Agonistic anti-ICAM-1 antibodies in scleroderma: Activation of endothelial pro-inflammatory cascades

作者：Wolf Sabine I; Howat Sarah; Abraham David J; Pearson Jeremy D; Lawson Charlotte^*

来源：Vascular Pharmacology, 2013, 59(1-2): 19-26.

DOI：10.1016/j.vph.2013.05.002

• Systemic sclerosis
• ICAM-1
• Autoantibodies
• Vascular inflammation

Background: Scleroderma (SSc) is a complex autoimmune disorder that can be characterised by the presence 2of circulating autoantibodies to nuclear, cytoplasmic and cell surface antigens. In particular antibodies directed against endothelial cell antigens (anti-endothelial cell antibodies; AECA) have been detected.
ICAM-1 is an adhesion molecule expressed on the surface of human endothelial cells. We have previously shown that cross-linking ICAM-1 with monoclonal antibodies leads to pro-inflammatory activation of human endothelial and vascular smooth muscle cells and that cardiac transplant recipients with transplant associated vasculopathy make antibodies directed against ICAM-1.
Objectives: To determine whether SSc patients make antibodies directed against ICAM-1 and whether these antibodies induce pro-inflammatory activation of human endothelial cells in vitro.
Methods: Using recombinant ICAM-1 as capture antigen, an ELISA was developed to measure ICAM-1 antibodies in sera from SSc patients. Antibodies were purified using ICAM-1 micro-affinity columns. HUVEC were incubated with purified anti-ICAM-1 antibodies and generation of reactive oxygen species, and expression of VCAM-1 was measured.
Results: Significantly elevated levels of anti-ICAM-1 antibodies were detected in patients with diffuse (dSSc; 10/31 32%) or limited (ISSc; 14/36 39%) scleroderma. Cross-linking of HUVEC with purified anti-ICAM-1 antibodies caused a significant increase in ROS production (2.471 +/- 0.408 fold increase above untreated after 150 min p < 0.001), and significant increase in VCAM-1 expression (10.6 +/- 1.77% vs 4.12 +/- 1.33%, p < 0.01).
Conclusion: AECA from SSc patients target specific endothelial antigens including ICAM-1, and cause pro-inflammatory activation of human endothelial cells, suggesting that they are not only a marker of disease but that they contribute to its progression.

• 出版日期2013-8