The Molecular and Cellular Basis for Multiple Sclerosis 2020

Dear Colleagues,

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease. Despite extensive research, the question of whether it is triggered by an initial event outside the CNS (outside–in hypothesis) or whether it is a CNS-intrinsic event (inside–out hypothesis) is still not resolved. The discovery of several molecular and cellular mechanisms has provided valuable insight into the disease mechanism of multiple sclerosis (MS). The former concept that inflammation is only confined to white matter lesions and that autoreactive CD4+ T cells are the exclusive disease contributors no longer holds true. MS is a systemic disease that affects both the grey and white matter of the central nervous system (CNS). Inflammatory and degenerative mechanisms take place at the same time, and their balance probably determines a relapsing–remitting or a progressive disease course. It remains elusive whether primary progressive MS is a disease entity of its own or merely a disease phenotype that lacks superimposed high-grade inflammatory mechanisms. The same question is valid for highly active MS with tumefactive lesions, and the question arises whether there is a molecular key that determines an excessive or a more subtle immune response. Recent research reveals that it does not seem to be a single mechanism, and that there is a need to discover and classify inflammatory molecular and cellular patterns. Understanding these patterns and their dynamics in association with clinical and imaging data will be of utmost importance in deciphering disease mechanisms. In contrast to inflammation, our knowledge about axonal and neural degeneration is quite more restricted. It has been shown that mechanisms underlying neurodegeneration, at least in the long term, proceed autonomously and may be the central pathological feature. The elucidation of emerging cellular and molecular pathways and their relationship to demyelination and inflammation will herald a breakthrough in our understanding of the disease and in developing targeted therapies for neurodegeneration. Moreover, the significant progress made in analyzing genetic risk factors by using genome-wide association studies may not only help to shed light on individual susceptibility and environmental risk factors to develop the disease but also to unravel supervisory roles at the genetic and epigenetic level. More than 150 single nucleotide polymorphisms (SNP) outside the human leucocyte antigen (HLA) system have been discovered and mostly implicate immune genes. For most of the genes located at those SNPs, it must first be verified whether they are functionally relevant at all.

The inclusion of the oligoclonal bands (OCBs) in the new 2017 revised McDonald criteria supports the concept of early diagnosis and treatment but also underlines the need of further molecular and cellular predictors in MS. The current spotlight is on the soluble neurofilament light chain as a disease marker with the capability to follow the footsteps of OCBs. Indeed, there is an urgent need for molecular and cellular biomarkers not only to evaluate MS therapies but also to fill the gap between relapses and MRI lesions. A biomarker that exactly displays the inflammatory and degenerative components of the disease will enable an exactly adapted therapy without losing time in treatment optimization and without hesitation in the treatment of special conditions like radiologically isolated syndrome.

It is fascinating to see how many new drugs have been approved for MS in the last years. Changing the focus to B cells or the idea to “grow a healthier” or more anti-inflammatory immune system after cell depletion are new treatment approaches, but molecular and cellular mechanisms that may explain their effects are lacking. Research focused on the mode of action of MS drugs is of great interest, since it is inevitably associated with the unveiling of disease mechanisms.

This Special Issue is dedicated to the description of pathological cellular and molecular mechanisms, the identification of the fundamental basis of the disease, and the development of molecular interventions to prevent or treat them towards a molecular medicinal perspective of MS.

Prof. Dr. Christoph Kleinschnitz
Prof. Dr. Sven G. Meuth
Dr. Refik Pul
Guest Editors

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• multiple sclerosis
• demyelination
• remyelination
• inflammation
• neurodegeneration
• biomarker
• disease mechanism
• mode of action of MS drugs