AB1168 SIGLEC1/CD169 IS A SENSITIVE MARKER FOR MONOGENIC INTERFERONOPATHIES
Authors: Banu Orak, Marc Nikolaus, Ellen Knierim, Angela Kaindl, Manuela Theophil, Axel Panzer, Barbara Zieba, Frédéric Ebstein, Elke Krüger, Nadine Unterwalder, Christian Meisel, Tilmann Kallinich
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Monogenic Interferonopathies are a rare group of inflammatory diseases that are difficult to diagnose in the onset phase given the lack of well-defined disease-markers.<sup>1</sup>A correlation with interferon-stimulated genes (ISG) has been reported for <i>SIGLEC1</i> (syn. CD169), in systemic lupus erythematodes (SLE).<sup>2</sup> Furthermore, expression of <i>SIGLEC1</i> on monocytes is the second highest ISG in SLE.<sup>3</sup> <h3>Objectives</h3> To study the relevance of <i>SIGLEC1</i> as a putative diagnostic marker for early detection of interferonopathies. <h3>Methods</h3> Clinical data, classical inflammatory markers, blood count values and genetic information were obtained from the medical files of eight patients with genetically confirmed monogenic interferonopathies. <i>SIGLEC1</i> expression was measured by flow cytometry with a highly standardized quantitative assay with a reference range in healthy controls less than 2500 <i>SIGLEC1</i> molecules/monocyte. Additionally, transcriptional level of <i>SIGLEC1, IFI44L, IFI27, ISG15</i> and <i>RSAD2</i> as type I Interferon stimulated genes were assessed by real-time PCR. <h3>Results</h3> All eight patients with interferonopathies carried mutations in the genes <i>TREX</i>-1 (n=3), <i>IFIH</i>-1 (n=2), <i>SAMDH1</i> (n=2) and <i>RNASE2HB</i> (n=1). Mean age of patients was 12 years (range 6 months to 49 years). Six of eight patients showed neurological symptoms consistent with Aicardi-Goutieres-Syndrome presenting developmental delay and microcephaly. Five patients showed abnormalities on cranial MRI including periventricular calcifications and corpus callosum thinning. Two patients were diagnosed with Singleton-Merten-Syndrome presenting abnormal ossification of extremities and dental anomalies. One patient with homozygous <i>TREX1</i> mutation presented with postnatal glaucoma, microcephaly, sensorimotor polyneuropathia and recurrent fever with persistent chilblain lesions. All patients had elevated <i>SIGLEC1</i> levels (mean molecules/monocyte +/- SD: 10272 +/- 3746) without high levels of standard inflammatory markers. In six patients, elevated <i>SIGLEC1</i> expression showed dysregulation of the type 1 interferon pathway prior to genetic testing. The relative expression (ΔCt) of all ISG's was significantly elevated in comparison to healthy controls (<i>SIGLEC1</i> p= 0,0167, <i>ISG15</i> p=0,0015, <i>RSAD2</i> p=0,0067, <i>IFIL44</i> p=0,0001, <i>IFI27</i> p=0,0056). <h3>Conclusion</h3> We report high expression of <i>SIGLEC1</i> in monogenic interferonopathies like Aicardi-Goutières-Syndrome. Therefore, <i>SIGLEC1</i> qualifies as an easy accessible and cheap diagnostic marker to screen patients with suspected interferonopathy. <h3>References</h3> [1] Crow, Y.J., Type I interferonopathies: mendelian type I interferon up-regulation. Curr Opin Immunol, 2015. 32: p. 7-12. [2] Rose, T., et al., Are interferon-related biomarkers advantageous for monitoring disease activity in systemic lupus erythematosus? A longitudinal benchmark study. Rheumatology (Oxford), 2017. 56(9): p. 1618-1626. [3] Biesen, R., et al., Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum, 2008. 58(4): p. 1136-45. <h3>Disclosure of Interests</h3> Banu Orak: None declared, Marc Nikolaus: None declared, Ellen Knierim: None declared, Angela Kaindl: None declared, Manuela Theophil: None declared, Axel Panzer: None declared, Barbara Zieba: None declared, Frédéric Ebstein: None declared, Elke Krüger: None declared, Nadine Unterwalder: None declared, Christian Meisel: None declared, Tilmann Kallinich Grant/research support from: Novartis, Speakers bureau: Sobi, Roche, Novartis, CLB