Advanced glycation end-products as potential triggering factors of self-reactivity against myelin antigens in Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is a demyelinating autoimmune disease in which autoreactive T lymphocytes infiltrate the central nervous system (CNS) and react against antigens derived from proteins of the myelin sheath. The reason why T lymphocytes recognize certain myelin antigens as exogenous, activating the autoimmune response, remains unknown and represents the key to understand the pathogenesis of MS. Neurons are characterized by an elevated glycolytic metabolism. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde spontaneously formed as a by-product of glycolysis, and it reacts with proteins, nucleotides and phospholipids forming stable adducts called advanced glycation end-products (AGEs). Several studies demonstrate that MG-derived AGEs accumulate in the plasma and brain of MS patients. Furthermore, there are evidences that post-myelinated oligodendrocytes, the myelin-forming glial cells, increase their glycolytic metabolism to maintain their survival and functions, likely explaining the progressive accumulation of MG in MS lesions. The hypothesis proposed here is that the MG-derived AGEs, accumulated on the proteins composing the myelin sheath, are responsible for the altered antigen presentation process, mimicking exogenous antigens and triggering the autoimmune response. If this hypothesis will be experimentally confirmed a new pathogenic mechanism of MS will be identified.