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 Blood, 1 May 2007, Vol. 109, No. 9, pp. 3881-3889.
Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2006-08-044669.

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IMMUNOBIOLOGY

Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between Fc{gamma}RIIa and CXCR1/2

Oliver J. Florey1, Michael Johns1, Olubukola O. Esho1, Justin C. Mason1, and Dorian O. Haskard1

1 British Heart Foundation (BHF) Cardiovascular Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, United Kingdom

Antiendothelial cell antibodies (AECAs) are commonly detectable in diseases associated with vascular injury, including systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Wegener granulomatosis, Behçet syndrome, and transplant arteriosclerosis. Here, we explore the hypothesis that these antibodies might augment polymorphonuclear leukocyte (PMN) adhesion to endothelium in inflammation. Initially, we established that a mouse IgG mAb bound to endothelial cells (ECs) significantly increased PMN adhesion to cytokine-stimulated endothelium in an Fc{gamma}RIIa-dependent manner. Neutralizing antibodies, and adenoviral transduction of resting ECs, demonstrated that the combination of E-selectin, CXCR1/2, and ß2 integrins is both necessary and sufficient for this process. We observed an identical mechanism using AECA IgG isolated directly from patients with SLE. Assembled immune complexes also enhanced PMN adhesion to endothelium, but, in contrast to adhesion because of AECAs, this process did not require CXCR1/2, was not inhibited by pertussis toxin, and was Fc{gamma}RIIIb rather than Fc{gamma}RIIa dependent. These data are the first to demonstrate separate nonredundant Fc{gamma}RIIa and Fc{gamma}RIIIb-mediated mechanisms by which EC-bound monomeric IgG and assembled immune complexes amplify leukocyte adhesion under dynamic conditions. Furthermore, the observation that Fc{gamma}RIIa and CXCR1/2 cooperate to enhance PMN recruitment in the presence of AECAs suggests a mechanism whereby AECAs may augment tissue injury during inflammatory responses.


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Related Article in Blood Online:

Fc{gamma}Rs join in the cascade
Francis W. Luscinskas and Tanya Mayadas
Blood 2007 109: 3615-3616. [Full Text] [PDF]





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