Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

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

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 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 altered soluble CD18 (sCD18) complexes in the blood and synovial fluid of arthritis patients to 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 SpA patients and matched healthy controls were analyzed with a time resolved immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synovial cells (FLS) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMC) was studied with flow cytometry and TRIFMA. RESULTS: Plasma levels of sCD18 were decreased in SpA patients compared with healthy volunteers (P < 0.001) with the lowest levels 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 (BASMI) (P < 0.05), the physician global assessment score (P < 0.01), and the sacroiliac MRI activity score (P < 0.05). The mechanisms for these changes could be simulated in vitro. First, sCD18 in plasma adhered to inflammation induced ICAM-1 on endothelial cells and FLS indicating increased consumption. Second, CD18 shedding from SpA PBMC correlated inversely with the BASDAI (P < 0.05) suggesting insufficient generation. CD18 was primarily shed from intermediate CD14++ CD16+ monocytes supporting that alterations in innate immunity can regulate the inflammatory processes in SpA. CONCLUSIONS: Taken together, the failure of SpA patients 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.