TGFβ receptor mutations impose a strong predisposition for human allergic disease

Area of Science:

• Immunology
• Genetics
• Allergy Research

Background:

• Transforming growth factor-β (TGFβ) is a cytokine crucial for immune homeostasis and regulatory T cell (Treg) function.
• The role of TGFβ signaling in human allergic diseases remains incompletely understood.
• Genetic manipulation of TGFβ impacts immune tolerance in mouse models.

Purpose of the Study:

• To investigate the contribution of TGFβ signaling to human allergic phenotypes.
• To explore the link between Loeys-Dietz syndrome (LDS) and allergic disease predisposition.
• To elucidate the mechanisms by which TGFβ pathway alterations influence immune responses.

Main Methods:

• Analysis of patients with Loeys-Dietz syndrome (LDS), caused by TGFβ receptor mutations (TGFBR1, TGFBR2).
• Measurement of immunoglobulin E (IgE) levels, eosinophil counts, and T helper 2 (TH2) cytokines in patient plasma.
• Flow cytometry to assess CD4(+) T cell populations (including Foxp3 and IL-13 expression).
• In vitro culture of naïve CD4(+) T cells with TGFβ stimulation.

Main Results:

• LDS patients show a strong predisposition to allergic diseases like asthma, food allergy, and eczema.
• Elevated IgE, eosinophils, and TH2 cytokines were observed in LDS patients.
• LDS patients exhibited increased CD4(+) T cells expressing Foxp3 and IL-13, with retained suppressive function.
• TGFβ stimulation of naïve T cells from LDS subjects, but not controls, led to TH2 cytokine accumulation.

Conclusions:

• Monogenic alterations in TGFβ signaling, as seen in LDS, predispose humans to allergic conditions.
• TGFβ plays a significant role in directing immune responses to environmental and food antigens.
• These findings suggest TGFβ inhibition as a potential therapeutic strategy for allergic diseases.