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Abstract
Objective The most prominent alteration in the immune system of patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) is the increased expression of type I interferon (IFN) inducible genes, known as the IFN signature. This signature is related to disease activity, vascular disease and predicts future flares and the response to anifrolumab. There is an urgent need for easily measurable biomarkers to detect an IFN signature. Galectin-9 may steer T-cell responses and is a potential biomarker for autoimmune diseases. In the present study we investigated the performance of galectin-9 as a biomarker to detect the IFN signature in SLE and APS and its production by dendritic cell (DC) subsets.
Methods Serum levels of galectin-9 and CXCL10 were measured by Luminex in an identification cohort (n=43) and replication cohort (n=148) of patients with SLE, SLE +APS and primary APS (PAPS) and healthy controls (HC). Isolated monocytes were used to quantify IFN scores by measuring the expression of 4 type I IFN inducible genes. The performance of potential biomarkers for the IFN signature were assessed by Receiver Operating Characteristics curves. RNA sequencing on plasmacytoid and myeloid DC isolated from patients with SLE, SLE +APS and PAPS (n=54) were analysed to identify potential sources of galectin-9 in SLE and APS.
Results In both identification and replication cohort, serum levels of galectin-9 and CXCL10 were elevated in SLE, SLE +APS and PAPS patients as compared with HC (all p<0.05) and both galectin-9 and CXCL10 correlated with the IFN signature (r=0.66, p<0.001 and r=0.46, p<0.001 respectively). ROC-curve analysis revealed a better performance of galectin-9 (AUC 0.86) than CXCL10 (AUC 0.78) or traditional serological biomarkers for SLE (AUC <0.75) to detect an IFN signature. The expression of galectin-9 was increased in both pDC and mDC in SLE and APS, in particular in IFN-high patients. In vitro, IFNα upregulated galectin-9 expression in pDC and mDC.
Conclusion Galectin-9 is produced by dendritic cells in SLE and APS upon activation by IFNα and serves as an easily measurable biomarker that outclasses CXCL10 or traditional measures of disease activity to detect an IFN signature in patients with SLE and APS.
