C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid.

Lars Hornum,Henning Bliddal,Else Marie Bartels,Inger Falbe Wätjen,Anker Jon Hansen,Marianne Scheel Fjording,Paula Colmenero,Ditte Tornehave,Niels Henrik Søe Nielsen,Cordula M. Stover

doi:10.1371/journal.pone.0189017

Abstract

Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis–both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects. Cells infiltrating synovial tissue were analysed by immunohistochemistry and flow cytometry. SF and blood were analysed for biomarkers by flow cytometry or ELISA. The effect of a blocking anti-human C5aR mAb on leukocyte migration was determined using a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found in lymphoid aggregates in close contact with T cells. C5a levels were increased in both rheumatoid arthritis and psoriatic arthritis synovial fluid compared to osteoarthritis, and in blood from rheumatoid arthritis compared to healthy subjects. Neutrophil and monocyte migration to rheumatoid arthritis synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both diseases.

Highlights

The complement system plays a central role in the immune system by constituting a non-cellular system for protection against pathogens via a protease cascade leading to the activation of several effector molecules downstream of three activation pathways
IHC analyses were performed on synovial tissue samples from joint replacement from patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and OA, as well as on synovectomy biopsies from patients with RA
In synovial samples from joint replacement, infiltrating C5a or its receptor (C5aR)-positive (C5aR+) cells were demonstrated in 80% of patients with RA, in 100% of patients with PsA and in 73% of patients with OA, whereas no C5aR+ cells were infiltrating the synovium from non-inflammatory controls

Summary

Introduction

The complement system plays a central role in the immune system by constituting a non-cellular system for protection against pathogens via a protease cascade leading to the activation of several effector molecules downstream of three activation pathways (classical, lectin and alternative). An alternative non-signalling receptor is identified, but the function of this receptor is disputed, but data indicates that C5L2 functions as a intracellular inhibitor of C5a-induced C5aR signalling [2, 3]. The complement system is suggested to play a major role in rheumatoid arthritis (RA) pathogenesis, where complement activation products are found to be increased in synovial fluid (SF) to higher levels than in the matching plasma [4]. Complement polymorphism is shown as a likely player when increasing the concentration of active C5a in RA joints [8]

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