Background/Purpose:

Spondyloarthritis (SpA) comprise a group of diseases characterized by inflammation of the entheses and joints of the axial skeleton primarily driven by innate immune cells such as monocytes, fibroblasts and granulocytes.(1) The family of CD18 integrins is pivotal in guiding leukocytes to sites of inflammation and has been shown to form soluble complexes in the blood (sCD18).(2) CD18 hypomorphic mice develop a disease resembling psoriatic arthritis, demonstrating that decreased CD18 expression can result in development of SpA-like disease.(3) Here, we investigated whether sCD18 plays a role in SpA disease pathogenesis.

Methods:

The level of sCD18 in plasma from a well characterized study population with 84 SpA patients and age- and sex-matched healthy controls was analyzed with a time resolved immunoflourometric assay (TRIFMA). Shedding of CD18 from peripheral blood mononuclear cells was studied by using flow cytometry and TRIFMA. Binding of sCD18 to endothelial cells and fibroblast-like synovial cells (FLS) was studied by using confocal microscopy.

Results:

Plasma levels of sCD18 were decreased in SpA patients compared with healthy volunteers (P< 0.001). The sCD18 levels exhibited an inverse correlation with the BASDAI (P< 0.05), the level of morning stiffness (P< 0.05), the BASMI (P< 0.05), the physician global assessment score (P< 0.01), and the sacroiliac MRI activity score (P< 0.05) in multiple regression models, including multivariate analysis to account for differences in CRP levels. Remarkably, this situation could be simulated in vitro. First, CD18 shedding from SpA PBMC correlated inversely with the BASDAI (P< 0.05), suggesting insufficient generation (Fig 1A). Second, sCD18 in plasma adhered to inflammation induced ICAM-1 on endothelial cells and FLS, indicating increased consumption (Fig 1B). Importantly, both ICAM-1 expression and CD18 shedding were increased by TNFα, suggesting that sCD18 plays a role in regulating leukocyte migration during the normal immune response. CD18 was primarily shed from monocytes, supporting the notion that alterations in innate immunity dominate the inflammatory processes in SpA (Fig 1C).

Conclusion:

Taken together, the failure of SpA patients to maintain normal sCD18 levels may reflect insufficient CD18 shedding from monocytes to counterbalance the capture of sCD18 complexes to inflammation induced ICAM-1. This results in increased availability of ICAM-1 molecules on the endothelium and in the synovium facilitating increased leukocyte migration to the entheses and joints and increased inflammatory burden. In this way, our findings on sCD18 link leukocyte migration with SpA disease activity.

References:

1. Ambarus C et al. Curr Opin Rheumatol. 2012 Jul;24(4):351–8.

2. Gjelstrup LC et al. J. Immunol. 2010 Oct 1;185(7):4154–68.

3. Wang H et al. J. Immunol. 2008 Apr 15;180(8):5520–9.