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Published online before print November 1, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607339

Received for publication June 1, 2007.
Revised September 24, 2007.
Accepted for publication September 24, 2007.

Article

Vimentin autoantibodies induce platelet activation and formation of platelet-leukocyte conjugates via platelet-activating factor

H. S. Leong ^*, B. M. Mahesh ^*, J. R. Day , J. D. Smith , A. D. McCormack ^*, G. Ghimire , T. J. Podor , and M. L. Rose ^*@

*National Heart and Lung Institute, Imperial College at Harefield Hospital, and Transplant Immunology, Harefield Hospital, Harefield, Middlesex, United Kingdom; Eric Bywaters Centre, BHF Cardiovascular Medicine Unit, Imperial College at Hammersmith Hospital, London, United Kingdom; and James Hogg iCAPTURE Centre for Pulmonary and Cardiovascular Research, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

^@ To whom correspondence should be addressed. E-mail: marlene.rose{at}imperial.ac.uk.

	Abstract

Anti-vimentin antibodies (AVA) are associated with autoimmunity and solid organ transplantation, conditions associated with vascular disease, but their contribution to disease pathogenesis is unknown. Here, we have examined interactions between AVA (mAb and serum from patients) and various leukocyte populations using whole blood and flow cytometry. Normal blood treated with patient sera containing high AVA-IgM titers or with a vimentin-specific monoclonal IgM led to activation of platelets and other leukocytes, as demonstrated by induced expression of P-selectin, fibrinogen, tissue factor, and formation of platelet:leukocyte (P:L) conjugates and a reduction in platelet counts. This activity was antigen (vimentin)-specific and was not mediated by irrelevant IgM antibodies. Flow cytometry demonstrated that AVA do not bind directly to resting platelets in whole blood, but they bind to 10% of leukocytes. Supernatant, derived from AVA-treated leukocytes, induced platelet activation, as measured by the generation of platelet microparticles, when added to platelet-rich plasma. When AVA were added to whole blood in the presence of CV-6209, a platelet-activating factor (PAF) receptor inhibitor, platelet depletion was inhibited. This suggests that PAF is one of the mediators released from AVA-activated leukocytes that leads to P:L conjugation formation and platelet activation. In summary, AVA bind to leukocytes, resulting in release of a PAF and prothrombotic factor that exert a paracrine-activating effect on platelets. Overall, this proposed mechanism may explain the pathogenesis of thrombotic events in autoimmune diseases associated with AVA.

Key Words: neutrophils • senescence • complement