MS

Question 1

What does MS lead to?

Answer 1

focal plaques of primary demyelination and diffuse neurodegeneration in the grey and white matter of the brain and spinal cord.

Question 2

What is there general agreement on?

Answer 2

active destruction of myelin and axons in MS lesions is invariably associated with activated macrophages or microglia

Question 3

Why is MS considered an autoimmune condition?

Answer 3

initiated by autoreactive immune cells that cross the blood brain barrier (BBB) and mediate damage against central neurons and their axons

Question 4

What does data show about inflammation in MS?

Answer 4

Data suggests that inflammation is always present when active demyelination or neurodegeneration occurs, and that the extent of T-cell and B-cell infiltration is related to the extent of demyelination and axonal injury.

Question 5

Who showed that T-cells are pathogenically primed?

Answer 5

Several factors including cell surface factors and cytokines lead to the facilitation of pathogenic T-cell priming (Chihara,2018)

Question 6

What do differentiated pathogenic T-cells mediate?

Answer 6

1. induce cytotoxicity through breaching the BBB -> B-cell autoantibodies
2. binding of proteins normally found in the myelin sheath
3. production of cytokines such as TNF-a -> microglia activation

Question 7

How do we know that autoantibodies cause damage?

Answer 7

MS-specific autoantibodies in intact CNS tissue of mouse cerebellar slice cultures, Liu and colleagues (2017) found that MS-specific autoantibodies recognised surface antigens on oligodendrocyte processes and outer layers of myelin ensheathing axons, initiating the classical complement pathway activation that leads to oligodendrocyte death

Question 8

What do cytokines do?

Answer 8

Cytokines induce microglia and macrophage activation which helps to maintain a chronic state of activation throughout the disease (Dendrou et al.,2015), forming plaques that involve loss of myelin sheaths and oligodendrocytes.

Question 9

What are the combined effects of inflammation thought to cause?

Answer 9

Induction of hypoxia

Question 10

Cumulative evidence suggests a role of

Answer 10

hypoxia and subsequent energy deficiency in driving tissue injury in MS lesions

Question 11

What did first evidence of hypoxia in MS come from?

Answer 11

observation that the pathology of a subset of active MS lesions revealed initial patterns of tissue injury, which are very similar to those observed in WM stroke lesions (Aboul-Enein et al., 2003)

Question 12

What do shared WM and MS lesions consist of?

Answer 12

distal oligodendrogliopathy, characterized by degeneration of the most distal oligodendrocytes processes and the selective loss of myelin-associated glycoprotein from affected myelin sheaths, as well as the subsequent apoptotic destruction of oligodendrocytes

Question 13

What is interesting about myelin sheaths in shared WM and MS lesions?

Answer 13

Myelin sheaths in such lesions remain preserved for a prolonged time period, resulting in focal lesions with loss of oligodendrocytes and reduced staining intensity of myelin with conventional histochemical myelin stains,
but complete preservation of immunoreactivity for major myelin proteins, such as myelin basic protein of proteolipid protein.

Question 14

What are the proportion of MS and WM stroke patients with this type of lesion?

Answer 14

observed in around 30% of MS patients in early and active disease stages, in some patients with virus induced inflammatory WM disease, and, in particular, in all patients within the first days after initiation of a WM stroke lesion

Question 15

How can we induce this type of MS and WM lesion?

Answer 15

by focal injection of lipopolysaccharide (LPS) into the spinal cord (Felts et al., 2005)

Question 16

Who showed that MS lesions are related to mitochondrial damage?

Answer 16

acute and chronic mitochondrial damage, (Dutta et al., 2007; Witte et al., 2010) most likely attributed to chronic oxidative injury

Question 17

What concept was proposed from evidence from hypoxia and mitochondrial damage in MS?

Answer 17

inflammation drives microglia and macrophage activation, which leads to oxidative stress and mitochondrial dysfunction and damage

Question 18

How might defective mitochondria amplify MS tissue injury and why would this be the case?

Answer 18

Defective mitochondria may amplify oxidative injury by electron leakage, given that it is also induced in elderly patients by iron liberation from oligodendrocytes during demyelination (Mahad et al.,2005)

Question 19

What does mitochondrial dysfunction lead to and what does this result in?

Answer 19

a stage of energy deficiency (“histotoxic or virtual hypoxia”), resulting in cell death or axonal transection by a disbalance of ionic homeostasis.

Question 20

How can we show mitochondrial injury in MS?

Answer 20

liberation and nuclear translocation of apoptosis-inducing factor from mitochondrial stores, which might induce DNA damage and apoptosis, as suggested by nuclear accumulation of fragmented DNA in affected cells

Question 21

What does increased intra-axonal calcium do?

Answer 21

activates calpains, which cause intra-axonal proteolytic degradation of cytoskeletal proteins and axonal degeneration

Question 22

What are ionic disbalances amplified by in MS?

Answer 22

aberrantly expressed voltage-gated calcium channels and glutamate receptors in the lesions.

alterations in the expression of different sodium channel subunits have been described in axons in MS lesions, which might further amplify ionic imbalance and axonal demise.

Question 23

What did Desai’s 2016 paper show?

Answer 23

initial tissue injury occurs already within the first hours and days after LPS injection, which paves the way for focal demyelination occurring, at the earliest, 5 to 7 days later

Question 24

Who showed that lesions didn’t appear at the site of LPS injection?

Answer 24

Davies et al.,2013

Question 25

Who and what type of evidence showed that lesions accumulate at areas of low perfusion?

Answer 25

Evidence from neuropathology (Haider et al., 2016) and magnetic resonance imaging (MRI) (Holland et al., 2012) provide evidence that lesions in brain WM of MS patients also accumulate in areas of low perfusion and oxygen supply

Question 26

Longitudinal MRI demonstrated that initial lesion formation in the MS brain occurs randomly in any brain regions, around veins and venules. However, permanent lesions in the brain, which accumulate in patients with progressive disease, are much more likely located in so-called watershed areas. What is the significance of this?

Answer 26

initial lesions in the brain of MS patients in the early disease stages are related to sites where leukocytes enter the CNS in the course of an inflammatory process. However, severe demyelination and neurodegeneration, leading to permanent WM lesions, are more likely to develop in areas with low arterial blood perfusion and oxygen tension.

Question 27

What three things were present early in Desai’s experimental model and what two things could these cause?

Answer 27

microglia activation, oxidative injury, and hypoxia

mitochondrial injury and virtual hypoxia

present in the early lesion stages at sites of subsequent tissue injury.

Question 28

When was nombardic oxygen provided?

Answer 28

during the short period of lesion

Question 29

What causes oxygen supply disturbances in inflammatory lesions?

Answer 29

It is currently not clear what causes the disturbance of oxygen supply in inflammatory demyelinating lesions in the brain. Microglia activation appears to be an early phenomenon

Question 30

How might treatment vary based on the information gained about MS?

Answer 30

therapies, which raise the tissue energy levels over prolonged time periods, may not only have a symptomatic effect, but also may be neuroprotective:

• High-dose biotin treatment
• Mitochondrial protection and replenishment strategies
• Target different ion channels

Question 31

What makes finding new therapies difficult?

Answer 31

absence of suitable animal models for the progressive stage of the disease