title: TGFβ receptor mutations impose a strong predisposition for human allergic disease.
abstract: Transforming growth factor-β (TGFβ) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGFβ regulates regulatory T cell (Treg) maturation and immune homeostasis. Although genetic manipulation of the TGFβ pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGFβ, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in their plasma. They had an increased frequency of CD4(+) T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. TH2 cytokine-producing cells accumulated in cultures of naïve CD4(+) T cells from LDS subjects, but not controls, after stimulation with TGFβ, suggesting that LDS mutations support TH2 skewing in naïve lymphocytes in a cell-autonomous manner. The monogenic nature of LDS demonstrates that altered TGFβ signaling can predispose to allergic phenotypes in humans and underscores a prominent role for TGFβ in directing immune responses to antigens present in the environment and foods. This paradigm may be relevant to nonsyndromic presentations of allergic disease and highlights the potential therapeutic benefit of strategies that inhibit TGFβ signaling.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Frischmeyer-Guerrerio
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Guerrerio
authors.forename: Gretchen
authors.initials: G
authors.lastname: Oswald
authors.forename: Kristin
authors.initials: K
authors.lastname: Chichester
authors.forename: Loretha
authors.initials: L
authors.lastname: Myers
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Maria
authors.initials: M
authors.lastname: Oliva-Hemker
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wood
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D055947:Loeys-Dietz Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018793:Interleukin-13; D018125:Receptors, Transforming Growth Factor beta; D007073:Immunoglobulin E; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II