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Open Access Research article

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

Tue W Kragstrup12, Babak Jalilian1, Malene Hvid13, Anders Kjærgaard4, René Østgård1, Berit Schiøttz-Christensen5, Anne G Jurik6, William H Robinson2, Thomas Vorup-Jensen1* and Bent Deleuran127

Author Affiliations

1 Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus, Denmark

2 Division of Immunology and Rheumatology, Stanford University, 296 Campus Drive, Stanford, CA 94305, USA

3 Department of Clinical Medicine, Aarhus University, Brendstrupgårdsvej 100, DK-8200 Aarhus N Denmark

4 Department of Anaesthesiology, Aarhus University Hospital, Aarhus, Denmark

5 Aarhus Rheumatology Clinic, Skt. Clemens Torv 17, DK-8000 Denmark

6 Department of Radiology, Aarhus University Hospital, Aarhus, Denmark

7 Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark

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Arthritis Research & Therapy 2014, 16:R42  doi:10.1186/ar4471

Published: 4 February 2014

Abstract

Introduction

Spondyloarthritis (SpA) comprises a group of diseases often associated with HLA-B27 and characterized by inflammation of the entheses and joints of the axial skeleton. The inflammatory process in SpA is presumably driven by innate immune cells but is still poorly understood. Thus, new tools for monitoring and treating inflammation are needed. The family of CD18 integrins is pivotal in guiding leukocytes to sites of inflammation, and CD18 hypomorphic mice develop a disease resembling SpA. Previously, we demonstrated that altered soluble CD18 (sCD18) complexes in the blood and synovial fluid of patients with arthritis have anti-inflammatory functions. Here, we study the mechanisms for these alterations and their association with SpA disease activity.

Methods

Plasma levels of sCD18 in a study population with 84 patients with SpA and matched healthy controls were analyzed with a time-resolved immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synoviocytes (FLSs) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMCs) was studied with flow cytometry and TRIFMA.

Results

Plasma levels of sCD18 were decreased in patients with SpA compared with healthy volunteers (P <0.001), and the lowest levels were in the HLA-B27-positive subgroup (P <0.05). In a multiple regression model, the sCD18 levels exhibited an inverse correlation with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (P <0.05), the level of morning stiffness (P <0.05), the Bath Ankylosing Spondilitis Metrology Index (P <0.05), the physician global assessment score (P <0.01), and the sacroiliac magnetic resonance imaging activity score (P <0.05). The mechanisms for these changes could be simulated in vitro. First, sCD18 in plasma adhered to inflammation-induced intercellular adhesion molecule 1 (ICAM-1) on endothelial cells and FLS, indicating increased consumption. Second, CD18 shedding from SpA PBMCs correlated inversely with the BASDAI (P <0.05), suggesting insufficient generation. CD18 was shed primarily from intermediate CD14++ CD16+ monocytes, supporting the view that alterations in innate immunity can regulate the inflammatory processes in SpA.

Conclusions

Taken together, the failure of patients with SpA to maintain adequate sCD18 levels may reflect insufficient CD18 shedding from monocytes to counterbalance the capture of sCD18 complexes to inflammation-induced ICAM-1. This could increase the availability of ICAM-1 molecules on the endothelium and in the synovium, facilitating leukocyte migration to the entheses and joints and aggregating disease activity.