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Clinical observations and mechanistic studies in dedicator of cytokinesis 8 (DOCK8)-deficient patients and mice have revealed multiple mechanisms that could contribute to their unusually prevalent and severe allergic disease manifestations. Physical interactions of DOCK8 with STAT3 in B cells and T cells may contribute to increased IgE isotype switching or defective immune synapse formation that decreases T-cell receptor signal strength. A newly discovered TFH13 cell type promotes the development of life-threatening allergy via production of IL-13 and is increased in DOCK8 deficiency. Cytoskeletal derangements and cytothripsis, which were previously shown to account for the increased susceptibility to viral skin infection in DOCK8 deficiency, can lead to interplay between myeloid cells and T cells to ultimately increase production of IL-4, IL-5, and IL-13. Finally, the effects on type-2 innate lymphoid cells may also contribute to allergic disease.

Section snippetsBackground

Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency (CID) that is caused by mutations in an atypical guanine-nucleotide exchange factor for activating CDC42 1, 2. The disease is hallmarked by not only increased infection susceptibility but also allergic disease. The infections in these patients show a predilection for the skin, and they are typically caused by Staphylococcus aureus or various persistent viruses, with human papillomavirus also predisposing to development

Mechanisms of allergic disease in dedicator of cytokinesis 8 deficiency

Atopic disease in DOCK8 deficiency encompasses a spectrum of phenotypes. Immediate type-I hypersensitivity reactions underlie classical IgE-mediated food allergen-induced anaphylaxis and environmental aeroallergen-triggered allergic rhinoconjunctivitis or allergic asthma. When combined with more delayed, non-IgE-mediated allergen-induced inflammation or other factors such as disrupted epithelial barriers and microbial colonization, the IgE-mediated mechanisms can evolve into other presentations

Conclusions

DOCK8 deficiency is a monogenic infection susceptibility disorder that is less recognized as also being a bona fide monogenic allergic susceptibility disorder. Recent studies have provided new insights into the regulation of allergic responses and have raised interesting questions for future research. Foremost among these is the potential role of TFH13 cells in allergic manifestations in other inborn errors of immunity such as actinopathies, including the Wiskott–Aldrich syndrome, whether they

Conflict of interest statement

None.

Acknowledgements

I thank Joshua Milner, Alexandra Freeman, and Huie Jing for helpful comments. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (ZIAAI001193), National Institutes of Health.

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