SIGLEC1 (CD169) as a potential diagnostical screening marker for monogenic interferonopathies

Orak, Banu; Ngoumou, Gonza; Ebstein, Frédéric; Zieba, Barbara A.; Goetzke, Carl Christoph; Knierim, Ellen; Kaindl, Angela M.; Panzer, Axel; Theophil, Manuela; Berns, Monika; Krüger, Elke; Meisel, Christian; Unterwalder, Nadine; Kallinich, Tilmann

doi:10.1111/pai.13400

Cited by 15 publications

(9 citation statements)

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“…In all severe COVID-19 PAD patients, SIGLEC1 expression on monocytes was analyzed in EDTA whole blood based on a method described previously ( 32 ). SIGLEC1 levels on monocytes were investigated using an admitted flow cytometry protocol at the clinical diagnostics laboratory (Labor Berlin GmbH).…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity

et al. 2022

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Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4+ T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.

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Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity

et al. 2022

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“…In this study, expression of SIGLEC1—which is mostly type I interferon regulated34 45—was lower in antisynthetase syndrome than in dermatomyositis. It has been proposed that type II interferons might play a more prominent role in the etiopathogenesis of antisynthetase syndrome 40 46.…”

Section: Discussionmentioning

confidence: 50%

“…Hence, a cell-specific approach to analysing type I interferon activity by measuring cell surface expression of SIGLEC1 on monocytes by flow cytometry could be advantageous 26. The utility of SIGLEC1 assessment by flow cytometry has been shown very recently in juvenile dermatomyositis,27 adult and juvenile systemic lupus erythematosus,25 28–31 systemic sclerosis,32 Sjögren’s syndrome,33 genetic interferonopathies34 and viral infections including COVID-19,35 but has not been analysed in adult dermatomyositis and other subtypes of idiopathic inflammatory myopathies.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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ObjectiveTo evaluate sialic acid binding Ig-like lectin 1 (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 paediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment or Childhood Myositis Assessment Scale disease activity scores. Mann Whitney U test and receiver operating characteristic 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 analysed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared with interferon-stimulated gene 15/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 necrotising 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 of 0.92 (95% CI 0.83 to 1) in DM and correlated with disease activity longitudinally (aDM: standardised beta=0.54, p<0.001; jDM: standardised beta=−0.70, p<0.001). Response to treatment in DM was associated with a decreasing SIGLEC1 (p<0.01, Wilcoxon test). SIGLEC1 was found upregulated in 8 of 19 patients with AS, 2 of 9 patients with IBM but 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.

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“…Our data suggest that validated, worldwide available interferon biomarkers may further improve diagnostic procedures and, potentially, classification of SLE [14]. With a sensitivity of nearly 100 % in juvenile dermatomyositis [15], a sensitivity of 100 % in monogenic interferonopathies [16], and a sensitivity of > 95 % in early SARS-CoV2 infection [17], SIGLEC1 may also provide a valuable screening tool for other disorders associated with increased IFN-I activity.…”

Section: Discussionmentioning

confidence: 95%

Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus

Zorn-Pauly

Stuckrad

Rose

et al. 2021

Preprint

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Objectives: To evaluate and compare the diagnostic accuracy utility of SIGLEC1, a surrogate marker of type I IFN, compared to with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE). Methods: SIGLEC1 was analysed by flow cytometry in our central laboratory facility in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020. Results: SLE was confirmed in 76 of 232 patients (32.8%) according to the 2019 EULAR/ACR classification criteria and their . SIGLEC1 values were significantly higher in patients with SLE compared to patients without SLE (p<0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were > 99.9 % and 0.1 %, respectively. Using ROC analysis and DeLlong testing, the area under the curve (AUC) for SIGLEC1 (AUC=0.95) was significantly higher than for ANA (AUC=0.88, p=0.031), C3 (AUC=0.83, p=0.001) and C4 (AUC=0.83, p=0.002) but not for anti-dsDNA antibodies (AUC=0.90, p=0.163). Conclusion: IFN-I pathway activation is detectable in almost most all newly diagnosed SLE patients, where SIGLEC1 outcompetes the performance of other biomarkers to exclude SLE with high predictability in suspected cases. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.

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SIGLEC1 (CD169) as a potential diagnostical screening marker for monogenic interferonopathies

Abstract: ME, et al. International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-Workgroup Report of the Adverse Reactions to Foods Committee,

Cited by 15 publications

References 11 publications

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity

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

Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus

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