Nat Med 2003 Feb 24
Yan SS, Wu ZY, Zhang HP, Furtado G, Chen X, Yan SF, Schmidt AM, Brown C, Stern A, Lafaille J, Chess L, Stern DM, Jiang H.
Departments of Pathology, Surgery, Medicine, and Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role.
The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium.
Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE).
Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-alpha and TCR-beta chains.
Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells.
Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4(+) T cells were resistant to MBP-induced EAE.
These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4(+) T cells that infiltrate the CNS.