Current concepts of the cellular and molecular pathophysiology of multiple sclerosis

Abstract

Multiple sclerosis (MS) is the most common demyelinating disease. It poses many challenges both clinically and scientifically. Progress made in understanding the genetics, immunology, and neurobiology of MS to date has positioned the field for further breakthroughs both in understanding the etiology and pathogenesis as well as the development of rationally based therapeutics. This review will cover fundamental aspects of the clinical and pathologic features of MS. Identified genetic markers will be considered as well as the evolving understanding of immunologic and neurobiological aspects of the disease. The development of immune therapy based on this knowledge is already apparent and it is likely that neuroprotective therapies will evolve to complement immune modulation in treating the disease.

Autoimmune Disease-Associated Histamine Receptor H1 Alleles Exhibit Differential Protein Trafficking and Cell Surface Expression

“…In this study, we show that the polymorphic residues of the H 1 R R allele interfere with its ability to complement EAE in H1RKO mice. This is in accordance with genetic complementation studies in F 1 Recently, IL-17-producing Th17 CD4 T cells have been considered more pathogenic in EAE (19). We show here, for the first time, that H 1 R signaling regulates IL-17 production and that H 1 R polymorphisms influence IL-17 production by T cells.…”

“…3 is the major demyelinating disease of the CNS in humans, affecting Ͼ2.5 million people worldwide (1). Both environmental and genetic factors contribute to the immunopathologic etiology of the disease.…”

Abnormal morphology of myelin and axon pathology in murine models of multiple sclerosis

“…EAE, an animal model of human MS, induces inflammatory demyelination in the CNS white matter (Dhib-Jalbut, 2007;Greenstein, 2007;Martin et al, 1992;Noseworthy et al, 2000). MOG-induced EAE mice developed demyelination, inflammation with infiltrating peripheral immune cells and glial cell activation in spinal cord white matter (Appendix: Supplementary Figs.…”

Mechanism of oxidative stress p38MAPK-SGK1 signaling axis in experimental autoimmune encephalomyelitis (EAE)

“…The inflammatory cascade is initiated by the CD4+ T cells in the CNS microenvironment, and subsequent secretion of toxicants like reactive oxygen species (ROS) by other immune and resident cells mediate the killing of oligodendrocytes. Neurological dysfunction in MS results as a result of axonal (oligodendrocyte-myelin-axon) damage [6, 7]. Hence, it is not surprising that oxidative stress driven by inflammation is also a critical node in both EAE and MS pathogenesis [1, 8].…”