Multiple sclerosis (MS) has been classically regarded as an inflammatory demyelinating disease of the central nervous system. In recent years, the classification and pathogenesis of the disease have become controversial, particularly with respect to whether an individual patient demonstrates a single or multiple pathogenetic mechanisms in the establishment of the focal plaque of MS. It is also becoming increasingly apparent that there is a significant neurodegenerative component in the disease, involving not only plaques but the non-plaque parenchyma as well. Magnetic resonance imaging, together with histopathologic studies, will continue to shed light on the pathogenesis of these focal and diffuse abnormalities in MS.

Multiple sclerosis (MS) is traditionally considered an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) with much knowledge available to support this view. However, this characterization implies that the primary event is an aberrant immune response directed at CNS antigens, promoting inflammation and later driving progressive axo-glial degeneration. Trials with potent anti-inflammatory agents and detailed neuropathological studies raise questions about this sequence of events. This hypothetical paper argues that MS may be primarily a “cytodegenerative” disease, possibly first involving the oligodendrocyte/myelin unit. Liberation of autoantigens secondarily recruits an immune response, the force of which heavily depends on the host's immune predisposition. Thus, the spectrum of MS from highly aggressive Marburg type, to primary progressive disease with little inflammatory burden, is governed by a “convolution” between the underlying cytodegeneration and the host's immune predilection. Clinical heterogeneity may be a reflection of a variable immune response, whereas in reality, the “real MS” may be a homogeneous degenerative process analogous to well known primary neurodegenerative diseases.

The human microbiome is comprised of commensal and pathogenic microorganisms, which exert diverse effects in close proximity to the site of intection as well as in remote tissues through immune-mediated mechanisms. Multiple infectious agents have been implicated in the pathogenesis of multiple sclerosis (MS) with variable findings depending on the agent, techniques, and disease phenotype. Herein, the contributions of individual infectious agents to MS and their effects on the immune and nervous systems are reviewed, focusing on herpes viruses, coronaviruses, retroviruses, and synchronic infections. While infectious agents are often assumed to be pathogenic, their effects might also be beneficial to the host in the long-term, depending on age and the type of immunogen/pathogen exposure, as proposed by the hygiene hypothesis. The human microbiome has potential impact on future diagnostic and therapeutic issues in MS.

Stem cell based therapies hold great promise for repair and functional restoration following neurological injury and disease. Skin-derived precursors (or “SKPs”) are a novel, multipotent somatic stem cell that resides within the mammalian dermis. SKPs persist within the skin throughout adulthood and yet intriguingly, exhibit many similarities to embryonic neural crest stem cells (NCSCs). For example, SKPs give rise to both neural and mesodermal cell types, and the former appear biased to peripheral nervous system fates. As such, SKPs are capable of generating Schwann cells, the myelinating glial cell of the peripheral nervous system. Here we discuss our current understanding of the biological origin of SKPs and specifically the potential therapeutic utility of SKPs as a highly accessible and autologous source of Schwann cells for remyelination and repair of the injured or diseased nervous system.

All currently approved therapies for multiple sclerosis (MS) modulate systemic immune components prior to their entry into the central nervous system (CNS). Available data indicate they lack impact on the progressive phases of disease; the more potent systemic immune-directed agents predispose to development of infectious or neoplastic disorders. Development of new agents that enhance disease stage related efficacy and limit systemic toxicity will need to consider the underlying mechanisms related to each phase of the clinical disorder, namely relapses, remission, and progression. This report focuses on disease related mechanisms ongoing within the CNS that contribute to the different phases of MS and how these may serve as potential therapeutic targets. Such mechanisms include CNS compartment specific immunologic properties especially as related to the innate immune system and neural cell-related properties that are determinants of the extent of actual tissue injury and repair (or lack thereof).

The adaptive immune response in multiple sclerosis is complex. We have devised large scale arrays to measure the antibody response to myelin proteins and lipids. Despite the widespread immune responses to myelin, we have devised an inverse vaccine aimed at turning off key drivers of this diverse response. Clinical trials in patients with multiple sclerosis show that it is possible to constrain antibody responses to myelin on a large scale with this approach.