disease (EGID) in 10%. LDS patients had elevated IgE levels, eosinophil counts, and TH2 cytokines (IL-5, IL-13) in their serum. LDS patients demonstrated high levels of CD4+ T cells that expressed both Foxp3 and IL-13, but retained the ability to suppress effector T cell proliferation. Naive CD4+ T cells from LDS patients differentiated into TH2-cytokine producing cells in a TGFb-dependent manner in vitro. Levels of pSmad2 were elevated in thymi and peripheral CD4+lymphocytes from LDS patients. Asthma was diagnosed in 45%, allergic rhinitis in 48%, eczema in 38%, food allergy in 31%, and eosinophilic gastrointestinal disease (EGID) in 10%. LDS patients had elevated IgE levels, eosinophil counts, and TH2 cytokines (IL-5, IL-13) in their serum. LDS patients demonstrated high levels of CD4+ T cells that expressed both Foxp3 and IL-13, but retained the ability to suppress effector T cell proliferation. Naive CD4+ T cells from LDS patients differentiated into TH2-cytokine producing cells in a TGFb-dependent manner in vitro. Levels of pSmad2 were elevated in thymi and peripheral CD4+lymphocytes from LDS patients. ConclusionsLDS is the first Mendelian disorder to be associated with the development of food allergy, EGID, and other allergic disease. These data will inform efforts to elucidate pathogenesis in nonsyndromic presentations of allergic disease and potentially reveal novel therapeutic strategies. LDS is the first Mendelian disorder to be associated with the development of food allergy, EGID, and other allergic disease. These data will inform efforts to elucidate pathogenesis in nonsyndromic presentations of allergic disease and potentially reveal novel therapeutic strategies.