Background/Purpose: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with a large heterogeneity in clinical phenotype. The IFN type I signature is present in over half of PSS patients, associated with higher disease activity [Brkic Z. et al. Ann Rheum Dis 2013]. Novel evidence in pSS salivary glands indicates IFN activation to be also partly attributed to IFN type II [Hall J.C. et al. PNAS 2012]. Furthermore, a large modular analysis revealed distinct Type I and Type II IFN signatures related to disease severity in systemic lupus erythematosus (SLE) [Chiche L. et al. Arthritis Rheumatol 2014]. Increasing interest in development of therapeutic interventions to target the IFN signalling pathway is emerging. To date, clinical trials with anti-IFNα monoclonal antibodies in SLE have generated mixed results. Better understanding the molecular pathways causal to the IFN signature is essential for specific therapeutic targeting. Thus, identifying the pathways responsible for the sustained IFN overactivation in pSS could lead to a more selective, targeted therapy. The aim of this study was to investigate the contribution of IFN type II, to the IFN signature in pSS.

Methods: Here we used previous findings from the modular transcriptional repertoire analysis described by Chiche et al., the 3 IFN-annotated modules: M1.2=mild (predominantly IFNα), M3.4=moderate (predominantly IFNβ), and M5.15=strong (also IFNβ and IFNγ),  in a class comparison to find overlapping genes in pSS. Differentially expressed genes were considered significant using a cut-off: p<0.05 and Fold change≥2. Whole blood mRNA expression of the top genes was validated in a cohort of 36 healthy controls (HC), and 55 pSS patients fulfilling the 2002 AE-criteria (stratified in 20 IFNnegative and 35 IFNpositive pSS).

Results: Class comparison analyses between pSS genome wide microarray data, and the genes annotated for the IFN modules M1.2, M3.4 and M5.12, revealed n=19 genes overlapping in M1.2, n=31 genes in M3.4 and n=10 genes in M5.12. For M1.2 most genes were already previously validated to determine the IFN type I signature, thus predominantly driven by IFNα (MxA (p<0.0001), IFI44L (p<0.0001), IFIT3 (p<0.0001) e.g.). Interesting genes validated for M3.4 were amongst others ZBP1 (p<0.001), GBP1 (p<0.001), PKR (p<0.001), IFIH1 (p<0.0001) and for M5.12 ISG20 (p<0.01), IFI16 (p<0.001) and TAP1 (p<0.001), all significantly upregulated in IFNpositive compared to HC and IFNnegative pSS. Similar to findings in SLE, only a subset of IFN type I positive pSS patients showed upregulation of M3.4 genes and an even smaller subset for M5.12 genes. We are currently assessing the relation of these findings to disease activity and other aspects of disease such as fatigue and depression. Data will be further validated using the gene expression data from the UK pSS registry (n=29 HC and n=133 pSS). 

Conclusion: Here we find evidence for the presence of complex IFN signatures driven by IFN type I and IFN type II in pSS. Subtyping pSS patients according to distinct IFN signature modules might aid in more selective therapeutic targeting, as well as better disease monitoring and control.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-interferon-type-i-and-type-ii-signatures-present-in-distinct-subsets-of-primary-sjogrens-syndrome-en-route-towards-more-selective-targeting/