title: Matrix metalloproteinase expression during experimental autoimmune neuritis.
abstract: Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.
authors.affiliation: British Biotech Pharmaceuticals Ltd, Oxford, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Hughes
authors.forename: G M
authors.initials: GM
authors.lastname: Wells
authors.forename: J M
authors.initials: JM
authors.lastname: Clements
authors.forename: A J
authors.initials: AJ
authors.lastname: Gearing
authors.forename: E J
authors.initials: EJ
authors.lastname: Redford
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: K J
authors.initials: KJ
authors.lastname: Smith
authors.forename: R A
authors.initials: RA
authors.lastname: Hughes
authors.forename: M C
authors.initials: MC
authors.lastname: Brown
authors.forename: K M
authors.initials: KM
authors.lastname: Miller
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism*; D007150:Immunohistochemistry; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009443:Neuritis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D012584:Sciatic Nerve / Q000378:metabolism; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases