Dataset Information

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

ABSTRACT:

Objective

JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM.

Methods

Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay.

Results

Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01).

Conclusion

Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.

SUBMITTER: Lerkvaleekul B

PROVIDER: S-EPMC9071568 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

Lerkvaleekul Butsabong B Veldkamp Saskia R SR van der Wal M Marlot MM Schatorjé Ellen J H EJH Kamphuis Sylvia S M SSM van den Berg J Merlijn JM Hissink Muller Petra C E PCE Armbrust Wineke W Vastert Sebastiaan J SJ Wienke Judith J Jansen Marc H A MHA van Royen-Kerkhof Annet A van Wijk Femke F

Rheumatology (Oxford, England) 20220501 5

<h4>Objective</h4>JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM.<h4>Methods</h4>Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during ...[more]

PMID: 34387304

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Project description:BackgroundJuvenile dermatomyositis (JDM) is an immune-mediated disease characterized by chronic organ inflammation. The pathogenic mechanisms remain ill-defined.MethodsRaw microarray data of JDM were obtained from the gene expression omnibus (GEO) database. Based on the GSE3307 dataset with 39 samples, weighted correlation network analysis (WGCNA) was performed to identify key modules associated with pathological state. Functional enrichment analyses were conducted to identify potential mechanisms. Based on the criteria of high connectivity and module membership, candidate hub genes were selected. A protein-protein interaction network was constructed to identify hub genes. Another dataset (GSE11971) was used for the validation of real hub genes. Finally, the real hub genes were used to screen out small-molecule compounds via the Connectivity map database.ResultsThree modules were considered as key modules for the pathological state of JDM. Functional enrichment analysis indicated that responses to interferon and metabolism were dysregulated. A total of 45 candidate hub genes were selected according to the pre-established criteria, and 20 genes could differentiate JDM from normal controls by validation of another external dataset (GSE11971). These real hub genes suggested the pivotal role of mitochondrial dysfunction and interferon signature in JDM. Furthermore, drug repositioning highlighted the importance of acacetin, helveticoside, lanatoside C, deferoxamine, LY-294002, tanespimycin and L01AD from downregulated genes with the potential to perturb the development of JDM, while betonicine, felodipine, valproic acid, trichostatin A and sirolimus from upregulated genes provided potentially therapeutic goals for JDM.ConclusionsThere are 20 real hub genes associated with the pathological state of JDM, suggesting the pivotal role of mitochondrial dysfunction and interferon signature in JDM. This analysis predicted several kinds of small-molecule compounds to treat JDM.

Project description:BackgroundJuvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI.MethodsA peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics.ResultsIRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients' IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (rs = 0.33-0.47) and more strongly with skin activity (rs = 0.58-0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S.ConclusionsOur findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.

Dataset Information

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

Objective

Methods

Results

Conclusion

Publications

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

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