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Open Access Research article

FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis

Maria I Ramos12, Samuel Garcia Perez12, Saida Aarrass12, Boy Helder12, Pleun Broekstra12, Daan M Gerlag1, Kris A Reedquist12, Paul Peter Tak134 and Maria C Lebre12*

Author Affiliations

1 Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, K0-126 Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands

2 Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, K0-126 Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands

3 University of Cambrigde, U.K. Trinity Lane, Cambridge CB2 1TN, UK

4 ImmunoInflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, U.K. Gunnels Wood Road, Stevenage Herts SG1 2NY, UK

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Arthritis Research & Therapy 2013, 15:R209  doi:10.1186/ar4403

Published: 6 December 2013

Abstract

Introduction

The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients.

Methods

The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab.

Results

Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy.

Conclusions

The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.