Microglia in the pathogenesis of MS

A forum to discuss research on the origins of MS and its development.

Microglia in the pathogenesis of MS

Postby frodo » Mon Jul 23, 2018 12:13 pm

Microglia in the pathogenesis of MS

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499932/



We postulate that the immune reaction initiates in the CNS and immune cells (including T cells/B cell) infiltrate into the CNS as a result.

An unknown causative agent sets off a local inflammatory reaction, after which activated microglia are stimulated by the microenvironment to differentiate into many subgroups that then serve as APCs, phagocytes, and immune effector cells to activate T cells. Activated T cells can then cross the blood–brain barrier and result in a peripheral immune response.

Subsequently, activated T cells, B cells, and macrophages migrate from the periphery into the CNS, which exacerbates the inflammation or leads to relapse.

This hypothesis could explain some phenomena in MS patients. First, the APCs (microglia and macrophages) originate in the CNS, are recognized by CNS-resident cells, and remain localized within the CNS, which could explain why MS patients experience no peripheral complications, such as autoimmune nephritis and arthritis. Second, the inflammatory cascade occurs entirely within the CNS, which could explain the insufficiency or the absence of lymphocyte recruitment into the CNS after the initial relapsing phase of MS
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Re: Microglia in the pathogenesis of MS

Postby Petr75 » Tue Jul 24, 2018 9:14 am

frodo wrote:.. Second, the inflammatory cascade occurs entirely within the CNS, which could explain the insufficiency or the absence of lymphocyte recruitment into the CNS after the initial relapsing phase of MS


December 7, 2017
Department of neuroradiologie, Heidelberg University Hospital, Heidelberg, NěmeckoIn the Pipeline-Multiple Sclerosis: Neurographic MRI Reveals Peripheral Nerve Lesions in MS Patients
https://journals.lww.com/neurotodayonli ... hic.6.aspx

.. Current opinion is that pathological changes in MS are restricted to the central nervous system (CNS) and cranial nerves, but the new proof-of-concept study may offer new insights into the pathophysiology of the disease and help guide new treatment options, said lead author Jennifer Kollmer, MD, a neuroradiologist at Heidelberg University Hospital..
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Re: Microglia in the pathogenesis of MS

Postby NHE » Wed Jul 25, 2018 3:16 am

Petr75 wrote:December 7, 2017
Department of neuroradiologie, Heidelberg University Hospital, Heidelberg, NěmeckoIn the Pipeline-Multiple Sclerosis: Neurographic MRI Reveals Peripheral Nerve Lesions in MS Patients
https://journals.lww.com/neurotodayonli ... hic.6.aspx

.. Current opinion is that pathological changes in MS are restricted to the central nervous system (CNS) and cranial nerves, but the new proof-of-concept study may offer new insights into the pathophysiology of the disease and help guide new treatment options, said lead author Jennifer Kollmer, MD, a neuroradiologist at Heidelberg University Hospital..


It sounds like they may not be exactly sure of what the significance is of the lesions they're detecting.

Dr. Jacobs added that it is also worth noting that the healthy controls had quite a few lesions, implying that MRN may pick up very subtle disturbances of peripheral nerve myelin which don't have any functional importance.
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Re: Microglia in the pathogenesis of MS

Postby frodo » Wed Jul 25, 2018 1:26 pm

It looks like microglia is the root of all evil. Microglia activation is the first step in the so-called "preactive lesions" (with some doubts, see below), it appears in the "normal appearing white matter" and also in the cortical lesions.

Why that happens is unknown, but microglia activation is something that happens when a virus or antigen is present. Anyway it could be just a metabolic problem, because fingolimod prevents microglia activation without bad consequences.

There is a review about Microglia activation here:

Microglial Phenotypes and Functions in Multiple Sclerosis

http://perspectivesinmedicine.cshlp.org ... 28993.full

Some excerpts:

"In line with this concept, preactive lesions have been described in MS, which are defined by clusters of activated microglia in the white matter of MS patients, which develop without demyelination and peripheral cell infiltration (van Horssen et al. 2012), and thus may represent the early stage of inflammatory lesion (van Noort et al. 2011). However, these “preactive” lesions have been described in progressive MS, are very frequent and widespread, and it is therefore highly unlikely that such lesions develop into classical active MS plaques. In addition, they are poorly defined and may also reflect areas of diffuse microglia activation in the normal-appearing white matter of MS patients as well as areas of secondary Wallerian degeneration or even remyelination"

"From all these studies, it is clear that active demyelination and neurodegeneration is associated with microglia activation. Whether this microglia activation is the primary trigger of lesion formation, whether they are activated by T lymphocytes or B cells, or they are secondary to tissue injury mediated by soluble factors produced by cells of the adaptive immune system is currently unresolved. "

"A proof-of-principle, that inhibition of microglia activation has a beneficial effect on MS, has recently been obtained in a trial using minocycline. This drug, which has been shown to target microglia activation and has beneficial effects in several different experimental models of inflammation and neurodegeneration, reduced the conversion of clinically isolated syndrome (CIS) into definite MS in MS patients and reduced clinically or radiologically identified activity of the disease"
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Re: Microglia in the pathogenesis of MS

Postby Petr75 » Fri Jul 27, 2018 9:46 am

2018 Jul 3
Neuroscience Laboratory, Laval University, Quebec, QC, Canad
mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/30018535

Abstract
A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.

full https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037698/
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