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.

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

“…Understanding the complex and varied pathophysiology of the disease is vital for the future of research and clinical practice. Recent data suggest that altered TGF-b signaling can predispose to allergic phenotypes in humans, and underscores a prominent role for TGF-b in directing immune responses to antigens present in the environment (41). This paradigm may be relevant to nonsyndromic presentations of allergic disease, and highlights the potential therapeutic benefit of strategies that inhibit TGF-b signaling.…”

Eosinophilic Esophagitis

“…72 Loeys-Dietz syndrome is caused by mutations in genes encoding the TGF-b receptor, which allows for increased signals via TGF-b1. In Loeys-Dietz syndrome, FoxP3-positive regulatory T cells seem to enhance, rather than suppress, allergic inflammation by producing T helper cell type 2 cytokines, including IL-13.…”

Emerging therapies for food allergy

“…The predominant mechanism by which food allergy develops remains controversial, with some studies suggesting that primary sensitization through skin contact may be even more important than exposure via the gut (9). Active gastrointestinal tolerogenic mechanisms appear to be important in preventing food allergy in general, as children with genetic defects in generating regulatory T cells frequently have severe allergic disease (10,11). APCs in the gut, particularly DCs, clearly direct these T cell responses and are themselves responsive to the context in which they receive antigen.…”