Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP‐10

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–Barre 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‐γ‐inducible 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.