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* Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910;
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Department of Medicine, Section of Rheumatology, Washington Hospital Center, Washington, DC 20010; and
Department of Pathology, University of Virginia, Charlottesville, VA 22908
Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disease characterized by autoantibody production and abnormal T cells that infiltrate tissues through not well-known mechanisms. We report that SLE T lymphocytes display increased levels of CD44, ezrin, radixin, and moesin (ERM) phosphorylation, stronger actin polymerization, higher polar cap formation, and enhanced adhesion and chemotactic migration compared with T cells from patients with rheumatoid arthritis and normal individuals. Silencing of CD44 by CD44 small interfering RNA in SLE T cells inhibited significantly their ability to adhere and migrate as did treatment with Rho kinase and actin polymerization inhibitors. Forced expression of T567D-ezrin, a phosphorylation-mimic form, enhanced remarkably the adhesion and migration rate of normal T cells. Anti-CD3/TCR autoantibodies present in SLE sera caused increased ERM phosphorylation, adhesion, and migration in normal T cells. pERM and CD44 are highly expressed in T cells infiltrating in the kidneys of patients with lupus nephritis. These data prove that increased ERM phosphorylation represents a key molecular abnormality that guides T cell adhesion and migration in SLE patients.
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 National Institutes of Health Grants RO1 AI42269 and RO1 AI49954.
2 The opinions expressed herein are those of the authors and do not represent those of Department of Defense.
3 Address correspondence and reprint requests to Dr. George C. Tsokos, Beth Israel Deaconess Medical Center, HIM-244, 4 Blackfan Circle, Boston, MA 02115. E-mail address: gtsokos{at}bidmc.harvard.edu
4 Abbreviations used in this paper: SLE, systemic lupus erythematosus; HA, hyaluronic acid; ROCK, Rho kinase; PKC, protein kinase C; RA, rheumatoid arthritis; siRNA, small interfering RNA; WT, wild type; RIPA, radioimmunoprecipitation assay; Bis, bisindolylmaleimide; arp2/3, actin-related protein 2/3; CytD, cytochalasin D; IB, Immunoblot.
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