Acta Neuropathologica: Analysis of the causes associated with the lesions phase of myelin regeneration damage from multiple sclerosis.

Multiple sclerosis (MS) is the most common inflammatory and demyelination disease in the central nervous system, affecting about 2.3 million people worldwide.
10-15 years after the course of the disease, about 50% of patients need a helper.
socio-economic costs are enormous.
2013, MS's annual cost in the United States was estimated at about $10 billion a year.
In histopathology, MS is characterized by multifavette demyelination, inflammatory immersion (macrophages, T-cells and B-cells), reduced axon damage and number, and less dexterous glial cell loss.
Based on the density and distribution of single-nucleocytes from blood sources and small glial cells resident in the central nervous system (which are subsequently summarized as myelin-like cells), activity, in activity, in activity and mixed lesions can be distinguished according to the descriptions in the updated MS histological classification.
desylinic destrucement are either myelin regeneration or long-term demyelination, making them particularly vulnerable to the immune system.
and loss of axons have already appeared in the early stages of MS lesions and are the root cause of disease progression.
de-myelin, a new myelin is formed around the axon, called myelin regeneration, which represents an endogenal repair process that restores the conduction of the actional level, provides nutritional support for the axon, and prevents axon damage.
addition, recent histological and imaging studies have shown that myelin regeneration contributes to clinical recovery.
in different lesions from the same patient, the degree of myelin regeneration may change significantly, and the lesion site may affect the degree of myelin regeneration.
in animal experiments, successful re-myelinization required the proliferation and migration of less protrusive glial prescellular cells (OPCs), as well as the differentiation of them into mature myelin-based glial cells.
these complex processes are regulated by the interaction of OPC and less dexterity glial cells with neurons and axons, astrocytes, and immune cells such as macrophages/small glial cells, T cells, and B cells.
, OPC is still present in MS lesions, although the number is reduced and unevenly distributed, while mature, less dextinant glial cells are almost completely lacking.
the concept that these findings lead to damage to the differentiation of less dextent glial cells is a factor in the limited regeneration of chronic MS myelin.
in animal studies, several signal conduction cascades have been identified to inhibit OPC differentiation into mature myelin-less protrusive glial cells, which may be activated by inflammatory cells in MS lesions.
, in experimental animal studies, M2 (anti-inflammatory) esogen cells promote less protrusion glial cell differentiation.
extensive research and drug development efforts have been carried out to identify drugs that promote cell differentiation and regeneration through myelin.
the drugs identified, anti-Lingo-1 antibodies and clemastine were tested in clinical Phase II trials.
two compounds have successfully promoted myelin regeneration in several demyelinated animal models.
, however, they play a small role in clinical Phase II trials.
authors have shown that mature, less protrusive glial cells are preserved in active/demyelinated lesions, some of which show significant myelin regeneration.
in mixed and in activity lesions, the loss of less protrusion glial cells was most pronounced at the center of the lesions, indicating that prolonged demyelination time led to the death of less protrusion glial cells.
mixed lesions are almost completely lacking in myelin formation, which is associated with a relative increase in TMEM119 plus small glial cells and iNOS plus myelin-like cells.
addition, in-body experiments have shown that the upper liquid from the primary generation of M1 (inflammatory) polarized small glial cells does not damage M2 or M0 (unstinstated) polarized small glial cells.
: The study collected samples of paraffin buried brain biopsies and autopsy tissues from 62 patients.
included 38 biopsy tissue samples from 32 patients and 113 MS lesions (81 tissue blocks) from 30 patient autopsies.
all lesions included in this study are located in the whiteness of the brain and meet recognized MS diagnostic histological standards.
classification is based on the MS lesions histological classification updated by Kuhlmann et al.
immunologic chemistry (IHC) to detect myelin demyelination, CD68 determines the number and distribution of myelin cells, including single-core cells from blood sources and small glial cells in the central nervous system.
disease into high cell lesions, characterized by diffuse immersion throughout the lesions region, which can be seen in a large number of CD68 plus myelin-like cells.
these cells are denser than the peripheral white mass (PPWM) and the normal white mass (NAWM) farther away from the lesions.
In biopsy lesions, NAWM and PPWM are summed up as non-demyelinated whiteness (NDWM) because biopsy specimens are often fragmented and the distance between lesions and non-demyelinated whiteness is not always clear.
further divided into active/demyelinative lesions and active/demyelination lesions.
In active/demyelinated lesions, a large number of myelin cell plasma contains MP-myelin degradation products, while myelin cells in active/demyelination disease lack these myelin degradation products.
Mixed activity/in activity lesions (formerly known as chronic active lesions, including so-called pubic and slow-expansion lesions) are characterized by low cells at the center of the lesions, a circle of active myelin-like cells at the edge of the lesions, and almost no myelin cells at the center of the lesions.
for simplicity, inactive lesions are in a low-cell state throughout the lesions region, with only a small number of myelin-like cells present.
density of myelin cells with in activity lesions is lower.
in biopsies and autopsies, semi-quantitative scores were used to assess the degree of myelin regeneration in all lesions.
biopsy, myelin regeneration was identified as the use of IHC irregularly formed myelin.
Because biopsy samples often show only a portion of the lesions, the authors used the following categories to quantify the extent of myelin regeneration: 0 , no myelin regeneration at all, 1 , a single small dendrites glial cell to expand myelin regeneration process, 2 , plaque myelin regeneration, 3 , myelin regeneration of the entire sampled lesions region.
in the autopsy case, the myelin regeneration region was identified by light staining in IHC's MBP thin myelin and Luxol solid blue (LFB)-Iodate Schiff (PAS) staining.
in most autopsy cases, complete lesions were sampled.
Therefore, the lesions are classified according to the percentage of myelin regeneration in the lesions region: 0 - no myelin regeneration or only exist at the lesions boundary of 10% of the entire lesions region, 1 - myelin regeneration is found in more than 10 areas, but less than 50% of the entire lesions region, 2 - more than 50% of the disease becomes myelin regeneration, 3 - completely re-myelin lesions.
results: The number of less protrusion glial cells in MS tissue slices was checked using different less protrusion glial markers (e.g. OLEG2, NOGOA, and micro-tube protein polymerization promoting proteins (TPPP / p25).
OLIG2 labeled OPC as well as mature less protrusive glial cells, while NOGOA and TPP/p25 are expressed only by mature less protrusion glial cells (Figure 1a, b).
, however, the data show that NOGOA and TPPP / p25 cannot mark the exact same group of less protrusive glial cells because the absolute number of NOGOA plus and TPPP / p25 plus cells is different.
The first step is to quantify the number of NDWM (n s 117), active/demyelination (n s 24), activity/demyelination (n s 16), mixed (n s 34) of TPPP / p25 s less dendrient glial spectrome genealogy cells and in activity lesions (n s 46).
Compared to NDWM, the number of TPP / p25 s less protrusive glial cells in active/demdy myelin, mixed and in activity lesions decreased significantly, while the number of TPP / p25 / less protrusive glial cells in active/demlintic lesions decreased (Figure 1d).
In order to verify the number of TPPP / p25 and further identify the number of cells in the NDWM with less protrusion glial cell line and active/demeaning lesions, the authors quantified the number of oleg2 plus and NOGOA plus less protrusion glial cells without observing significant differences (Figure 1e, f).
, no significant reduction in the number of less protrusive glial cells was observed when comparing individual lesions that contained NDWM and active/demyelination areas (Figure 1g).
the number of glial cells in mixed lesions, from which the total lesions region can be understood in more detail.
Among the autopsy materials buried in formarin fixed paraffin, TPPP / p25 more reliably labeled less protrusive glial spectrometry cells than OLEG2 or NOGOA, indicating that the TPP/p25 table is more stable than the NOGOA and OLEG2 tables identified by appropriate antibodies.
focused on TPPP / p25 to quantify the number of less protrusive glial cells in the autopsy material.
identified the number of TPPS / p25 and less protruding glial cells at the lesions boundary, between the lesions boundary and the center, and in the lesions center (Figure 2a).
in mixed lesions, boundaries represent the edges of myelin-like cells.
observed a significant decrease in the number of dendient glial cells in different lesions areas, including boundaries and PPWM, compared to NAWM (Figure 2b).
similar changes in the number of less protrusive glial cells were observed in in activity lesions.
, however, less sudden glial cell loss was more pronounced at the mixing boundary than in activity lesions.
authors, the root cause of MS myelin regeneration failure depends on the stage of lesions.
In active/demyelinating lesions, lack of myelin formation can lead to myelin regeneration failure, and less sudden glial loss and unfavourable tissue environment in in activity/mixed lesions may prevent successful myelin regeneration.
The pharmacological approach of focusing only on promoting less protrusion of glial cells to enhance myelin regeneration may fail, consideration should be given to treatment strategies for the multiple steps required for successful re-myelinization, i.e. less protrusion, migration, differentiation, myelin formation and survival.
authors also suggest that promoting myelin regeneration in both hybrid and in activity lesions may require different treatments than RRMS, which is characterized by active diseases.
in order to understand the molecular mechanisms that prevent myelin regeneration and to develop new treatments that successfully promote MS myelin regeneration, better animal models are needed to simulate the pathological characteristics of different lesions.
original link: He?, K., Starost, L., Kieran, N.W. et al. Lesion stage-dependent causes for impaired remyelination in MS. Acta Neuropathol 140, 359-375 (2020). MedSci Original Source: MedSci Originals !-- content presentation ends -- !-- to determine whether the login ends.