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Rheumatology Advance Access published online on September 27, 2005
Rheumatology, doi:10.1093/rheumatology/kei118
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received May 24, 2005
Accepted August 12, 2005

Original Papers

Autoantibody to CD40 ligand in systemic lupus erythematosus: association with thrombocytopenia but not thromboembolism

M. Nakamura 1, Y. Tanaka 1, T. Satoh 1, M. Kawai 1, M. Hirakata 2, J. Kaburaki 3, Y. Kawakami 1, Y. Ikeda 2, and M. Kuwana 1*

1 Institute for Advanced Medical Research, Tokyo Electric Power Company Hospital, Tokyo, Japan
2 Department of Internal Medicine, Keio University School of Medicine, Tokyo Electric Power Company Hospital, Tokyo, Japan
3 Department of Internal Medicine, Tokyo Electric Power Company Hospital, Tokyo, Japan

* To whom correspondence should be addressed.
M. Kuwana, E-mail: kuwanam{at}sc.itc.keio.ac.jp


  Abstract

Objectives. To examine the prevalence, clinical associations and pathogenic roles of autoantibodies to CD40 ligand (CD40L) in patients with systemic lupus erythematosus (SLE).

Methods. Plasma anti-CD40L antibodies from 125 patients with SLE, 24 with primary antiphospholipid syndrome (APS) and 90 with idiopathic thrombocytopenic purpura (ITP) and from 62 healthy individuals were measured with an enzyme-linked immunosorbent assay (ELISA). HeLa cells transfected with human CD40L cDNA (HeLa/CD40L) were used to confirm the presence of anti-CD40L autoantibodies. The effect of anti-CD40L antibodies on the CD40L-CD40 interaction was evaluated by observing CD40L-induced I{kappa}B activation in CD40-expressing fibroblasts.

Results. Anti-CD40L autoantibody was detected in seven (6%) SLE, three (13%) primary APS and 11 (12%) ITP patients, but in no healthy controls. Antibody binding in an ELISA was competitively inhibited by membrane components of HeLa/CD40L. Anti-CD40L antibody-positive IgG specifically bound the surface of living HeLa/CD40L, as shown by flow cytometry. The frequency of thrombocytopenia was significantly higher in SLE patients with the anti-CD40L antibody than in those without (100 vs 14%; P<0.00001), whereas there was no association between the anti-CD40L antibody and thrombosis. Binding of the anti-CD40L antibodies in patients' plasma to CD40L was competitively inhibited by a series of mouse anti-CD40L monoclonal antibodies. Anti-CD40L antibody-positive IgG failed to inhibit CD40L-induced I{kappa}B activation.

Conclusions. Anti-CD40L autoantibody is associated with thrombocytopenia but not thromboembolism. Our findings are potentially useful in understanding the complex roles of CD40L in the pathophysiology of thrombosis and haemostasis as well as the thromboembolic complications that occur during treatment with anti-CD40L humanized antibody.

Keywords: Autoantibody; CD40 ligand; Costimulatory molecule; Humanized antibody; Platelet; Systemic lupus erythematosus; Thrombocytopenia; Thrombosis.
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