Phospholipase Cγ2 (PLCγ2) is a signaling molecule of tyrosine kinase-coupled receptors in cells of hematopoietic origin. Gain-of-function mutations of PLCγ2 have been reported to cause a complex syndrome involving inflammation and bullous skin eruptions in both mice and humans. Previously we showed that PLCγ2 deficient mice remained protected in an autoimmune skin blistering model induced by the passive transfer of autoantibodies against collagen type VII (C7), which is a key anchoring fibril in the dermal-epidermal junction. Our aim was to further characterize the mechanisms leading to this phenotype in PLCγ2 deficient mice. Anti-C7 deposition, dermal-epidermal separation and inflammatory infiltration in the skin were evaluated in histological sections stained with H&E and immunostaining. Leukocyte accumulation in the skin was measured by flow cytometry. Migrating capacity of myeloid cells was checked both in vitro and in an in vivo competitive migration assay. Generation of the proinflammatory microenvironment in the skin was analyzed by ELISA and in vivo luminescence-based imaging. PLCγ2 deficiency prevented dermal-epidermal separation and the infiltration of neutrophils, eosinophils and monocytes/macrophages to the skin, however, autoantibody deposition was not affected. In vitro neutrophil migration, as well as the in vivo intrinsic migrating capacity of the 3 major myeloid cell population remained intact in PLCγ2 deficient animals. Contrarily, in vivo accumulation of proinflammatory chemokines, cytokines and lipid mediators, as well as the in vivo production of reactive oxygen species were completely blocked in the absence of PLCγ2. Taken together, our results identify PLCγ2 as a critical component of autoantibody-induced skin blistering by creating a proinflammatory milieu after autoantibody deposition in the skin.

ESDR194 - Phospholipase Cγ2 is Essential in Autoantibody-induced Skin Blistering

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING