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

Maria I Ramos,Saida Aarrass,Pleun Broekstra,Boy Helder,Samuel Perez,Paul Tak,Kris A Reedquist,Maria C Lebre,Daan M Gerlag

doi:10.1186/ar4403

Abstract

IntroductionThe 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.MethodsThe 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.ResultsFlt3L 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.ConclusionsThe 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.

Highlights

The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs)
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease characterized by persistent synovitis and hyperplasia of the joint synovium, development of pannus, and invasion of leukocytes into the joint followed by destruction of local articular components such as cartilage and bone [1,2]
Flt3L levels in rheumatoid arthritis (RA) serum, synovial fluid and synovial tissue are significantly elevated We found significantly higher levels of Flt3L in serum of RA patients compared with healthy individuals (HI) (Figure 1A, P = 0.0027)

Summary

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. Individuals with autoimmune disease show a high number of aberrantly activated DCs either in circulation or in the autoimmune lesions, secreting large amounts of proinflammatory cytokines that mediate inflammation and differentiation of pathogenic T-helper type 1 and T-helper type 17 cells [7]. Rheumatoid synovial DCs have been described as having a more mature, differentiated phenotype, expressing high levels of HLA-DR, CD86 and nuclear RelB, and have been observed to associate with T cells in perivascular mononuclear cell aggregates surrounding the postcapillary venules, and in germinal center-like structures [8]. By coordinating the recruitment and/or activation of other immune cells, DCs can drive the generation of ectopic lymphoid tissues, as in the case of inflamed synovia in RA and systemic lupus erythematosus [10]

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