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SAT0002 The intracellular itam tyrosines of fc receptor gamma-chain are critical for experimental autoimmune arthritis

Background Activating Fcγ-receptors on neutrophils associate with the Fc-receptor γ-chain (FcRγ), an immunoreceptor tyrosine-based activation motif (ITAM) containing transmembrane adapter molecule. Previously, we carried out in vitro experiments that showed not only a chaperon-like function of FcRγ, but also a signalling role through its intracellular ITAM-tyrosines. Objectives Here, we investigated the participation of these tyrosines in an autoantibody-induced arthritis model (in the KBxN serum transfer arthritis, for the development of which neutrophils and Fc-receptors are essential) using wild type and ITAM tyrosine mutant (Y65F/Y76F) transgenic mice. Methods The experimental animals expressed wild type or ITAM tyrosine mutant (Y65F/Y76F) Fc-receptor γ-chain on the FcRγ–/– genetic background. The arthritis was initiated by a single intraperitoneal injection of control or arthritic serum. The severity of joint inflammation was followed by clinical scoring, measuring ankle thickness changes and detecting joint dysfunction. Homozygous transgenic mice were identified by quantitative PCR. Results Compared to wild type mice, FcRγ knockout animals failed to exhibit a measurable joint inflammation. Surprisingly, the arthritis could not develop in wild type FcRγ transgene heterozygous mice. To enhance the expression level of the wild type transgene (which was approximately one third of the expression of the mutant transgene), we crossed our wild type transgene heterozygous mice with each other. As a consequence, wild type FcRγ transgene homozygous mice on the γ-chain knockout background were able to undergo arthritic development. In contrast, FcRγ knockout mice carrying the ITAM-mutant FcRγ transgene (both at heterozygous and homozygous forms) were fully protected from the development of arthritis despite of comparable neutrophil cell surface Fcγ receptor expressions. Conclusions Our in vivo experiments show that the intracellular Fc receptor γ-chain ITAM tyrosines play a critical role in the initiation and progression of an autoantibody-induced experimental arthritis model, confirming a signalling, rather than just a chaperon-like function of the molecule. Acknowledgements MTA-SE “Lendulet” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary and MTA-SE “Lendulet” Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary Disclosure of Interest None declared