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Systemic Lack of Canonical Histamine Receptor Signaling Results in Increased Resistance to Autoimmune Encephalomyelitis

Naresha Saligrama, Laure K. Case, Roxana del Rio, Rajkumar Noubade and Cory Teuscher
J Immunol July 15, 2013, 191 (2) 614-622; DOI: https://doi.org/10.4049/jimmunol.1203137
Naresha Saligrama
*Department of Medicine, University of Vermont, Burlington, VT 05405; and
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Laure K. Case
*Department of Medicine, University of Vermont, Burlington, VT 05405; and
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Roxana del Rio
*Department of Medicine, University of Vermont, Burlington, VT 05405; and
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Rajkumar Noubade
*Department of Medicine, University of Vermont, Burlington, VT 05405; and
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Cory Teuscher
*Department of Medicine, University of Vermont, Burlington, VT 05405; and
†Department of Pathology, University of Vermont, Burlington, VT 05405
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Abstract

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein–coupled receptors: H1, H2, H3, and H4 (histamine receptors; H1–4R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood–brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase–deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35–55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein–coupled-HRs (H1–4RKO mice). In this article, we report that in contrast to HDCKO mice, H1–4RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H1–4RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1–4RKO mice suggest that HA may signal independently of H1–4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.

Footnotes

  • This work was supported by National Institutes of Health Grants NS061014, AI041747, NS060901, NS036526, and NS069628 (to C.T) and by the Young Investigator Award (second prize) presented by the European Histamine Research Society (to N.S.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    B6
    C57BL/6J
    BBB
    blood–brain barrier
    DC
    dendritic cell
    DLN
    draining lymph node
    EAE
    experimental allergic encephalomyelitis
    GABA
    γ-aminobutyric acid
    GPCR
    G-protein–coupled receptor
    HA
    histamine
    HDC
    histidine decarboxylase
    HR
    histamine receptor
    MOG35–55
    myelin oligodendrocyte gp35–55
    MS
    multiple sclerosis
    OCT
    organic cation transporter
    P450
    cytochrome P450
    PTX
    pertussis toxin
    SNP
    single nucleotide polymorphism
    WT
    wild-type.

  • Received November 14, 2012.
  • Accepted May 18, 2013.
  • Copyright © 2013 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 191 (2)
The Journal of Immunology
Vol. 191, Issue 2
15 Jul 2013
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Systemic Lack of Canonical Histamine Receptor Signaling Results in Increased Resistance to Autoimmune Encephalomyelitis
Naresha Saligrama, Laure K. Case, Roxana del Rio, Rajkumar Noubade, Cory Teuscher
The Journal of Immunology July 15, 2013, 191 (2) 614-622; DOI: 10.4049/jimmunol.1203137

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Systemic Lack of Canonical Histamine Receptor Signaling Results in Increased Resistance to Autoimmune Encephalomyelitis
Naresha Saligrama, Laure K. Case, Roxana del Rio, Rajkumar Noubade, Cory Teuscher
The Journal of Immunology July 15, 2013, 191 (2) 614-622; DOI: 10.4049/jimmunol.1203137
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