Inflammation in the Central Nervous System
Wednesday, December 5, 2007
Organizer: Carol S. Reiss, New York University
Speakers: Michael K. Racke, The Ohio State University Medical Center; Ann Marie Schmidt, Columbia University; Robert Finberg, University of Massachusetts Medical Center.
Inflammation in the brain is stimulated by multiple different pathways including those initiated by activation of Toll-like receptors (TLR) and RAGE (receptor for advanced glycation end-products). This symposium will focus on the latest in our understanding of the molecular basis of CNS inflammation caused by stimulation of these systems and how this understanding may lead to the development of novel therapeutic interventions.
Natalizumab Therapy for Multiple Sclerosis and its Effects on CNS Immune Surveillance
Michael K. Racke, MD, The Ohio State University
Natalizumab is a humanized recombinant monoclonal antibody against the alpha (α)4 chain of the α4 beta (β)1 (very late activation antigen-4; VLA-4), and the α4β7 integrins approved for treatment of relapsing forms of the human central nervous system (CNS) inflammatory disease multiple sclerosis (MS). We previously demonstrated that natalizumab therapy decreases the numbers of all lymphocyte subsets in the cerebrospinal fluid (CSF) of patients on active therapy. In addition, we demonstrated that the cell numbers remained unchanged even 6 month after cessation of natalizumab therapy. Effects on latent CNS viruses such as HHV-6 have also been examined.
RAGE & the Adaptive Immune Response: Implications for Nervous System Inflammation - From Injury to Repair
Ann Marie Schmidt, MD, Columbia University
The Receptor for Advanced Glycation Endproducts (RAGE) was first described as a signal transduction receptor for AGEs, the products of nonenzymatic glycation and oxidation of protein and lipids. AGEs accumulate in hyperglycemia, natural aging and in settings characterized by oxidative stress and inflammation. In addition to AGEs, RAGE is a signal transduction receptor for pro-inflammatory S100/calgranulins and High Mobility Group Box-1 (HMGB1). Interestingly, RAGE is also a signaling receptor for amyloid-β peptide (Aβ) and β-sheet fibrils.
Our studies have illustrated that in conditions of CNS inflammation and stress, such as in murine models of experimental allergic encephalomyelitis (induced by myelin basic protein, or MBP) and in Alzheimer-type mouse models, blockade or deletion of RAGE imparted functional and pathological benefit. Of note, in EAE murine models, suppression of RAGE signaling in CD4T lymphocytes exerted protection in mice injected with MBP. However, roles for RAGE in the nervous system may be linked, in part, to repair. Pharmacological blockade of RAGE in a murine model of unilateral sciatic nerve crush results in impaired regeneration; further, in vivo, blockade of RAGE signaling in axonal elements or macrophages suppressed regenerative responses to peripheral nerve crush.
Interaction of RAGE with its ligands was shown to stimulate migration and activation of monocytes/macrophages in a manner dependent on RAGE signaling. Recent work has illustrated conclusively that RAGE plays key roles in the adaptive immune response. Specifically, we have found that RAGE is inducibly upregulated during T cell activation. Transfer of RAGE deficient OT II T cells (CD4) into ovalbumin-immunized hosts resulted in reduced proliferative responses that were further diminished in RAGE deficient recipients. RAGE deficient T cells showed markedly impaired proliferative responses in vitro to nominal and alloantigen, in parallel with decreased production of IFN-γ and IL-2. Thus, RAGE expressed on T cells is required for efficient priming of T cells. These findings revealed critical roles for RAGE engagement during cognate DC:T cell interactions.
Taken together, we propose that interaction of RAGE with its ligands critically contributes to nervous system