Dedicator of cytokinesis 8 (DOCK8) is a negative regulator of skin mast cell function

Abstract Dysregulated expansion and/or activation of mast cells have detrimental consequences in allergic disease. In humans, homozygous or compound heterozygous deletions DOCK8 cause a combined immunodeficiency characterized by disorders. Based on this evidence, we hypothesized that may be negative regulator cell function. To address hypothesis, used mice with loss-of-function mutation Dock8 (primuris, pri/primice) and conditional which is ablated connective tissue (Mcpt5-Cre +; fl/flmice). pri/primice exhibited increased plasma levels protease-1 (MCPT1) homeostatic conditions. Furthermore, Mcpt5-Cre fl/flmice experienced more severe IgE-dependent passive cutaneous anaphylactic reaction (PCA) than control mice. This data suggests deficiency linked to conditions upon stimulation mechanisms. Fetal skin derived cultured (FSMCs) generated from released amounts β-hexosaminidase activation. Consistent finding, naïve DOCK8-deficient FSMCs alterations cytoskeletal dynamics facilitate degranulation. Finally, observed an number tryptase positive biopsies obtained three pediatric patients diagnosed hyper IgE syndrome (HIES) due mutations, suggesting contribute humans. Our findings provide strong evidence can regulation expansion. R01 AI140626-05