MATRIX METALLOPROTEINASE EXPRESSION DURING EXPERIMENTAL AUTOIMMUNE NEURITIS

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 w hen 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 t he exact function and expression patterns of MMPs in acute inflammatio n of the PNS have not been investigated. MMP-like enzymes are also inv olved in the processing of tumour necrosis factor-alpha (TNF-alpha), w hich has been implicated previously in the pathology associated with E AN. In the present study we investigated the profile of MMP and TNF-al pha expression and their localization in sciatic nerve tissue during E AN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS,Sour of the 10 MMPs studied were constitutively expressed and fou r MMPs were differentially regulated during EAN. Expression of TNF-alp ha was elevated at peak disease severity and localized to Schwann cell s, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-l were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coinc ident with maximum disease severity. Schwann cells and endothelial cel ls were the main cellular source of these enzymes. Prominent infiltrat ion of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macro phage metalloelastase. Both matrilysin and macrophage metalloelastase were defected in invading macrophages, T lymphocytes and resident Schw ann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifact orial 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 int o the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Gui llain-Barre syndrome.