Sarcoidosis: Unveiling a type I interferon driven immunopathogenesis

Summary: Abstract Body: Sarcoidosis is a multisystemic granulomatous disease with unclear origins, primarily affecting the lungs, lymph nodes, skin, and eyes. While most patients experience mild symptoms with spontaneous resolution, a subset requires intensive interventions such as lung transplants due to severe respiratory issues. The disease presents a diagnostic challenge due to its heterogeneous triggers and overlapping symptoms with other conditions. Type I interferons (IFNs), previously associated with numerous autoimmune conditions, may be implicated in the immunopathogenesis of sarcoidosis. Plasmacytoid dendritic cells (pDCs), key producers of type I IFNs, are found in sarcoid granulomas, suggesting a role in disease progression. Type I IFNs drive inflammation and also influence macrophage polarization, tipping the balance between the pro-inflammatory M1 and anti-inflammatory M2 macrophages. This modulation may underlie the chronicity of the disease and the formation of granulomas. Moreover, type I IFN-induced signaling pathways, including those involving STAT1 and STAT3, are critical in regulating immune responses and fibrosis, which are central to sarcoidosis immunopathogenesis. Novel therapies targeting type I IFN signaling, including TYK2 inhibitors like deucravacitinib and monoclonal antibodies like anifrolumab, show promise for treating sarcoidosis. This review focuses on the role of type I IFNs in the immunopathogenesis of sarcoidosis and highlights emerging treatments aimed at targeting these pathways. Word Count: Jiwon Park¹, Gabriela Soto-Canetti^{2, 3}, Jordan Talia² 1. The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, TX, United States. 2. Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 3. Ponce Health Sciences University School of Medicine, Ponce, Puerto Rico. Clinical Research: Interventional Research