An unbiased map of FcγR signaling in neutrophils reveals druggable nodes in immune complex-mediated autoimmune disease
Year: 2026
Type: preprint
Abstract: Immune complexes drive tissue damage in autoimmune diseases through Fragment crystallizable γ receptor (FcγR) signaling, yet the underlying kinase networks are largely unexplored and treatment remains broadly immunosuppressive. We mapped signaling in immune complex-stimulated human neutrophils by combining an unbiased screen of 155 signal transduction inhibitors with multiplex kinase activity profiling, identifying 51 modulated kinases, 44 of them not previously linked to pemphigoid disease. Nine inhibitors, targeting PLC, PDK-1, PKC, DNA-PK, KSP, BTK, p38, c-Met and TBK-1, reduced neutrophil activity in vitro and disease severity in experimental epidermolysis bullosa acquisita, six of them after topical application. BTK emerged as a dominant node as inhibition with ibrutinib was effective therapeutically in immunization-induced disease, in mice reconstituted with a human immune system, and in models of arthritis and immune thrombocytopenia, the latter largely independent of neutrophils. These data provide a resource for FcγR signaling in neutrophils and identify BTK as a cross-disease therapeutic target in antibody-mediated autoimmune disease.
Authors: Mareile Schlotfeldt, Colin Osterloh, Anika Kasprick, Carla Zünkeler, Mikko Armbrust, Georg Kaiser, Katharina Schulze Dieckhoff, Thorge Mester, Pia Stüssel, Nancy Ernst, Ann-Kathrin Schneider, Leonie Voss, Adrian P. Mansini, Seyed Mohammad Vahabi, Yulu Wang, Haley Gainer, Jing Li, Gestur Vidarsson, Remco Visser, Frank Petersen, Xinhua Yu, Kyle T. Amber, Anja Lux, Ralf J. Ludwig, Katja Bieber
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7170830947