Galectins-1, -3, -9 and type I interferon signature in systemic lupus erythematosus: Is there a relationship?

The aim of the study – to clarify the relationship between serum levels of galectins-1, -3, and -9 and type I interferon gene signature (IFNGS) and to compare its potential as biomarkers of “positive” interferon status in patients with systemic lupus erythematosus (SLE).

Material and methods. The cross-sectional study included 60 women and 11 men with a diagnosis of SLE established according to the SLICC (Systemic Lupus International Collaborating Clinics) 2012 criteria. The patients’ age was 33 [25; 43] years, and the median duration of the disease was 30 [2; 132] months. 19 (26.8 %) patients had high and very high SLE activity (SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) >10), and 24 (33.8%) had moderate activity (SLEDAI-2K=5–10). Glucocorticoids were received by 58 (81.7%), hydroxychloroquine – by 57 (80.3%), immunosuppressants – by 28 (39.4%) patients. The control group included 20 people without immunoinflammatory rheumatic diseases. IFNGS were evaluated by the expression of interferoninduced genes (MX1, RSAD2, EPSTI1) using real-time polymerase chain reaction. If the average indicated genes expression in the patient exceeded that in the control group, IFNGS was considered “positive”, if not – “negative”. Galectin-1, -3 and -9 levels were determined in the blood serum of SLE patients by the enzyme-linked immunosorbent assay (reagents by Cloud-Clone Corp., China).

Results. “Positive” IFNGS was detected in 53 (74.6%) of 71 patients with SLE. The galectin-1 and galectin-3 concentrations were comparable in patients with “positive” and “negative” IFNGS, while the level of galectin-9 was higher in patients with gene overexpression (0.009 [0.002; 0.69] vs 0.002 [0.001; 0.003] pg/ml, respectively; p=0.02). A weak correlation was found between serum galectin-9 levels and EPSTI1 gene expression (r=0.26; p=0.03). In the ROC analysis of using galectin-9 levels as a marker of “positive” IFNGS, the area under the curve was 0.682 (95% confidence interval: 0.537–0.827; p=0.021), and the cutoff point was 0.0025 pg/ml (sensitivity 71.7%, specificity 72.2%).

Conclusion. In SLE patients, serum concentrations of galectin-9, but not galectin-1 and galectin-3, were associated with overexpression of type I interferon-induced genes, namely, EPSTI1. ROC-analysis demonstrated the average quality of the model in the case of using galectin-9 as the only serological biomarker of “positive” IFNGS in SLE. Further research is needed to clarify the diagnostic value of the combination of galectin-9 with other proteins whose synthesis depends on type I interferon.

1. Nasonov EL, Soloviev SK, Arshinov AV. Systemic lupus erythematosus: History and modernity. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2022;60(4):397-412 (In Russ.). doi: 10.47360/1995-4484-2022-397-412

2. Avdeeva AS, Aleksankin AP, Tchetina EV, Gorbunova YuN, Popkova TV, Markova GA, et al. Immunophenotypes of systemic lupus erythematosus – features of clinical and laboratory disorders. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2024;62(4):394-401 (In Russ.). doi: 10.47360/1995-4484-2024-394-401

3. Guthridge JM, Wagner CA, James JA. The promise of precision medicine in rheumatology. Nat Med. 2022;28(7):1363-1371. doi: 10.1038/s41591-022-01880-6

4. Guthridge JM, Lu R, Tran LT, Arriens C, Aberle T, Kamp S, et al. Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study. EClinicalMedicine. 2020;20:100291. doi: 10.1016/j.eclinm.2020.100291

5. Enocsson H, Wetterö J, Eloranta ML, Gullstrand B, Svanberg C, Larsson M, et al. Comparison of surrogate markers of the type I interferon response and their ability to mirror disease activity in systemic lupus erythematosus. Front Immunol. 2021;12:688753. doi: 10.3389/fimmu.2021.688753

6. van den Hoogen LL, van Roon JAG, Mertens JS, Wienke J, Lopes AP, de Jager W, et al. Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis. 2018;77(12):1810-1814. doi: 10.1136/annrheumdis-2018-213497

7. Kondratyeva LV, Popkova TV, Nasonov EL. Galectins, antibodies to them and galectin-3 binding protein in systemic lupus erythematosus. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2025;63(1):37-45 (In Russ.). doi: 10.47360/1995-4484-2025-37-45

8. Kondrateva LV, Panafidina TA, Gorbunova YN, Popkova TV, Diatroptov ME, Avdeeva AS. Galectins 1, 3 and 9 in patients with systemic lupus erythematosus: Is there an association with disease activity or clinical manifestations? Modern Rheumatology Journal. 2025;19(5):20-25 (In Russ.). doi: 10.14412/1996-7012-2025-5-20-25

9. Gómez-Bañuelos E, Goldman DW, Andrade V, Darrah E, Petri M, Andrade F. Uncoupling interferons and the interferon signature explains clinical and transcriptional subsets in SLE. Cell Rep Med. 2024;5(5):101569. doi: 10.1016/j.xcrm.2024.101569

10. Panafidina TA, Popkova TV, Gorbunova YuN, Kondratyeva LV, Tchetina EV, Avdeeva AS, et al. Clinical significance of interferon status in patients with systemic lupus erythematosus. Preliminary data. NauchnoPrakticheskaya Revmatologia = Rheumatology Science and Practice. 2025;63(1):95-103 (In Russ.). doi: 10.47360/1995-4484-2025-95-103

11. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-2686. doi: 10.1002/art.34473

12. Kuca-Warnawin E, Skalska U, Janicka I, Musiałowicz U, Bonek K, Głuszko P, et al. The phenotype and secretory activity of adiposederived mesenchymal stem cells (ASCs) of patients with rheumatic diseases. Cells. 2019;8(12):1659. doi: 10.3390/cells8121659

13. Yaseen H, Butenko S, Polishuk-Zotkin I, Schif-Zuck S, PérezSáez JM, Rabinovich GA, et al. Galectin-1 facilitates macrophage reprogramming and resolution of inflammation through IFN-β. Front Pharmacol. 2020;11:901. doi: 10.3389/fphar.2020.00901

14. Mobergslien A, Sioud M. Galectin-1 and -3 gene silencing in immature and mature dendritic cells enhances T cell activation and interferon-γ production. J Leukoc Biol. 2012;91(3):461-467. doi: 10.1189/jlb.0711361

15. Beccaria CG, Amezcua Vesely MC, Fiocca Vernengo F, Gehrau RC, Ramello MC, Tosello Boari J, et al. Galectin-3 deficiency drives lupus-like disease by promoting spontaneous germinal centers formation via IFN-γ. Nat Commun. 2018;9(1):1628. doi: 10.1038/s41467-018-04063-5

16. Gieseke F, Kruchen A, Tzaribachev N, Bentzien F, Dominici M, Müller I. Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation. Eur J Immunol. 2013;43(10):2741-2749. doi: 10.1002/eji.201343335

17. Ishii T, Onda H, Tanigawa A, Ohshima S, Fujiwara H, Mima T, et al. Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients. DNA Res. 2005;12(6):429-439. doi: 10.1093/dnares/dsi020

18. Yang Y, Zhang H, Xiao X, Guo M. Identification of EPSTI1 as a new potential biomarker for SLE based on GEO database. Clin Rheumatol. 2024;43(5):1531-1540. doi: 10.1007/s10067-024-06881-z

19. Fanouriakis A, Kostopoulou M, Andersen J, Aringer M, Arnaud L, Bae SC, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15-29. doi: 10.1136/ard-2023-224762

20. Nasonov EL, Lila AM, Popkova TV, Soloviev SK, Reshetnyak TM, Aseeva EA, et al. Systemic lupus erythematosus: Clinical recommendations. Moscow;2025 (In Russ.). URL: https://cr.minzdrav.gov.ru/view-cr/484_2 (Accessed: 2nd February 2026).