Date of Award
Doctor of Philosophy (PhD)
Pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), play a pivotal role in the pathogenesis of Guillain-Barré Syndrome (GBS), a debilitating autoimmune disorder that affects the peripheral nervous system. By up-regulating endothelial expression of chemokines and cell adhesion molecules (CAMs), TNF-α facilitates the recruitment and trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves, an early pathological hallmark of GBS. Literature indicates that TNF-α, monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) are locally increased in patients with GBS, correlating with disease severity. Similar findings have been demonstrated in an animal model of GBS, experimental autoimmune neuritis (EAN).
Treatment options for patients with GBS are limited to nonspecific, immune-modulating strategies, including plasmapheresis and IVIg. Half of GBS patients fail to respond, and many remain severely disabled despite receiving treatment. Despite advancements, there remains a pressing need for the development of effective and specific immune-modulating therapeutic strategies for the management of GBS.
Our group previously reported that statins therapeutically attenuate the course of EAN by inhibiting leukocyte migration. This dissertation project was designed to determine the mechanism(s) by which statins attenuate pathological transendothelial migration. We hypothesized that statins limit transendothelial migration of leukocytes into peripheral nerves by attenuating TNF-α-mediated, RhoGTPase-dependent secretion of chemokines by the peripheral nerve vascular endothelial cells (PNVECs) that form the blood-nerve barrier. Experiments using PNVECs are lacking, and there is no commercially available cell line. We formed a novel, immortalized cell line of PNVECs by SV40 large T antigen transduction. We report in these cells that TNF-α increases mRNA and protein expression of MCP-1 and ICAM-1, and secretion of MCP-1. Simvastatin pretreatment does not alter intracellular levels of MCP-1 or ICAM-1 mRNA or protein, but does markedly attenuate TNF-α-mediated MCP-1 secretion. This effect is mimicked by a specific inhibitor of protein geranylgeranylation.
Our novel findings suggest that TNF-α-mediated migration of autoreactive leukocytes into peripheral nerves during EAN proceeds, in part, by a mechanism that involves geranylgeranylation-dependent secretion of MCP-1. We argue that identifying this precise geranylgeranylated target that mediates chemokine secretion will significantly advance the development of novel treatment options for patients with GBS.
Langert, Kelly Ann, "Statin-Mediated Attenuation of Chemokine Expression in Peripheral Nerve Vascular Endothelial Cells" (2012). Dissertations. 363.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Copyright © 2012 Kelly Ann Langert