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-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-gamma-inducible protein of 10 kDa (IP-10) and monokine induced by interferon-gamma (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.
Kieseier
Bernd C
BC
Department of Neurology, Karl-Franzens-University, Graz, Austria. bernd.kieseier@uni-duesseldorf.de
Tani
Marie
M
Mahad
Don
D
Oka
Nobuyuki
N
Ho
Tony
T
Woodroofe
Nicola
N
Griffin
John W
JW
Toyka
Klaus V
KV
Ransohoff
Richard M
RM
Hartung
Hans-Peter
HP
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D020275:Guillain-Barre Syndrome / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics*; D013497:Sural Nerve / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C080810:CXCL9 protein, human