Blau syndrome is systemic granulomatosis associated with gain-of-function mutations in NOD2. Clinical symptoms appear before the age of 4 years and mainly affect the skin, joints, and eyes. While treatments with anti-TNF agents have been reported effective, the underlying molecular mechanisms remain unclear. To elucidate the mechanisms of autoinflammation in Blau syndrome and to clarify how TNF-targeting treatment controls the disease phenotype at the cellular level, macrophages were differentiated from peripheral monocytes of 7 patients with Blau syndrome, among them 4 patients received anti-TNF, and global transcriptional profiles were analyzed. Macrophages were also generated from induced pluripotent stem (iPS) cells with or without Blau syndrome-associated mutation in NOD2 and their transcriptomes were examined. Aberrant inflammatory responses were observed upon IFNgamma-treatment, accompanied with the induction of NOD2 expression and inflammatory cytokine production, in macrophages from the patients who did not receive anti-TNF. Macrophages derived from iPS cells carrying Blau syndrome-associated mutation also showed IFNgamma-dependent accelerated inflammatory responses with up-regulation of NF-kappaB targets. Interestingly, long-term treatment with anti-TNF agents ameliorates such ex vivo abnormalities even in the presence of IFNgamma. Thus, pre-exposure to TNF induces NF-kB-driven proinflammatory signaling during macrophage development that is a prerequisite for accelerated inflammatory responses upon IFNgamma stimulation in Blau syndrome. These findings should aid understanding of molecular mechanisms underlying granuloma formation in Blau syndrome and support the validity of anti-TNF treatment.

ESDR209 - TNF-Targeting Treatment Corrects Proinflammatory Signatures of Autoinflammatory Blau Syndrome

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