Inside-out model: supporting papers.

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frodo
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Inside-out model: supporting papers.

Post by frodo » Wed Jan 30, 2019 2:28 am

The inside-out model is an alternative theoretical model for MS that postulates that something within the neurons is the cause of the later autoimmune attack. I am collecting here some papers that support this model.

Biochemically altered myelin triggers autoimmune demyelination (2018)
http://www.pnas.org/content/early/2018/ ... 5115.short

Early axonal damage in normal appearing white matter in multiple sclerosis (2017)
https://ieeexplore.ieee.org/abstract/document/8037494

Myelin Basic Protein Citrullination in Multiple Sclerosis (2016)
https://link.springer.com/article/10.10 ... 016-1920-2
"This review describes the MBP citrullination and its consequence, as well as offering further support for the “inside-out” hypothesis that MS is primarily a neurodegenerative disease with secondary inflammatory demyelination"

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Re: Inside-out model: supporting papers.

Post by frodo » Sun Feb 03, 2019 1:38 am

New paper challenging the outside-in model

https://www.sciencedirect.com/science/a ... 821930049X

Evidence of early microstructural white matter abnormalities in multiple sclerosis from multi-shell diffusion MRI


We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p < .05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM.

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Oligodendrocytes differences between patients and controls

Post by frodo » Sun Feb 03, 2019 7:46 am

Altered human oligodendrocyte heterogeneity in multiple sclerosis

https://www.nature.com/articles/s41586-019-0903-2

Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases as OLs both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system (CNS) thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, suggesting that other factors contribute to this variability. One such factor may be OL heterogeneity. Not all OLs are the same—mouse spinal cord OLs inherently produce longer myelin sheaths than cortical OLs2, and single-cell analysis of mouse CNS identified further differences3,4. However, the extent of human OL heterogeneity and its possible contribution to MS pathology remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and MS patients. We identified sub-clusters of oligodendroglia in Ctr human WM, some similar to mouse, and defined new markers for these cell states.

Strikingly, some sub-clusters were under-represented in MS tissue, while others were more prevalent. These differences in mature OL sub-clusters may indicate different functional states of OLs in MS lesions. Since this is similar in normal appearing white matter (NAWM), MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important to understanding disease progression and developing therapeutic approaches.

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Re: Inside-out model: supporting papers.

Post by frodo » Tue May 14, 2019 3:10 am

Potential role of calcifying nanoparticles in the etiology of multiple sclerosis

https://www.sciencedirect.com/science/a ... 771930221X

There are currently two models to explain the development of lesions in MS. For many years it was believed that demyelination happens before axonal damage and loss, as the so called “outside-in” model states. However, the “inside-out” model of MS, which is supported by recent data, states that the initial axonal degeneration in the CNS occurs before demyelination and subsequently stimulates an auto-immune attack.

[---]

... calcifying nanobacteria or nanoparticles may have a role in the etiology and/or pathophysiology of MS due to their coexistence with fetuin-A, a biomarker of MS.

It has been suggested that nanoparticles can easily cross the blood-brain barrier. Particles larger than 10 nm, such as antibodies, cannot pass the blood-brain barrier. Nanoparticles are much larger than this, however, their association with phospholipids may render them lipid-soluble and therefore facilitate their entrance to the CNS. Therefore, the initial event causing neurodegeneration may be due to calcifying nanoparticles and may, thus, be a candidate etiological factor in MS. Moreover, nanoparticles may have dual roles in the pathophysiology of MS.

They may first pass the blood-brain barrier, create nanoruptures of the axonal membrane, increase the calcium concentration around and within the neurons by forming nidi for calcification, and eventually cause neurodegeneration. Finally, breakdown of the blood-brain barrier enables entry of T-lymphocytes to the CNS.

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abnormal myelin could be the cause

Post by frodo » Wed May 29, 2019 11:50 pm

Abnormal myelin could be the cause:

Down-regulation of ERMN expression in relapsing remitting multiple sclerosis.

https://europepmc.org/abstract/med/31123898

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory disease causing demyelination and neurodegeneration in the central nervous system (CNS). Although the exact etiology of MS is still unclear, both genetic and environmental elements are regarded as causative factors.

Environmental factors can induce a cascade of events in immune system leading to neuronal death and nerve demyelination. This paper aims to compare the peripheral transcript levels of Ermin (ERMN) (a gene with putative role in cytoskeletal rearrangements during myelinogenesis) and Listerin E3 Ubiquitin Protein Ligase 1 (LTN1) (a gene with functions in regulating innate immune system) between relapsing-remitting MS (RR-MS) patients and healthy controls. The results showed a significant decrease in ERMN expression (p = 0.022); whereas, no significant difference was detected in LTN1 expression between two groups (p = 0.935).

The reduction in ERMN expression in leukocytes could be the cause of demyelinating process in RR-MS patients. Current findings might also have practical importance in prognosis and targeted therapies.

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Re: Inside-out model: supporting papers.

Post by ElliotB » Thu May 30, 2019 7:10 am

All very interesting theories, thanks for posting them!

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