Background/Purpose: Defective or sustained activation of Interferon (IFN) signaling has been associated with enhanced susceptibility to systemic lupus erythematosus (SLE). The cytosolic RIG-I-like receptors (RLRs), RIG-I (DDX58) and MDA5 (IFIH1) are intracellular pattern recognition receptors involved in the recognition of double-stranded RNA, leading to production of IFN type I. It is thought that overexpression of these receptors potentially promotes autoimmunity and contributes to the systemic IFN overactivation. Recent evidence showed a gain-of-function mutation in the IFIH1-gene, supporting the role of these cell-intrinsic sensors in autoimmune disease [Funabiki et al., Immunity 2014]. Childhood onset SLE (cSLE) is an incurable systemic autoimmune disease and medication is by far not effective enough, leaving children with significant side effects, especially due to prednisone. The aim of this study was to determine the prevalence of the IFN type I signature in cSLE, in relation to disease activity and the expression of the cytosolic RLRs.

Methods: In 34 healthy controls (HC), and 22 cSLE patients fulfilling ≥ 4 ACR criteria, whole blood (Paxgene) samples were collected. cSLE patients with a mean disease duration of 2.7 (± 1.6) years were followed-up prospectively and disease activity was assessed using the SELENA-SLEDAI score, including Physician Global Assessment and Flare-scores. Whole blood expression levels of 14 IFN-inducible genes, as determined by real-time quantitative PCR, were submitted to a principle component analysis (PCA) to identify 5 genes explaining >95% of the total variance. The IFNscore, a quantitative measure for total IFN type I bioactivity, was calculated using expression levels of the 5 indicator genes – IFI44, IFIT1, IFIT3, Ly6e and MX1 – to define the whole blood IFN type I signature in cSLE.  cSLE patients positive for the IFN type I signature (IFNscore >10) were compared with patients negative for the IFN signature (IFNscore <10). Additionally, mRNA expression of the RLRs was assessed.

Results: We identified the presence of an IFN type I signature in 54.5% (12/22) of the cSLE patients. At time of inclusion, we found no significant difference in disease activity between IFNpositive and IFNnegative cSLE patients (p=0.0744). Disease activity and other biological markers are being assessed longitudinally. Interestingly the RLRs, RIG-I (p<0.001) and MDA5 (p<0.001) were significantly upregulated in IFNpositive cSLE compared to HC and IFNnegative cSLE patients. Furthermore, RIG-I (p<0.0001; r=0.954) and MDA5 (p<0.0001; r=0.904) highly correlated with the IFNscore.

Conclusion: The prevalence of the IFN type I signature in cSLE was 54.5%. Interestingly, overexpression of RIG-I and MDA5 is evident in cSLE, and strongly related to the presence of the IFN signature. Further investigating the role of these RLRs in disease pathogenesis is warranted and might offer new opportunities for selective therapeutic targeting.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nucleic-acids-sensing-receptors-rig-i-and-mda5-as-potential-amplifiers-of-the-interferon-signature-in-childhood-onset-systemic-lupus-erythematosus/