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Agrin Signalling Contributes to Cell Activation and Is Overexpressed in T Lymphocytes from Lupus Patients¹

Elizabeth C. Jury^2,*, Jillian Eldridge^*, David A. Isenberg^* and Panagiotis S. Kabouridis^2,

^* Centre for Rheumatology, Royal Free and University College Medical School, University College London, and Bone and Joint Research Unit, Queen Mary’s School of Medicine and Dentistry, London, United Kingdom

It is shown in this study that the heparan sulfate proteoglycan agrin is overexpressed in T cells isolated from patients with the autoimmune disease systemic lupus erythematosus (SLE). Freshly isolated CD4⁺ and CD8⁺ subpopulations both exhibited higher expression over healthy controls, which however, gradually declined when cells were cultured in vitro. Agrin expression was induced following in vitro activation of cells via their Ag receptor, or after treatment with IFN-, a cytokine shown to be pathogenic in lupus. Furthermore, serum from SLE patients with active disease was able to induce agrin expression when added to T cells from healthy donors, an increase that was partially blocked by neutralizing anti-IFN- Abs. Cross-linking agrin with mAbs resulted in rapid reorganization of the actin cytoskeleton, activation of the ERK MAPK cascade, and augmentation of anti-CD3-induced proliferation and IL-10 production, indicating that agrin is a functional receptor in T cells. These results demonstrate that agrin expression in human T cells is regulated by cell activation and IFN-, and may have an important function during cell activation with potential implications for autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Project Grants 16018 (to P.S.K.), 17319 (to E.C.J.), and I0538 (to J.E.) from the Arthritis Research Campaign U.K.

² Address correspondence and reprint requests to Dr. Panagiotis S. Kabouridis Bone and Joint Research Unit, Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, U.K.; E-mail address: p.s.kabouridis{at}qmul.ac.uk or Dr. Elizabeth C. Jury, Centre for Rheumatology, Royal Free and University College Medical School, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, U.K.; E-mail address: e.jury{at}ucl.ac.uk

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; AChR, acetylcholine receptor; TRITC, tetramethylrhodamine isothiocyanate; DRM, detergent-resistant membrane; siRNA, small interfering RNA; MFI, mean fluorescence intensity; GM1, ganglioside M1.