The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus

Oliveira, João J.; Karrar, Sarah; Rainbow, Daniel B.; Pinder, Christopher L.; Pamela, Clarke; Garćıa, Arcadio Rubio; Al-Assar, Osama; Burling, Keith; Morris, Sian; Stratton, Richard; Vyse, Tim J.; Wicker, Linda S.; Todd, John A.; Ferreira, Ricardo C.

doi:10.1186/s13075-018-1649-1

Cited by 43 publications

(56 citation statements)

References 35 publications

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“…Recently, we have reported that the plasma concentration of the soluble form of the adhesion receptor SIGLEC-1 (sSIGLEC-1) is sensitive marker of the type I IFN transcriptional signature (27). In addition, we have shown that the concentration of sSIGLEC-1 was also associated with increased disease activity in SLE patients.…”

Section: Resultsmentioning

confidence: 99%

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Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression

et al. 2019

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In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.

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Section: Resultsmentioning

confidence: 99%

“…Soluble SIGLEC-1 (sSIGLEC-1) concentrations were measured in plasma samples from all study participants using a time-resolved fluorescence immunoassay, as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression

et al. 2019

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“…Macrophages regulate the autoimmune system by modulating multiple pathways, not just through TNF expression and phagocytic activity. Abnormal expression of monocyte-surface markers, such as FcγRIII, CD40, CD244, CR4, Siglec-1, and Siglec-4, have been reported in monocytes from patients with SLE [62,64,65,66]; therefore, dysregulation of monocyte surface molecules could skew optimal immune responses, including pathogenic cytokine and chemokine expression [62].…”

Section: Discussionmentioning

confidence: 99%

Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice

Nagasu

Mukai

Iseki

et al. 2019

Cells

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SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4−CD8− T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.

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“…However, an IFN score was recently shown to predict the development of SLE in at-risk individuals 32. Alternative biomarkers of type I IFN activity have been evaluated and include the IFN-α response protein, sialic acid-binding Ig-like lectin 1, which is expressed exclusively on tissue-resident monocyte-derived dendritic cells and tissue-resident macrophages 33. Other gene signatures, such as plasmablast and neutrophil signatures, may correlate better with SLE disease activity than the IFNGS at the individual level 31…”

Section: Type I Ifns In Autoimmune Diseasesmentioning

confidence: 99%

Type I interferons in host defence and inflammatory diseases

Crow

Rönnblom

2019

Lupus Sci Med

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Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as ‘friend’ or ‘foe’, within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

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The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus

Cited by 43 publications

References 35 publications

Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression

Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression

Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice

Type I interferons in host defence and inflammatory diseases

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