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A potential association between IL-3 and type I and III interferons in systemic lupus erythematosus.

ABSTRACT: Objectives:Plasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL-3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL-3 and IFN levels, and a whole blood 'IL-3 gene signature', in human SLE. Methods:Serum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL-3-regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL-3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors. Results:Serum IL-3 levels correlated with IFN? (r = 0.612, 95% CI 0.455-0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406-0.720, P < 0.0001). IL-3 stimulation of WBC in vitro altered 794 genes (-1 ? logFC ? 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an 'IL-3 gene signature'. There was strong correlation between the IL-3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898-0.964, P < 0.0001). Conclusion:A dual IL-3/IFN gene signature is a feature of SLE. An association between IL-3 and IFN raises the possibility that dual blockade of IL-3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature.

SUBMITTER: Oon S

PROVIDER: S-EPMC6928763 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A potential association between IL-3 and type I and III interferons in systemic lupus erythematosus.

Oon Shereen S Monaghan Katherine K Ng Milica M Hoi Alberta A Morand Eric E Vairo Gino G Maraskovsky Eugene E Nash Andrew D AD Wicks Ian P IP Wilson Nicholas J NJ

Clinical & translational immunology 20191224 12

<h4>Objectives</h4>Plasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL-3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL-3 and IFN levels, and a whole blood 'IL-3 gene signature', in human SLE.<h4>Methods</h4>Serum cytokine levels were measured by ELISA in <i>n</i> = 42 SLE patients, and <i>n</i> = 44 health ...[more]

PMID: 31890206

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Project description:Background and aimInterferons (IFNs) are considered to be key molecules in the pathogenesis of systemic lupus erythematosus (SLE). We measured levels of type I, II and III IFNs in a large cohort of patients with systemic lupus erythematosus (SLE) and controls and explored associations among high levels of different IFN types and distinct SLE features.MethodsFour hundred ninety-seven well-characterized SLE patients and 322 population controls were included. Disease activity was assessed by SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM). Functional type I IFN activity was estimated by a WISH reporter cell assay. Levels of IFN-γ were estimated by MSD 30-plex assay. IFN-α and IFN-λ1 were measured by ELISA. Values above the third quartile of patients' measurements were defined as high. Associations among high IFN results and SLE features were investigated by nominal regression analysis.ResultsAll IFN measurements were higher in SLE patients than in controls. High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations. Specific SLE subsets were linked to the upregulation of different subtypes of circulating IFNs: high IFN-γ to arthritis, nephritis and anti-Ro60 antibodies and high IFN-α to mucocutaneous engagement and anti-Ro52 and anti-La antibodies. Isolated high IFN-λ1 was coupled to anti-nucleosome antibodies and less severe SLE.ConclusionsHigh functional type I IFN activity captures active SLE in most domains, but more distinct patterns of organ involvement are associated with profiles of circulating IFNs. High IFN-γ as well as high functional type I IFN activity is a characteristic of severe SLE with nephritis and arthritis, while elevated levels of IFN-α associate with active mucocutaneous inflammation and a more benign cardiovascular profile. IFN-λ1 in isolation is associated with milder disease. Our findings suggest that IFNs contribute to the heterogeneity of clinical manifestations in SLE, and measuring circulating IFNs could assist in designing clinical trials with therapies targeting IFN pathways.

Dataset Information

A potential association between IL-3 and type I and III interferons in systemic lupus erythematosus.

Publications

A potential association between IL-3 and type I and III interferons in systemic lupus erythematosus.

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