Brain, Vol 121, Issue 3 481-494, Copyright © 1998 by Oxford University Press
PM Hughes, GM Wells, JM Clements, AJ Gearing, EJ Redford, M Davies, KJ Smith, RA Hughes, MC Brown and KM Miller
Experimental autoimmune neuritis (EAN) is an animal model of Guillain-
Barre 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-Barre
syndrome.
ARTICLES
Matrix metalloproteinase expression during experimental autoimmune neuritis
British Biotech Pharmaceuticals Ltd, Oxford, UK.
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