SIGLEC1 enables straightforward assessment of type I interferon activity in inflammatory myopathies

AbstractObjectiveTo evaluate SIGLEC1 expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).MethodsWe performed a retrospective analysis of adult and pediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment (PGA) or Childhood Myositis Assessment Scale (CMAS) disease activity scores. Mann Whitney-U test and receiver operating characteristic (ROC) curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analyzed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared to ISG15/MxA status by immunohistochemical staining of muscle biopsies (n=17).Results96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotizing myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9), and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve (AUC) of 0.92 (95% CI: 0.83–1) in DM and correlated with disease activity longitudinally (aDM: standardized beta=0.54, p<0.001; jDM: standardized beta=-0.70, p<0.001). Response to treatment in DM was associated with a decreasing SIGLEC1 (p<0.01, Wilcoxon test). A positive ISG15/MxA stain was highly associated with a SIGLEC1 upregulation. SIGLEC1 was found upregulated in AS (42.1%) and IBM (22,2%) and not in IMNM.ConclusionSIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.Key messagesWhat is already known about this subject?There is an unmet need for routine clinical biomarkers to assess type I interferon activity in rheumatic musculoskeletal diseasesSIGLEC1 is part of the type I interferon signature and transcripts were found to be upregulated in various autoimmune diseases such as systemic lupus erythematosus (SLE), Sjoegren syndrome and dermatomyositis.SIGLEC1 is expressed on the surface of monocytes and thus is easily assessable by flow cytometry, which enables straightforward monitoring of type I interferon activityWhat does this study add?An activation of the type I interferon system in IIM can be identified by flow cytometry analysing SIGLEC1 expression. SIGLEC1 correlated to disease activity and improvement under therapy in juvenile and adult dermatomyositis.How might this impact on clinical practice or future developments?SIGLEC1 expression is a suitable biomarker for monitoring type I interferon activation in rheumatic musculoskeletal diseases, which has clinical implications for patient stratification and treatment decision making especially in the context of interferon inhibitory therapies.

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FRI0309 Type I Interferon Activity Is Associated with Mucocutaneous but Not Musculoskeletal Disease Activity in Systemic Lupus Erythematosus:

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-eular.5570 ◽

2016 ◽

Vol 75 (Suppl 2) ◽

pp. 547.1-547

Author(s):

A.A.A. Mohamed ◽

Y. El-Sherbiny ◽

E.M. Hensor ◽

M.Y. Md Yusof ◽

S.H. Goma ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Musculoskeletal Disease ◽

Type I ◽

Systemic Lupus ◽

Interferon Activity

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POS0183 SIGLEC1 AS A TYPE I INTERFERON BIOMARKER IN IDIOPATHIC INFLAMMATORY MYOPATHIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2816 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 305.1-305

Author(s):

M. Graf ◽

A. S. L. Von Stuckrad ◽

A. Uruha ◽

J. Klotsche ◽

L. Zorn-Pauly ◽

...

Keyword(s):

Flow Cytometry ◽

Disease Activity ◽

Lupus Erythematosus ◽

Idiopathic Inflammatory Myopathies ◽

Type I ◽

Longitudinal Analyses ◽

Type I Ifn ◽

Inflammatory Myopathies ◽

Control Groups ◽

Cross Sectional

Background:Idiopathic inflammatory myopathies (IIM) are autoimmune diseases that mainly affect skeletal muscle, lung, skin and joints. IIM can be separated into dermatomyositis (DM), inclusion body myositis (IBM), antisynthetase syndrome (AS) and immune-mediated necrotizing myopathy (IMNM). Type I interferons (IFN) are known to play a crucial role in the etiopathogenesis of some of these entities such as DM.[1] Sialic acid binding Ig-like lectin 1 (SIGLEC1, CD169) is part of the type I IFN signature found in SLE and DM and is expressed on the cell surface of monocytes. Thus, analysis of SIGLEC1 expression by flow cytometry enables a straightforward assessment of the type I IFN signature. Its utility has been shown for juvenile and adult SLE and other rheumatic diseases but not in IIM.[2,3] The assessment of the type I IFN system in clinical practice is an unmet need and, in this context, SIGLEC1 might be useful.Objectives:To assess SIGLEC1 expression on monocytes by flow cytometry as a type I IFN biomarker in IIMMethods:Pediatric and adult patients with a clinical diagnosis of DM, AS, IMNM and IBM and at least one measurement of SIGLEC1 who have been treated at the Department of Rheumatology, Charité - Universitätsmedizin Berlin between 2015 and 2020 were included in this retrospective study. Control groups of healthy individuals (n=19) and SLE patients (n=30) were included. Disease activity was assessed by Physician Global Assessment (PGA) and Childhood Myositis Assessment Scale (CMAS). SIGLEC1 expression on monocytes was analyzed by flow cytometry. Cross-sectional analyses (n=74) were performed using Mann Whitney-U test (MWU) and two-level mixed-effects linear regression model was used for longitudinal analyses (n=26, 110 visits). This study was approved by the local ethics committee of the Charité - Universitätsmedizin Berlin.Results:74 patients (adult/juvenile DM: n=21/n=17; AS: n=19; IMNM: n=8; IBM: n=9) were included. In cross-sectional analysis, SIGLEC1 expression was significantly upregulated in adult and juvenile DM patients with moderate to severe disease activity (PGA≥5) compared with adult/juvenile DM patients with no to moderate disease activity (PGA<5) (both p<0.001). In longitudinal analyses, SIGLEC1 correlated with disease activity in juvenile DM (SIGLEC1 vs. CMAS: betaST=-0.65; p<0.001) and adult DM (SIGLEC1 vs. PGA: betaST=0.52; p<0.001), better than Creatine Kinase (CK) (juvenile DM, CK vs. CMAS: betaST=-0.50; p<0.001; adult DM, CK vs PGA: betaST=0.17; p=0.149). In AS 42,1% of the patients showed elevated SIGLEC1 expression, while it was not upregulated in IMNM and only in two patients with IBM, who were concurrently positive for autoantibodies that affect the type I IFN system (see Figure 1).Conclusion:SIGLEC1 is a useful biomarker to identify an activated type I IFN system in IIM. Flow cytometry is used widely in laboratory medicine, which could facilitate the implementation of SIGLEC1 into clinical routine.References:[1]Gallay L, Mouchiroud G, Chazaud B. Interferon-signature in idiopathic inflammatory myopathies: Current Opinion in Rheumatology 2019;31:634–42. doi:10.1097/BOR.0000000000000653[2]Rose T, Grutzkau A, Hirseland H, et al. IFNalpha and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis 2013;72:1639–45. doi:10.1136/annrheumdis-2012-201586[3]Stuckrad SL von, Klotsche J, Biesen R, et al. SIGLEC1 (CD169) is a sensitive biomarker for the deterioration of the clinical course in childhood systemic lupus erythematosus. Lupus 2020;:961203320965699. doi:10.1177/0961203320965699Figure 1.SIGLEC1 expression on monocytes in IIM subgroups and control groups; in IIM subgroups, patients with low disease activity (PGA<5) are marked in blue, patients with high disease activity (PGA≥5) are marked in red; mAb/cell, monoclonal antibodies bound per cellDisclosure of Interests:None declared

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Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus

10.1101/2020.10.29.20222000 ◽

2020 ◽

Author(s):

Sarthak Gupta ◽

Shuichiro Nakabo ◽

Jun Chu ◽

Sarfaraz Hasni ◽

Mariana J. Kaplan

Keyword(s):

Systemic Lupus Erythematosus ◽

General Population ◽

Lupus Erythematosus ◽

Preventive Measures ◽

Type I Interferon ◽

Type I ◽

List Type ◽

Signal Transducer ◽

Systemic Lupus

AbstractObjectivesAnti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFNα autoantibodies was associated with COVID-19 infection in SLE patients.MethodsPatients with SLE who developed COVID-19 between April 1st to October 1st, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFNα IgG autoantibodies by ELISA. The ability of plasma anti-IFNα autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFNα in vitro was assessed by flow cytometry.ResultsTen SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFNα for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFNα induced STAT1 phosphorylation.None of the other SLE samples blocked IFNα signaling.ConclusionsWe noted an increased prevalence of pre-existing anti-IFNα autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFNα in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19.Key MessagesWhat is already known about this subject?-Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE) and have recently been associated with severe COVID-19 in the general population.What does this study add?-SLE subjects with COVID-19 had an increased prevalence of pre-existing anti-IFNα autoantibodies compared to the reported prevalence in lupus patients and the general population with severe COVID-19.-Plasma from 50% of subjects with these autoantibodies were able to block in vitro activity of IFNα.-SLE patients with pre-existing anti-IFNα autoantibodies had more severe COVID-19 manifestations.How might this impact on clinical practice or future developments?-Anti-IFNα autoantibodies may be pathogenic and could prove to be a helpful prognostic marker to predict which SLE patient may develop COVID-19 and inform preventive measures and management of this subset of patients.

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PS1:1 High type i interferon activity is associated with active class 3/4 lupus nephritis in european-american lupus patients independent of anti-dsdna antibodies

10.1136/lupus-2018-abstract.50 ◽

2018 ◽

Author(s):

T Iwamoto ◽

JM Dorschner ◽

MA Jensen ◽

D Vsetecka ◽

S Amin ◽

...

Keyword(s):

Lupus Nephritis ◽

Type I Interferon ◽

European American ◽

Type I ◽

High Type ◽

Interferon Activity ◽

Dsdna Antibodies ◽

Active Class

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Increased serum type I interferon activity in early systemic sclerosis patients is associated with antibodies against Sjögren’s syndrome antigens and nuclear ribonucleoprotein antigens

Scandinavian Journal of Rheumatology ◽

10.3109/03009742.2012.736532 ◽

2013 ◽

Vol 42 (3) ◽

pp. 235-240 ◽

Cited By ~ 9

Author(s):

DM Wuttge ◽

C Lood ◽

E Tufvesson ◽

A Scheja ◽

L Truedsson ◽

...

Keyword(s):

Systemic Sclerosis ◽

Type I Interferon ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Type I ◽

Interferon Activity ◽

Nuclear Ribonucleoprotein ◽

Early Systemic Sclerosis ◽

Serum Type ◽

Sjögren‘S Syndrome

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SAT0187 The Antimicrobial Peptide LL-37 and Type I Interferon in Idiopathic Inflammatory Myopathies

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-eular.5559 ◽

2016 ◽

Vol 75 (Suppl 2) ◽

pp. 736.1-736

Author(s):

X. Lu ◽

Q. Tang ◽

E. Lindroos ◽

M. Lindh ◽

B. Agerberth ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Type I Interferon ◽

Idiopathic Inflammatory Myopathies ◽

Type I ◽

Inflammatory Myopathies

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Characterization of Type-I IFN subtype autoantibodies and activity in SLE serum and urine

Lupus ◽

10.1177/0961203320935976 ◽

2020 ◽

Vol 29 (9) ◽

pp. 1095-1105

Author(s):

Bethany D Harris ◽

Srilalitha Kuruganti ◽

Ashlesha Deshpande ◽

Paul A Goepfert ◽

W Winn Chatham ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Interferon Α ◽

Type I ◽

Activity Levels ◽

Systemic Lupus Erythematosus Disease ◽

Systemic Lupus ◽

Interferon Activity ◽

Serum And Urine

Background/objective Type-I interferons contribute to pathogenesis in systemic lupus erythematosus, including nephritis. Interferons consist of a family of 16 proteins yet are often characterized in patients without knowledge of the specific interferon subtypes involved. Different interferons may function in the kidneys, and other organs, relative to what is often measured in patient blood. Moreover, antibodies to interferons may potentially modulate systemic or organ-specific interferon activity. The aim of this study was to characterize global interferon activity levels and identify autoantibodies to the 12 interferon α subtypes in patient serum and urine. Methods Interferon activity levels in serum and urine were measured using an interferon bioassay. Anti-interferon and anti-cytokine autoantibodies were measured by ELISA. Serum and urine samples were also characterized for their ability to neutralize the biological activity of exogenously added interferons. Results Serum interferon activity was increased in 62% of systemic lupus erythematosus patient samples, relative to healthy donor controls, whereas binding interferon α autoantibodies to at least one interferon α subtype were found in 68% of the samples evaluated. High Systemic Lupus Erythematosus Disease Activity Index scores were significantly ( p = 0.001) associated with patient samples containing interferon α autoantibodies to three or more interferon α subtypes in their serum. Interferon α autoantibodies that potently block interferon activity were rare (∼5% of samples), but collectively bound to all 12 interferon α subtypes. Urine interferon activity and interferon α autoantibody profiles did not correlate with their serum counterparts, suggesting immune responses in systemic lupus erythematosus kidneys can be distinct from those measured in serum. Analysis of autoantibodies to 15 additional cytokines in serum identified higher frequencies of granulocyte-macrophage colony-stimulating factor and interleukin 17A autoantibodies, suggesting these signaling pathways may potentially contribute, with interferons, to systemic lupus erythematosus pathogenesis. Conclusions The measurement of autoantibodies to multiple interferon subtypes in serum and urine may provide an alternative method for following interferon-mediated systemic lupus erythematosus disease activity. The results suggest autoantibodies might be used for patient monitoring and/or identifying additional cytokine signaling pathways that are functioning in different systemic lupus erythematosus patients.

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