The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

Horea Rus, Carlos A. Pardo, Lina Hu, Erika Darrah, Cornelia Cudrici, Teodora Niculescu, Florin Niculescu, Katharine M. Mullen, Rameeza Allie, Liping Guo, Heike Wulff, Christine Beeton, Susan I V Judge, Douglas A. Kerr, Hans Gunther Knaus, K. George Chandy, Peter A. Calabresi

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Multiple Sclerosis (MS) is characterized by central nervous system perivenular and parenchymal mononuclear cell infiltrates consisting of activated T cells and macrophages. We recently demonstrated that elevated expression of the voltage-gated potassium channel, Kv1.3, is a functional marker of activated effector memory T (TEM) cells in experimental allergic encephalomyelitis and in myelin-specific T cells derived from the peripheral blood of patients with MS. Herein, we show that Kv1.3 is highly expressed in postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3+ T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7-), consistent with an effector memory phenotype. Using double-labeling immunohistochemistry and confocal microscopy, we demonstrated localization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7+ central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3 high/CCR7- TEM, suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become T EM. These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.

Original languageEnglish (US)
Pages (from-to)11094-11099
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number31
DOIs
StatePublished - Aug 2 2005

Keywords

  • Cerebrospinal fluid
  • Effector memory
  • Lymphocytes
  • Macrophages

ASJC Scopus subject areas

  • Genetics
  • General

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    Rus, H., Pardo, C. A., Hu, L., Darrah, E., Cudrici, C., Niculescu, T., Niculescu, F., Mullen, K. M., Allie, R., Guo, L., Wulff, H., Beeton, C., Judge, S. I. V., Kerr, D. A., Knaus, H. G., Chandy, K. G., & Calabresi, P. A. (2005). The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proceedings of the National Academy of Sciences of the United States of America, 102(31), 11094-11099. https://doi.org/10.1073/pnas.0501770102