Expression Of TNF-a, Gelatinases And TIMPs In Peripheral Nerve Of Guillain-Barre Syndrome And Chronic Inflammatory Demyelinating Polyneuropathy

Background: The recent studies have shown that both chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain–Barre′syndrome (GBS) are inflammatory demyelinating peripheral polyneuropathy, and that both cellular and humoral immune responses are implicated in its pathogenesis. Normally, there is blood-nerve barrier (BNB) between blood and nerve tissue, which prevents toxic mediators from entering the peripheral nervous system (PNS) and resulting in demyelination and axonal damage. The process of demyelination and axonal damage is directly related with the breckage of BNB in CIDP and GBS. Matrix metalloproteinases (MMPs) are a group of proteins with overlapping proteolytic properties involved in numerous physiologic and pathologic processes. Among MMPs, some may be produced by immunocompetent cells and participate in the inflammatory reaction. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases that play an important role in inflammation and tissue degradation. MMP-9 (92-kd type IV collagenase, gelatinase B) and MMP-2 (72-kd type IV collagenase, gelatinase A) are gelatinases that have been implicated in the degradation of the blood-brain or blood-nerve barrier. Gelatinase are able to proteolysis of basement membranes and other matrix components, promoting transmigration of inflammatory cells and toxic mediators from circulation to nerve tissue, and resulting in demyelinating and axonal damage. Recently, MMP-2 and MMP-9 have also been implicated in the pathogenesis of experimental autoimmune neuritis (EAN), the animal model of GBS. In particular, MMP-9 were increased early in the course of EAN, peaking with maximum disease severity[2], and MMP-9 was detected in nerve tissue in schwann cells, endoneurial vessels, and infiltrating immune cells, and administration of an MMP inhibitor decreased severity of EAN[1]. Elevated serum concentrations of circulating matrix metalloproteinases (MMP-9) showed a positive correlation with the disease severity in patients with GBS[3].MMP-9 likely represents an important molecule in the pathogenesis of GBS. The proteolytic activity of MMPs may be modulated by specific tissue inhibitors of MPs (TIMPs), such as TIMP-1 that inhibits MMP-2, MMP-3, MMP-9, and other MMPs[4]. Elevated serum levels of tumor necrosis factor-a (TNF-α) have been reported and implicated in the pathogenesis of GBS. To study the expression and activity of TNF-α, gelatinase and tissue inhibitors of MPs (TIMPs) in patients with GBS and CIDP and explore the role of them in the pathogenesis of GBS and CIDP, we detected the localization of TNF-α, MMP-2, MMP-9, TIMP-1 and TIMP-2 in sural nerve from the patients (20 cases) with CIDP, the patients (13 cases) with GBS and the patients (10 cases) with NIN (non- inflammatory neuropathies) using immunohistochemistry and compared the expressing level of them in CIDP, GBS and NIN .Methods: we detected the localization of TNF-α, MMP-2, MMP-9, TIMP-1 and TIMP-2 in sural nerve from the patients (20 cases) with CIDP, the patients (13) with GBS and the patients (10 cases) with NIN using immunohistochemistry and compared the expressing level of them in CIDP, GBS and NIN.Results: (1) Immunohistochemical findings of sural nerves biopsies of twenty patients with CIDP and thirteen patients with GBS disclosed an immunoreactivity of MMP-9, TIMP-1 and TIMP-2 on nerve fibers, endothelial cells and T lymphocytes, and the expressing levels were higher in sural nerve of CIDP/GBS compared to NIN. (2) Immunohistochemical findings of sural nerves biopsies of patients with GBS and CIDP have principally disclosed an immunoreactivity of TNF-a on both Schwann cell membranes and in myelinated and unmyelinated axons.Conclusions: Our findings strongly suggest that MMP-9 and TNF-αplays an important role in the pathogenesis of GBS and CIDP, and increased expressions of TIMP-1 and TIMP-2 in GBS and CIDP have a possible role to inhibit the activity of MMP-9 and MMP-2. Given the important role of MMP-9 and TNF-αin the pathogenesis of inflammation, their specific inhibition may offer a new strategy in treatment of acute, and chronic inflammatory polyneuropathy.