Innate immunity and interferons in the pathogenesis of Sjögren’s syndrome

Bodewes, Iris L A; Björk, Albin; Versnel, Marjan A.; Wahren‐Herlenius, Marie

doi:10.1093/rheumatology/key360

Cited by 54 publications

(53 citation statements)

References 126 publications

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“…). Specifically, augmented activity in crucial parts of the defence against viruses in innate immune system, including Toll‐like receptor (TLR) signalling and the type I interferon (IFN) system , infers the involvement of viral infections in SS. Several infections can also mimic glandular or extraglandular symptoms of SS, which may lead to confusion regarding diagnosis .…”

Section: Biological Factorsmentioning

confidence: 99%

Environmental factors in the pathogenesis of primary Sjögren's syndrome

2020

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Section: Biological Factorsmentioning

confidence: 99%

Environmental factors in the pathogenesis of primary Sjögren's syndrome

2020

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“…Accordingly, increased serum levels of type I IFN and overexpression of type I IFN-stimulated genes (IFN signature) are found in both SLE and SS 6 7. Type I IFN affects both the innate and adaptive immune systems and contributes to loss of tolerance and development of autoimmune diseases 8 9. Recently, a profound effect of type I IFN on central nervous system (CNS) neuronal synaptic mass was also reported 10.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a profound effect of type I IFN on central nervous system (CNS) neuronal synaptic mass was also reported 10. Commonly used therapies in both SLE and SS, such as hydroxychloroquine and glucocorticoids, have been suggested to diminish the type I IFN system activity, and several emerging drugs have been developed to directly target IFN-related pathways 8 9…”

Section: Introductionmentioning

confidence: 99%

Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero

et al. 2020

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ObjectiveIn utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment.MethodsBlood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays.ResultsWe observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14+ monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma.ConclusionsRo/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.

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“…Uncontrolled immune activation can be observed with immune complex deposition and leucocyte infiltration of affected tissues, as well as skewed immune cell populations and high levels of proinflammatory cytokines in the peripheral circulation. Specifically, excessive activation of the interferon (IFN) system is a well-established phenomenon in several systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) 1 2…”

Section: Introductionmentioning

confidence: 99%

“…The contribution of IFNs to the pathology of systemic autoimmune diseases is well documented 1 2. Indeed, the importance of IFN-α is evidenced by the development of SLE or SLE-like symptoms in patients receiving treatment with IFN-α 4 5.…”

Section: Introductionmentioning

confidence: 99%

Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren’s syndrome

et al. 2020

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ObjectiveStandard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjögren’s syndrome (pSS).MethodsPatients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).ResultsmRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62–0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as ‘high’ or ‘low’ IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89–0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001).ConclusionsWe describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.

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Innate immunity and interferons in the pathogenesis of Sjögren’s syndrome

Cited by 54 publications

References 126 publications

Environmental factors in the pathogenesis of primary Sjögren's syndrome

Environmental factors in the pathogenesis of primary Sjögren's syndrome

Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero

Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren’s syndrome

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