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We read with great interest the article by van den Hoogen et al 1 describing galectin-9 (Gal-9) as a novel, easy-to-measure biomarker for the interferon (IFN) signature in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). We support the views expressed by the authors that IFN signature is an important biomarker in disease activity in SLE and there is certainly a need for easier to measure biomarkers for IFN signature, but to suggest that Gal-9 could aid in clinical decision making in steering anti-IFN therapy seems premature. We know that the common method to measure type I IFN activity is based on standardised expression levels of selected IFN stimulated genes—through an IFN score. One should keep in mind that it is an indirect measurement to show the type I IFN activity and is most likely to be the less sensitive method for capturing the change in type I IFNs. The direct quantification could be challenging, but recent progress using digital ELISA to capture IFN-α at attomolar concentrations is much promising.2
Gal-9 is a member of tandem repeat galectins, and it plays important regulatory roles in autoimmune diseases including SLE. Interestingly, Gal-9 inhibits the toll-like receptors (TLR)7/9-induced IFN production by plasmacytoid dendritic cells, suggesting that Gal-9 executes a negative feedback signal in SLE.3 Multiple non-immune and immune effector cells constitutively express galectins, and liver is one of the main sites where Gal-9 is highly expressed. Thus, patients with hepatitis B or C as well as other inflammatory liver disease have higher plasma levels of Gal-9 as compared with healthy individuals.4 Recent reports also indicate that under inflammatory conditions like cytomegalovirus or HIV infection, peripheral blood mononuclear cells and mesenchymal stromal cells increase its expression.5 Therefore, one wonders how reliable of a diagnostic or monitoring biomarker would Gal-9 be, for example, in differentiating an SLE flare from an infection. The design of the study lacks in detecting any changes in disease activity or relation to clinical manifestations, but shows an association between four IFN stimulated genes and Gal-9. The authors hasten to conclude that Gal-9 is a biomarker for disease activity without showing changes of Gal-9 levels in active/inactive states of a particular patient within a longitudinal study (figure 1). In addition, the authors neglected to mention any difference related to age, disease duration or ethnicity, which are known effectors of IFN-α expression.6 We therefore suggest that Gal-9 is further investigated in SLE and other inflammatory diseases, before this protein is applied as a biomarker for the IFN signature in SLE and APS.
Handling editor Josef S Smolen
Contributors Both authors contributed equally to writing and editing this letter.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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