Associated TP19: Drug repurposing to target neutrophil activation in autoimmune diseases

Neutrophils (polymorphonuclear leukocytes or PMNs) are the most abundant circulating leukocytes in humans and are the first line of cellular defense against foreign pathogens. When activated, these cells can produce toxic oxygen intermediates and release granule contents into the extracellular space or the phagosome (degranulation), all of which may contribute to tissue damage during autoimmune diseases. Prevention of neutrophil activation and thus inhibition of reactive oxygen species (ROS) release can be considered as a therapeutic purpose in treatment of neutrophil-mediated autoimmune conditions.             

In this project epidermolysis bullosa acquisita (EBA) will be used as a model for a prototypic organ-specific inflammatory autoimmune disease. Neutrophils and their “weaponry”, i.e. ROS production, are known as major cause of blister formation in EBA. The treatment of human skin cryosections with sera from EBA patients caused neutrophil infiltration to the dermal–epidermal junction (DEJ) and triggered the split of DEJ. Depletion of Gr-1+ myeloid cells also protected mice from disease induced by transfer of antibodies against type VII collagen (COL7) despite normal deposition of the pathogenic antibodies in the skin. Pharmacological inhibition of the NADPH oxidase with diphenylene iodonium or the genetic deficiency of NADPH oxidase in neutrophils from chronic granulomatous disease (CGD) patients prevented the ex vivo separation of DEJ in human cryosections treated with sera from EBA patients in the presence of human neutrophils. The aim of this study is to discover new substances which inhibit immune complex (IC)-induced neutrophil activation – with a focus on EBA.