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Cholera Toxin B Accelerates Disease Progression in Lupus-Prone Mice by Promoting Lipid Raft Aggregation¹

Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115

Infectious agents, including bacteria and viruses, are thought to provide triggers for the development or exacerbation of autoimmune diseases such as systemic lupus erythematosus in the genetically predisposed individual. Molecular mimicry and engagement of TLRs have been assigned limited roles that link infection to autoimmunity, but additional mechanisms are suspected to be involved. In this study we show that T cells from lupus-prone mice display aggregated lipid rafts that harbor signaling, costimulatory, inflammatory, adhesion, and TLR molecules. The percentage of T cells with clustered lipid rafts increases with age and peaks before the development of lupus pathology. We show that cholera toxin B, a component of Vibrio cholerae, promotes autoantibody production and glomerulonephritis in lupus-prone mice by enhancing lipid raft aggregation in T cells. In contrast, disruption of lipid raft aggregation results in delay of disease pathology. Our results demonstrate that lipid rafts contribute significantly to the pathogenesis of lupus and provide a novel mechanism whereby aggregated lipid rafts represent a potential link between infection and 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 in part by National Institutes of Health Grant R01AI42269.

² Address correspondence and reprint requests to Drs. George C. Tsokos or Guo-Min Deny, 330 Brookline Avenue, E/CLS 937, Boston, MA 02115. E-mail addresses: gtsokos{at}bidmc.harvard.edu or gdeng{at}bidmc.harvard.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; B6, C57BL/6 mice; CD, -cyclodextrin; C3, complement 3; CD40L, CD40 ligand; CT, cholera toxin; CTB, cholera toxin B; MβCD, methyl-β-cyclodextrin; NZB/W F₁, (New Zealand Black x New Zealand White)F₁ mice; PAS, periodic acid-Schiff.