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

138 Citations (Scopus)

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

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Voltage-Gated Potassium Channels
Multiple Sclerosis
Brain
T-Lymphocytes
Cerebrospinal Fluid
Immunological Synapses
Autoimmune Experimental Encephalomyelitis
Chemokine Receptors
Myelin Sheath
Confocal Microscopy
Central Nervous System
Immunohistochemistry
Macrophages
Phenotype

Keywords

  • Cerebrospinal fluid
  • Effector memory
  • Lymphocytes
  • Macrophages

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. / Rus, Horea; Pardo, Carlos A.; Hu, Lina; Darrah, Erika; Cudrici, Cornelia; Niculescu, Teodora; Niculescu, Florin; Mullen, Katharine M.; Allie, Rameeza; Guo, Liping; Wulff, Heike; Beeton, Christine; Judge, Susan I V; Kerr, Douglas A.; Knaus, Hans Gunther; Chandy, K. George; Calabresi, Peter A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 31, 02.08.2005, p. 11094-11099.

Research output: Contribution to journalArticle

Rus, H, Pardo, CA, Hu, L, Darrah, E, Cudrici, C, Niculescu, T, Niculescu, F, Mullen, KM, Allie, R, Guo, L, Wulff, H, Beeton, C, Judge, SIV, Kerr, DA, Knaus, HG, Chandy, KG & Calabresi, PA 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, vol. 102, no. 31, pp. 11094-11099. https://doi.org/10.1073/pnas.0501770102
Rus, Horea ; Pardo, Carlos A. ; Hu, Lina ; Darrah, Erika ; Cudrici, Cornelia ; Niculescu, Teodora ; Niculescu, Florin ; Mullen, Katharine M. ; Allie, Rameeza ; Guo, Liping ; Wulff, Heike ; Beeton, Christine ; Judge, Susan I V ; Kerr, Douglas A. ; Knaus, Hans Gunther ; Chandy, K. George ; Calabresi, Peter A. / The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 31. pp. 11094-11099.
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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.",
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T1 - The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

AU - Rus, Horea

AU - Pardo, Carlos A.

AU - Hu, Lina

AU - Darrah, Erika

AU - Cudrici, Cornelia

AU - Niculescu, Teodora

AU - Niculescu, Florin

AU - Mullen, Katharine M.

AU - Allie, Rameeza

AU - Guo, Liping

AU - Wulff, Heike

AU - Beeton, Christine

AU - Judge, Susan I V

AU - Kerr, Douglas A.

AU - Knaus, Hans Gunther

AU - Chandy, K. George

AU - Calabresi, Peter A.

PY - 2005/8/2

Y1 - 2005/8/2

N2 - 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.

AB - 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.

KW - Cerebrospinal fluid

KW - Effector memory

KW - Lymphocytes

KW - Macrophages

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