simultaneous-isolation-principal-central-nervous-system-resident-cell

Simultaneous Isolation of Principal Central Nervous System-Resident Cell Types from Adult Autoimmune Encephalomyelitis Mice

Experimental autoimmune encephalomyelitis (EAE) is the most common murine model for multiple sclerosis (MS) and is frequently used to further elucidate ...

Heinrich Heine University Duesseldorf

Cladribine is a synthetic purine analogue that interferes with DNA synthesis and repair next to disrupting cellular proliferation in actively dividing lymphocytes. The compound is approved for the treatment of multiple sclerosis (MS). Cladribine can cross the blood-brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. Here, we explored compartment-specific immunosuppressive as well as potential direct neuroprotective effects of oral cladribine treatment in experimental autoimmune encephalomyelitis (EAE) mice.

Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis.

Due to the growing complexity in monitoring and treatment of many disorders, disease-specific care and research networks offer patients certified healthcare. However, the networks' ability to provide health services close to patients' homes usually remains vague. Digital Health Technologies (DHTs) help to provide better care, especially if implemented in a targeted manner in regions undersupplied by specialised networks. Therefore, we used a car travel time-based isochrone approach to identify care gaps using the example of the neuroinflammation-focused German healthcare and research networks for multiple sclerosis (MS), myasthenia gravis (MG), myositis and immune-mediated neuropathy.

Driving time-based identification of gaps in specialised care coverage: An example of neuroinflammatory diseases in Germany.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is one of the most common immune neuropathies leading to severe impairments in daily life. Current treatment options include intravenous immunoglobulins (IVIG), which are administered at intervals of 4-12 weeks. Determination of individual treatment intervals is challenging since existing clinical scores lack sensitivity to objectify small, partially fluctuating deficits in patients. End-of-dose phenomena described by patients, manifested by increased fatigue and worsening of (motor) symptoms, are currently difficult to detect. From a medical and socio-economic point of view, it is necessary to identify and validate new, more sensitive outcome measures for accurate mapping of disease progression and, thus, for interval finding. Digital health technologies such as wearables may be particularly useful for this purpose, as they record real-life data and consequently, in contrast to classic clinical 'snapshots', can continuously depict the disease course.

Introducing electronic monitoring of disease activity in patients with chronic inflammatory demyelinating polyneuropathy (EMDA CIDP): trial protocol of a proof of concept study.

Inclusion body myositis (IBM) is unique across the spectrum of idiopathic inflammatory myopathies (IIM) due to its distinct clinical presentation and refractoriness to current treatment approaches. One explanation for this resistance may be the engagement of cell-autonomous mechanisms that sustain or promote disease progression of IBM independent of inflammatory activity. In this study, we focused on senescence of tissue-resident cells as potential driver of disease. For this purpose, we compared IBM patients to non-diseased controls and immune-mediated necrotizing myopathy patients. Histopathological analysis suggested that cellular senescence is a prominent feature of IBM, primarily affecting non-myogenic cells. In-depth analysis by single nuclei RNA sequencing allowed for the deconvolution and study of muscle-resident cell populations. Among these, we identified a specific cluster of fibro-adipogenic progenitors (FAPs) that demonstrated key hallmarks of senescence, including a pro-inflammatory secretome, expression of p21, increased β-galactosidase activity, and engagement of senescence pathways. FAP function is required for muscle cell health with changes to their phenotype potentially proving detrimental. In this respect, the transcriptomic landscape of IBM was also characterized by changes to the myogenic compartment demonstrating a pronounced loss of type 2A myofibers and a rarefication of acetylcholine receptor expressing myofibers. IBM muscle cells also engaged a specific pro-inflammatory phenotype defined by intracellular complement activity and the expression of immunogenic surface molecules. Skeletal muscle cell dysfunction may be linked to FAP senescence by a change in the collagen composition of the latter. Senescent FAPs lose collagen type XV expression, which is required to support myofibers' structural integrity and neuromuscular junction formation in vitro. Taken together, this study demonstrates an altered phenotypical landscape of muscle-resident cells and that FAPs, and not myofibers, are the primary senescent cell type in IBM.

Article	Year
Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis. Journal of neuroinflammation\| PubMed ID: 36348455	2022
Driving time-based identification of gaps in specialised care coverage: An example of neuroinflammatory diseases in Germany. Digital health\| PubMed ID: 36762020	2023
Introducing electronic monitoring of disease activity in patients with chronic inflammatory demyelinating polyneuropathy (EMDA CIDP): trial protocol of a proof of concept study. Neurological research and practice\| PubMed ID: 37612774	2023
Senescent fibro-adipogenic progenitors are potential drivers of pathology in inclusion body myositis. Acta neuropathologica\| PubMed ID: 37773216	2023

Christina B. Schroeter

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