Uncoupling interferons and the interferon signature explain clinical and transcriptional subsets in SLE.

Interferons (IFN) are thought to be key players in systemic lupus erythematosus (SLE). The unique and interactive roles of the different IFN families in SLE pathogenesis, however, remain poorly understood. Using reporter cells engineered to precisely quantify IFN-I, IFN-II and IFN-III activity levels in serum/plasma, we found that while IFNs play essential role in SLE pathogenesis and disease activity, they are only significant in specific subsets of patients. Interestingly, whereas IFN-I is the main IFN that governs disease activity in SLE, clinical subsets are defined by the co-elevation of IFN-II and IFN-III. Thus, increased IFN-I alone was only associated with cutaneous lupus. In contrast, systemic features, such as nephritis, were linked to co-elevation of IFN-I plus IFN-II and IFN-III, implying a synergistic effect of IFNs in severe SLE. Intriguingly, while increased IFN-I levels were strongly associated with IFN-induced gene expression (93.5%), in up to 64% of cases, the IFN signature was not associated with IFN-I. Importantly, neither IFN-II nor IFN-III explained IFN-induced gene expression in patients with normal IFN-I levels, and not every feature in SLE was associated with elevated IFNs, suggesting IFN-independent subsets in SLE. Together, the data suggest that, unlike the IFN signature, direct quantification of bioactive IFNs can identify pathogenic and clinically relevant SLE subsets amenable for precise anti-IFN therapies. Since IFN-I is only elevated in a subset of SLE patients expressing the IFN signature, this study explains the heterogeneous response in clinical trials targeting IFN-I, where patients were selected based on IFN-induced gene expression rather than IFN-I levels.

Déclaration de conflit d'intérêts

Competing Interests statement F.A. has received consulting fees and/or royalties from Celgene, Inova, Advise Connect Inspire, and Hillstar Bio, Inc. E.D. is currently a full-time employee at AztraZeneca, and has received grants, consulting fees, royalties and/or stocks from Pfizer, Celgene, Bristol Myers Squibb, Inova, and Ravel therapeutics. E.D. is an inventor on a licensed patent (US Patent #10,874,726), licensed provisional patents (048317-642P01US and US 63/515,854), and co-founder of Simmbion LLC. F.A. and E.D. are inventors on a licensed patent (US patent no. 14/617,412) and licensed provisional patent (US patent no. 62/481,158). E.G.B., D.W.G., V.A. and M.P. have declared no competing interests. There are no conflicts of interest with the work presented in this manuscript.