TGFβ Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease

Patients with mutations in the receptors for TGFβ (Loeys-Dietz syndrome) exhibit an increased prevalence of allergic diseases. Allergy Unveiled Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder closely related to Marfan syndrome caused by mutations in the genes encoding receptor subunits for transforming growth factor–β (TGFβ). Patients with LDS are predisposed to aortic aneurisms and other connective tissue disorders. Now, Frischmeyer-Guerrerio et al. report that patients with LDS are more likely to develop allergic diseases. Allergy occurs when the immune system responds to normally harmless substances. The authors observed that LDS patients had elevated incidence of allergic diseases, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. These patients had elevated levels of immune responses thought to contribute to allergy, including allergen-specific IgE, eosinophilia, and TH2 cytokines. Because regulatory T cell (Treg) development is regulated by TGFβ, the authors then examined Treg number and function in these patients. They found that the frequency of Tregs was increased in LDS patients, but that these cells produced TH2 effector cytokines, and in vitro studies suggested that LDS mutations promote TH2 inflammation. What’s more, children with allergic disease, but not LDS, had similar changes in Treg number and function. These data suggest that altered TGFβ signaling could promote allergic disease and support testing for U.S. Food and Drug Administration–approved drugs that affect TGFβ for treating allergy. 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.