Dedicator of cytokinesis 8 (DOCK8)-deficient patients are highly susceptible to food allergy and have elevated serum mast cell (MC) tryptase levels. Dock8-/- mice have exaggerated IgE-mediated oral anaphylaxis, expansion of jejunal mucosal MCs (MMCs), and elevated serum levels of MMC-derived tryptase. This results in increased intestinal permeability, which promotes antigen absorption and thereby oral anaphylaxis. These events are driven by an intestinal cascade in which reduced interleukin (IL)-17 cytokines leads to dysbiosis, which drives IL-25 production. Increased IL-25 enhances T helper (Th)2 production of IL-4 that expands MMCs and exaggerates oral anaphylaxis. Failure of DOCK8-deficient T regulatory (Treg) cells to suppress intestinal IL-4 production and MC expansion leaves the exaggerated anaphylaxis unrestrained. Thus, multi-faceted coordination between the microbiome, mucosal T cells, and MCs to restrict oral anaphylaxis.
DOCK8-deficient patients have severe eczema, are highly colonized by Staphylococcus aureus, and have an intrinsically normal skin barrier. Dock8-/- mice develop exaggerated allergic skin inflammation following cutaneous exposure to S. aureus or antigen. Treg cells in their skin are diminished unstable and produce Th2 cytokines. Importantly, adoptive transfer of antigen-specific WT Treg cells dampens allergic skin inflammation in Dock8-/- mice and Treg-selective deletion of DOCK8 results in exaggerated allergic skin inflammation. Thus, Treg cell impairment underlies the severe eczema in DOCK8 deficiency.
The mechanism of impaired Treg cell dysfunction in DOCK8 deficiency involves impaired WASP-dependent F-actin polymerization, which is important for immune synapse formation, and Treg–target cell interaction, as well as WASP-independent impaired STAT5B tyrosine phosphorylation, which is important for induced Treg (iTreg) cell generation and stability. Disruption of both pathways in DOCK8 deficiency results in severely impaired Treg cell function and predisposition to allergic diseases.
