Soluble BDCA-2 as a potential biomarker for rheumatoid arthritis and its role in enhancing IFN-α production through nucleic acid binding.

Abstract

Aberrant interferon (IFN) signalling is strongly associated with rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Blood dendritic cell antigen 2 (BDCA-2) regulates IFN production in plasmacytoid dendritic cells (pDCs). While heparin inhibits IFN formation via triggering surface BDCA-2, its soluble form (solBDCA-2) antagonizes heparin and thereby drives excessive IFN formation. However, the role of solBDCA-2 in RA and SLE is unknown. This study aims to determine whether solBDCA-2 can serve as a biomarker for RA and/or SLE and provide insights into its potential role in disease mechanisms. solBDCA-2 and IFN-α expression were analysed by ELISA in the serum of RA (n = 14) and SLE (n = 14) patients and compared with healthy controls (n = 15). To gain mechanistic insight of solBDCA-2 in RA and SLE, we studied the interaction of solBDCA-2 with nucleic acids, its role in enhancing type I IFN production in the plasmacytoid dendritic cell line CAL-1 and in human peripheral blood mononuclear cells (hPBMCs). IFN-α was upregulated in patient sera of both RA and SLE. In contrast, solBDCA-2 was exclusively upregulated in the serum of RA patients, but not in patients with SLE. solBDCA-2 interacted with phosphodiester CpG-oligodeoxynucleotides (ODN) 2006, a ligand of TLR9, and poly I:C, a ligand of TLR3, to form complexes that enhance type I IFN production in CAL-1 cells and hPBMCs. These findings show that solBDCA-2 enhances type I interferon production by forming immunostimulatory complexes with DNA and RNA. Dysregulated solBDCA-2 expression might contribute to RA pathogenesis.