Recent advances in understanding multiple sclerosis

Abstract

Emerging data point to important contributions of both autoimmune inflammation and progressive degeneration in the pathophysiology of multiple sclerosis (MS). Unfortunately, after decades of intensive investigation, the fundamental cause remains unknown. A large body of research on the immunobiology of MS has resulted in a variety of anti-inflammatory therapies that are highly effective at reducing brain inflammation and clinical/radiological relapses. However, despite potent suppression of inflammation, benefit in the more important and disabling progressive phase is extremely limited; thus, progressive MS has emerged as the greatest challenge for the MS research and clinical communities. Data obtained over the years point to a complex interplay between environment (e.g., the near-absolute requirement of Epstein–Barr virus exposure), immunogenetics (strong associations with a large number of immune genes), and an ever more convincing role of an underlying degenerative process resulting in demyelination (in both white and grey matter regions), axonal and neuro-synaptic injury, and a persistent innate inflammatory response with a seemingly diminishing role of T cell–mediated autoimmunity as the disease progresses. Together, these observations point toward a primary degenerative process, one whose cause remains unknown but one that entrains a nearly ubiquitous secondary autoimmune response, as a likely sequence of events underpinning this disease. Here, we briefly review what is known about the potential pathophysiological mechanisms, focus on progressive MS, and discuss the two main hypotheses of MS pathogenesis that are the topic of vigorous debate in the field: whether primary autoimmunity or degeneration lies at the foundation. Unravelling this controversy will be critically important for developing effective new therapies for the most disabling later phases of this disease.

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

“…It is the most common cause of neurologic disability in young adults [ 3 , 4 ]. The traditional “outside-in” hypothesis of MS etiology is based on an autoimmune provenance whereby dysregulated auto-reactive T cells in the periphery cross into the central nervous system (CNS) and, together with macrophages and B cells, proceed to attack predominantly myelin elements [ 1 , 5 , 6 ]. Ongoing inflammation then results in a relapsing–remitting clinical course and fundamentally contributes to comprehensive CNS injury [ 4 , 7 ].…”

“…However, in recent years, an alternative “inside-out” MS-caused hypothesis that proposes initial multifunctional failures within the CNS has come to the fore. MS is suspected of being a primary degenerative disease linked with local inflammation, leading to the release of antigenic cell components such as myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein [ 6 , 8 , 9 ]. However, its diagnosis and treatment strategies are complicated by the presence of disease heterogeneity with distinct courses and diverse therapy responses.…”

What is the role of Brain derived neurotrophic factor in Multiple Sclerosis neuroinflammation?

“…For some authors, MS is an exclusive autoimmune inflammatory disease caused by dysregulated autoreactive immune cells that traverse the blood-brain barrier (BBB) into the CNS parenchyma, attacking various cell types (the "outside-in" autoimmune hypothesis). For other authors it is a primary degenerative disease (the "inside-out" hypothesis) in which inflammation is secondary to the release of auto-antigens (components of myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein), promoting autoimmunity [4] . Thus far, it is difficult to discern whether the inflammatory processes of MS are a product or a cause for neurodegeneration with a background autoimmune etiology.…”

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

“…Whether early neurodegeneration drives autoimmune injury, or whether ongoing inflammation reaches a threshold to trigger neurodegeneration is still unclear, while another question is whether neurodegeneration is independent or not of chronic inflammation. The lack of understanding with regard to mechanisms of progression phase, when the most irreversible disability takes place, is responsible for the extremely limited treatment options that are currently available to patients with progressive MS. Until now, many different treatment approaches for progressive MS were proposed including mitochondrion-protective strategies, anti-inflammatory strategies, strategies targeting microglia and astrocytes, inhibitors of microglial activity, remyelination therapies, and strategies targeting lymphocytes [20,23,40].…”