Modulating inflammation and neuroprotection in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a neurological disorder of the central nervous system with a presentation and disease course that is largely unpredictable. MS can cause loss of balance, impaired vision or speech, weakness and paralysis, fatigue, depression, and cognitive impairment. Immunomodulation is a major target given the appearance of focal demyelinating lesions in myelin-rich white matter, yet progression and an increasing appreciation for gray matter involvement, even during the earliest phases of the disease, highlights the need to afford neuroprotection and limit neurodegenerative processes that correlate with disability. This review summarizes key aspects of MS pathophysiology and histopathology with a focus on neuroimmune interactions in MS, which may facilitate neurodegeneration through both direct and indirect mechanisms. There is a focus on processes thought to influence disease progression and the role of oxidative stress and mitochondrial dysfunction in MS. The goals and efficacy of current disease-modifying therapies and those in the pipeline are discussed, highlighting recent advances in our understanding of pathways mediating disease progression to identify and translate both immunomodulatory and neuroprotective therapeutics from the bench to the clinic.

A Tolerogenic Artificial APC Durably Ameliorates Experimental Autoimmune Encephalomyelitis by Directly and Selectively Modulating Myelin Peptide–Autoreactive CD4+ and CD8+ T Cells

“…The current therapeutics such as natalizumab (9,10), fingolimod, (11) and immunosuppressive regimens (laquinimod, cladribine, alemtuzumab, caclizumab, and rituximab) are primarily anti-inflammatory and non-Ag-specific in nature and have severe side effects (12)(13)(14). As a result of longterm medication, most of these treatments for MS display suppression of overall immune response, which increases the risks of infection and cancer (15,16).…”

The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer

“…MS is a CNS disease that affects over 2 million people and has no known cure. MS is considered as a chronic autoimmune inflammatory disease affecting brain, nerve, and spinal cord tissues, which causes demyelination of neurons, axonal damage, and neurodegeneration [ 76 ]. Myelin-specific T H 17 and T H 1 cells and B cells are believed to help initiate and/or promote the development of MS [ 76 ].…”

Vitamin D as an immune modulator in multiple sclerosis

“…Additionally, T regulatory cells secrete anti-inflammatory cytokines IL-10, IL-35, transforming in the CSF of patients with MS, complement deposition in type II lesions in CNS and B cell follicular structures in the meninges. Moreover, they can play several different roles: production of autoantibodies, formation of B-cell follicles with germinal centre activity, antigen presentation, production of pro-inflammatory cytokines, and anti-inflammatory immune regulation (Breg cells) [1,58].…”

“…UVB photons initiate a pathway of vitamin D production, from 7-dehydrocholesterol to the active form of vitamin D, as described previously. Several reviews have covered the immunomodulatory properties of vitamin D, particularly with reference to the regulation of cells proposed as being important to the development of MS [1,2,16]. However, additional factors should be taken into account.…”

“…Many studies suggest that B cells are equally important in MS pathogenesis. The presence of immunoglobulinG oligoclonal bands in the cerebrospinal fluid (CSF) of MS patients is a biomarker for disease and antibodies play a crucial role for demyelination in experimental autoimmune encephalomyelitis (EAE) [1]. The prevalence of MS is greater at higher latitudes, and tends to peak in areas with fewer sunny days.…”