Background/Purpose: Stills disease (SD) is an autoinflammatory syndrome characterized by severe innate immune dysregulation. The complement system, an essential component of innate immunity, can drive inflammatory cascades through the classical, lectin or alternative pathway. Although complement activation has been implicated in various inflammatory disorders, its involvement in SD remains largely undefined. Elucidating the role of complement in SD may provide valuable insights into disease mechanisms and uncover novel therapeutic targets.

Methods: To determine whether the complement pathway is activated in SD patients, we conducted transcriptomic analysis, proteomic measurements, and in vitro stimulation assays. RNA was extracted from whole blood of SD (active n=27, inactive n=26) and active non-systemic juvenile idiopathic arthritis (JIA) patients (n=538). Gene expression of classical complement components C1QB, C1QC and IFN-regulated genes (IFN-score) was quantified by NanoString. Additionally, RNA sequencing was conducted on sorted monocytes from SD patients (active n=7, inactive n=7). Inflammatory mediators (IL-18, CXCL9, CXCL10) and complement activation products (C1q, C3a, C5a) were quantified using Luminex and ELISA. Classical complement activity was evaluated in sera of SD (active n=32, inactive n=66) and non-systemic JIA patients (active n=12, inactive n=12). To explore potential mechanisms underlying complement activation, in vitro experiments were conducted to assess which inflammatory stimuli could induce C1q production in monocytes.

Results: RNA expression of classical complement protein C1q is upregulated in both whole blood and isolated CD14+ monocytes from active SD patients compared to those with inactive disease (NanoString: C1QB 43 vs. 11, p< 0.01; C1QC 24 vs. 6, p< 0.01; Monocytes: C1QB log2FC 3.6, p< 0.01; C1QC log2FC 3.9, p< 0.01) and to active non-systemic JIA patients (C1QB 43 vs 15, p< 0.01; C1QC 24 vs 8, p< 0.01). Moreover, whole blood C1QB and C1QC expression levels positively correlate with the IFN-score (r=0.34, p=0.01), plasma levels of IL18 (r=0.5, p< 0.01) and IFN related chemokines CXCL9 (r=0.4, p< 0.01) and CXCL10 (r=0.6, p< 0.01) in SD. Protein analysis revealed elevated levels of C1q, C3a, and C5a, as well as enhanced classical complement activity in active SD compared to inactive SD (94% vs 74%, p< 0.01) and active non-systemic JIA patients (94% vs 81%, p=0.02). Furthermore, in vitro stimulation of healthy control monocytes with IFNγ robustly and specifically induces C1q mRNA expression. Flow cytometry analysis confirmed that IFNγ stimulation promotes the emergence of a distinct monocyte subset characterized by high C1q expression.

Conclusion: Our findings indicate activation of the classical complement pathway in SD, closely linked with IFN-signalling. Obtaining a better understanding of the role of the complement system, particularly the role of C1q-high monocytes, may open novel avenues for personalized therapeutic approaches in SD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/flipping-the-switch-classical-complement-activation-closely-linked-to-ifn-signalling-in-stills-disease/