Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: A central role for IP-10

Bernd C. Kieseier, Marie Tani, Don Mahad, Nobuyuki Oka, Tony Ho, Nicola Woodroofe, John W. Griffin, Klaus V. Toyka, Richard M. Ransohoff, Hans Peter Hartung

Research output: Contribution to journalArticlepeer-review

Abstract

Inflammatory cell recruitment is an important step in the pathogenesis of autoimmune demyelinating diseases of the PNS. Chemokines might play a critical role in promoting leucocyte entry into the nervous system during immune-mediated inflammation. Here, we report the expression pattern of the chemokine receptors CCR-1, CCR-2, CCR-4, CCR-5 and CXCR-3 in sural nerve biopsies obtained from patients with classical Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy and various non-inflammatory neuropathies. A consistent chemokine receptor expression pattern was immunohistochemically detected in inflammatory demyelinating neuropathies and quantitation of labelled mononuclear cells revealed significantly elevated cell counts compared with controls. CCR-1 and CCR-5 were primarily expressed by endoneurial macrophages, whereas CCR-2, CCR-4 and CXCR-3 could be localized to invading T lymphocytes. Quantitative analysis revealed that CXCR-3 was expressed at highest numbers by infiltrating T cells compared with the other receptors. Thus, expression and distribution of CXCR-3 suggest a specific role of this receptor in chemokine-mediated lymphocyte traffic into the inflamed PNS tissue. Therefore, we further analysed the expression of its ligands interferon-γinducible protein of 10 kDa (IP-10) and monokine induced by interferon-γ (Mig). Significantly increased levels of IP-10 could be measured in the CSF of patients with inflammatory neuropathies, whereas no differences were observable for Mig. In situ hybridization for IP-10 mRNA mirrored the distribution of the cognate receptor within the inflamed PNS, and delineated endothelial cells as the primary cellular source of IP-10. Our results imply a pathogenic role for specific chemokine receptors and IP-10 in the genesis of inflammatory demyelinating neuropathies.

Original languageEnglish (US)
Pages (from-to)823-834
Number of pages12
JournalBrain
Volume125
Issue number4
DOIs
StatePublished - 2002

Keywords

  • CXCR-3
  • Chemokine receptors
  • Chronic inflammatory demyelinating polyradiculoneuropathy
  • Guillain-Barré syndrome
  • IP-10

ASJC Scopus subject areas

  • Clinical Neurology

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