Insights into the pathogenesis of allergic disease from dedicator of cytokinesis 8 deficiency

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.

Automated summary

Clinical observations and mechanistic studies in DOCK8-deficient patients and mice have uncovered multiple mechanisms contributing to their prevalent and severe allergic disease manifestations. Physical interactions of DOCK8 with STAT3 in B and T cells may lead to increased IgE isotype switching or defective immune synapse formation, resulting in weakened T-cell receptor signaling. The newly discovered TFH13 cell type, increased in DOCK8 deficiency, promotes life-threatening allergy through IL-13 production. Cytoskeletal derangements and cytothripsis can also lead to increased production of IL-4, IL-5, and IL-13 by myeloid cells and T cells, while impacts on type-2 innate lymphoid cells may contribute to allergic disease.