Complement activation linked to type II interferon signaling in Still disease

Still disease (SD) is an autoinflammatory syndrome characterized by innate immune dysregulation. While complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD.

Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n=15), non-systemic juvenile idiopathic arthritis (JIA, n=8), and SD patients at onset (n=19), remission (n=18), and macrophage activation syndrome (n=2). Whole-blood NanoString analysis of complement and interferon-related gene expression was conducted in SD (active n=41, inactive n=33) and JIA patients (n>600). Complement products and inflammatory mediators were measured by Luminex and ELISA. Functional complement activity was evaluated in SD (active n=30, inactive n=67) and JIA sera (n=12). In vitro assays examined monocytic C1q induction and complement-mediated CD8⁺ T cell activation.

Transcriptomic analysis of monocytes from SD patients at onset revealed enrichment of the complement cascade compared to patients in remission (Padj=3.7×10^-36), ranking among the top ten upregulated pathways. Classical complement genes (C1QB/C1QC) were markedly upregulated in onset SD compared to remission SD and JIA patients. Active SD patients showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole-blood C1QB/C1QC expression correlated with interferon-related markers, including IL-18, CXCL9 and CXCL10. Recombinant IFN-γ induced monocytic C1q, while C1q enhanced IFN-γ production by CD8⁺ T cells, supporting a feed-forward loop.

SD is characterized by complement activation with marked upregulation of C1q, which is closely linked to IFN-γ/type-II signaling.