Glial cells involved in progressive MS

G
We all know that the glial response may be involved in progressive MS

Do you want more evidence

Masvekar R et al.  Fluid Biomarkers Link Toxic Astrogliosis and Microglial Activation to Multiple Sclerosis Severity


MSARDS (Epub): https://doi.org/10.1016/j.msard.2018.11.032

BACKGROUND: Once multiple sclerosis (MS) reaches the progressive stage, immunomodulatory treatments have limited efficacy. This suggests that processes other than activation of innate immunity may at least partially underlie disability progression during late stages of MS. Pathology identified these alternative processes as aberrant activation of astrocytes and microglia, and subsequent degeneration of oligodendrocytes and neurons. However, we mostly lack biomarkers that could measure central nervous system (CNS) cell-specific intrathecal processes in living subjects. This prevents differentiating pathogenic processes from an epiphenomenon. Therefore, we sought to develop biomarkers of CNS cell-specific processes and link them to disability progression in MS.
Methods: In a blinded manner, we measured over 1000 proteins in the cerebrospinal fluid (CSF) of 431 patients with neuroimmunological diseases and healthy volunteers using modified DNA-aptamers (SOMAscan®). We defined CNS cell type-enriched clusters using variable cluster analysis, combined with in vitro modeling. Differences between diagnostic categories were identified in the training cohort (n = 217) and their correlation to disability measures were assessed; results were validated in an independent validation cohort (n = 214).
RESULTS: Astrocyte cluster 8 (MMP7, SERPINA3, GZMA and CLIC1) and microglial cluster 2 (DSG2 and TNFRSF25) were reproducibly elevated in MS and had a significant and reproducible correlation with MS severity suggesting their pathogenic role. In vitro studies demonstrated that proteins of astrocyte cluster 8 are noticeably released upon stimulation with proinflammatory stimuli and overlap with the phenotype of recently described neuro-toxic (A1) astrocytes.
CONCLUSION:  Microglial activation and toxic astrogliosis are associated with MS disease process and may partake in CNS tissue destruction. This hypothesis should be tested in new clinical trials.

  • Microglial/myeloid cell activation markers are present during all stages of MS.
  • Toxic astrocyte specific markers increase with MS duration.
  • Aberrant activation of glial cells contributes to CNS tissue destruction and enhance MS severity.

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MouseDoctor

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  • 'Glial cells (we all know) are involved in progressive MS'

    The first clear description and characterisation of the PRIMARY MS lesion (Gay et al Brain 1997 120;1461-1483 concluded that the activated microglial cell, stimulated by C3-IgG immune complexes was the first and key player in lesion development. Quote,'if this is so therapeutic strategies to inhibit macrophage activity…may be of greater benefit than efforts to inhibit T cells or other immune reactions'
    The antigen implicated in the activating complex has subsequently been identified (Gay F, MSARD 2013 @;213-232 and a clear route of access proposed. Wake up.

  • Great article MD thanks. Do you think that "hot" microglia and A1 astrocyte activity is why MS affects the CNS only and not the peripheral nervous system?

    More and more data is showing the answer for stopping progression of MS lies in the stopping, switching off or down-regulating the "hot"microglia and A1 astrocyte activity. This is how ibudilast works by inhibiting "hot" microglia.

    I would like to hear more of MD and MD2's thought on this matter as inhibition of the peripheral immune system seemingly works very minimally in progressive MS as they state in this publication: "Once multiple sclerosis (MS) reaches the progressive stage, immunomodulatory treatments have limited efficacy".

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