Time-Dependent Progression of Demyelination and Axonal Pathology in MP4-Induced Experimental Autoimmune Encephalomyelitis

Abstract

BackgroundMultiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination and axonal pathology. Myelin basic protein/proteolipid protein (MBP-PLP) fusion protein MP4 is capable of inducing chronic experimental autoimmune encephalomyelitis (EAE) in susceptible mouse strains mirroring diverse histopathological and immunological hallmarks of MS. Limited availability of human tissue underscores the importance of animal models to study the pathology of MS.MethodsTwenty-two female C57BL/6 (B6) mice were immunized with MP4 and the clinical development of experimental autoimmune encephalomyelitis (EAE) was observed. Methylene blue-stained semi-thin and ultra-thin sections of the lumbar spinal cord were assessed at the peak of acute EAE, three months (chronic EAE) and six months after onset of EAE (long-term EAE). The extent of lesional area and inflammation were analyzed in semi-thin sections on a light microscopic level. The magnitude of demyelination and axonal damage were determined using electron microscopy. Emphasis was put on the ventrolateral tract (VLT) of the spinal cord.ResultsB6 mice demonstrated increasing demyelination and severe axonal pathology in the course of MP4-induced EAE. In addition, mitochondrial swelling and a decrease in the nearest neighbor neurofilament distance (NNND) as early signs of axonal damage were evident with the onset of EAE. In semi-thin sections we observed the maximum of lesional area in the chronic state of EAE while inflammation was found to a similar extent in acute and chronic EAE. In contrast to the well-established myelin oligodendrocyte glycoprotein (MOG) model, disease stages of MP4-induced EAE could not be distinguished by assessing the extent of parenchymal edema or the grade of inflammation.ConclusionsOur results complement our previous ultrastructural studies of B6 EAE models and suggest that B6 mice immunized with different antigens constitute useful instruments to study the diverse histopathological aspects of MS.

Potential of Adult Endogenous Neural Stem/Progenitor Cells in the Spinal Cord to Contribute to Remyelination in Experimental Autoimmune Encephalomyelitis

“…The above data show that inflammatory responses and demyelination occur in MOG-induced EAE mice. However, previous studies have shown that remyelinated nerve fibers, which typically display thin and dense myelin lamellae by EM [4,36], are present in EAE. Thus, we subjected spinal cord samples obtained from MOG-injected mice under EM observation.…”

“…Some patients with MS suffer from various progressive neurological deficits, whereas others occasionally experience improved neurological function during the course of the disease. In experimental autoimmune encephalomyelitis (EAE), both demyelination and remyelination coexist at the same time [4]. Thus, although remyelination is considered responsible for the improvement of clinical symptoms [5,6,7], a detailed mechanism by which remyelination occurs during MS remains unknown.…”

Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease

“…We are currently investigating the benefits of similar therapies, which target anti-inflammatory and remyelinating mechanisms, in the models utilized in this study as well as other translationally-relevant EAE models. Specifically, the PLP-induced model of RRMS that simulates multiple relapses ( 55 , 56 ), or a more severe and progressive model, such as that induced by MP4, a myelin basic protein-proteolipid protein fusion peptide ( 57 ) or MOG immunization in DBA/1 mice ( 36 , 58 , 59 ), will likely show more dramatic differences between monotherapies and dual therapy and allow us to discern more temporal effects. Even as promoting remyelination emerges as a viable and potentially symptom-reversing therapeutic strategy, immune modulation will remain critical and our study shows that tuftsin works effectively in combination with benztropine in two primary MS models.…”

Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System

“…The mechanism via which some patients experience neurological improvement remains unclear. However, increasing evidence shows that remyelination occurs in the MS/EAE [57][58][59][60]. In addition, recent studies showed that activated neural stem/progenitor cells around region sites contribute to remyelination [61,62].…”