CD52 regulates monocyte adhesion and interferon type I signalling in systemic sclerosis patients

OBJECTIVES Systemic sclerosis (SSc) is characterised by dysregulation of type I interferon (IFN-I) signalling. CD52 is known for its immunosuppressive functions in T-cells. We aimed to investigate the role of CD52 in monocyte adhesion and IFN-I signalling in SSc. METHODS Transcriptome profiles of circulating CD14+ monocytes from lcSSc, dcSS and healthy controls were analysed by RNA sequencing. Levels of CD52, CD11b/integrin αΜ and CD18/integrin β2 in whole blood was assessed by flow cytometry. CD52 expression was analysed in relation to disease phenotype (early, lcSSc, dcSS) and autoantibody profiles. The impact of overexpression, knockdown, and antibody blocking of CD52 were analysed by gene and protein expressions and functional assays. RESULTS Pathway enrichment analysis indicated an increase in adhesion- and IFN-I-related genes in SSc monocytes. These cells displayed up-regulated CD11b/CD18, reduced CD52 expression and enhanced adhesion to ICAM1 and endothelial cells. CD52 expression was consistent with SSc subtypes, immunosuppressive treatment and autoantibody profiles of SSc patients and monocyte adhesion properties. Overexpression of CD52 decreased CD18 levels and monocyte adhesion, while knockdown of CD52 increased monocyte adhesion. Treatment with the anti-CD52 antibody Alemtuzumab increased monocyte adhesion, CD11b/CD18 expression, and enhanced IFN-I responses. Monocytic CD52 expression was up-regulated by IL-4/IL-13 via STAT6 pathway and down-regulated by LPS, IFN-α, IFN-β or IFN-γ in JAK1 and histone deacetylates (HDAC) IIa-dependent manner. CONCLUSIONS Down-regulation of anti-adhesive CD52 antigen in CD14+ monocytes represents a novel mechanism in the pathogenesis of SSc. Targeting of the IFN-HDAC-CD52 axis in monocytes might represent a new therapeutic option for early SSc patients.