Neuro BD Test 3 MS

What is the pathological hallmark of MS?

accumulation of demyelinating lesions in brain and spinal cord

dissemination in space

multiple regions of CNS have demyelinating lesions

dissemination in time

evidence of more demyelinating lesions over time

Does MS affect men or women more?

women

Do men or women have higher mortality from MS?

men

clinically isolated syndrome (CIS)

first symptomatic event

relapsing-remitting MS (RRMS)

clearly defined attacks followed by near or complete recovery

secondary progressive MS (SPMS)

progressive, irreversible disability, independent of inflammatory relapse

primary progressive MS (PPMS)

Disease progression from onset. Permanent neurological deficits

well-established environmental risk factors for MS

Susceptibility to environmental risk during adolescence (Epstein-Barr virus (EBV), Low vitamin D, Obesity), Tobacco exposure (active or passive), Lack of sun exposure

the dominant theory of why EBV is a risk factor

Possibly b/c cross-reactive T-cells and antibodies: Still correlational, considered more of a prerequisite or necessary factor than an adequate trigger

How does smoking/tobacco correlate to conversion from RRMS to SPMS?

Higher risk of conversion from RRMS to SPMS

What is a possible mechanism for low sun exposure increasing risk?

Low vitamin D associated w/Increased risk, Increased disease activity. Mechanism: Possibly vitamin D modulation of immune function

Is there evidence for G x E interactions?

Yes. Polymorphisms for genes for human leukocyte antigens (HLA*) x EBV, obesity, smoking

What are two things that risk genes for MS are associated with?

Immune system function & environment x gene interactions

Focal lesion location & description

Areas of demyelination. Around postcapillary venules, Characterized by breakdown of BBB, In white matter and gray matter

Is the location of white matter lesions or gray matter lesions associated with clinical symptoms?

Location of white matter lesions associated w/ clinical symptoms

2 ways the immune system is likely involved in breakdown of the blood brain barrier.

Microglia, astrocytes, and endothelial cells produce pro-inflammatory cytokines and chemokines (TNF, IL-1β, IL-6), Indirect cytokine-dependent, chemokine-dependent, leukocyte-mediated injury

the cycle of BBB breakdown and further inflammation and immune infiltration

Increase in trans-endothelial migration of activated leukocytes inc. macrophages, T cells, B cells into CNS → More inflammation and demyelination → Loss of oligodendrocytes, reactive gliosis, neuro-axonal degeneration

Active demyelinating lesions

Lymphocyte infiltration (T and B cells), Macrophages (contain myelin debris), Activated microglia (esp. at lesion edge, contain myelin debris), Large, reactive astrocytes

Inactive demyelinating lesions

Sharply circumscribed; Well-defined demyelination, Hypocellular, Reduced axonal density, Reactive astrocytes and variable microglial activation in periplaque white matter, Lower density of lymphocytes

2 other types of white matter lesions

Chronic active plaques (smoldering lesions) and slow expanding lesions. More frequent in SPMS, Inactive center w/ demyelination, Macrophages and/or microglia on edge of lesion, Transected axons, continuing demyelination

Normal appearing white matter

Macroscopically normal-appearing. Diffuse inflammation and neuro-axonal damage, Axonal degeneration and demyelination → decreased fiber density, Lymphocyte and macrophage infiltration, Microglia activation and reactive astrocytes, Observed in RRMS, but more severe in progressive disease

Grey matter lesions

From earliest phases of disease. More widespread in progressive disease, Extensive cortical demyelination in forebrain and cerebellum, Within deep nuclei (brain, cb), Within grey matter of spinal cord

Grey matter lesions comparisons

Less: BBB breakdown, edema, inflammation. More: myelin repair

4 main types of grey matter lesions

Based on location. Type III is most common & is sub pial lesions

What are some determinants of how much remyelination occurs?

age, disease duration, lesion location, presence of oligo progenitors, and axonal integrity

Is remyelination more common early or late in the disease?

ealier

What are shadow plaques?

global or patchy remyelination. Sharp demarcation from surrounding NAWM, axons w/thin myelin sheath and shortened internodes.

Does neurodegeneration occur only in late stages of the disease or earlier stages as well?

earlier as well

What is the most widely implicated proinflammatory T cells in MS?

CD4T, CD8T

What does it mean that it is pro-inflammatory?

promoting or causing inflammation in the body

What are the actions of the helper T cells and the cytotoxic T cells?

express IL-17. Contribute to injury to oligo dendrocytes and to neurons directly and indirectly (through activating macrophages)

What are 3 possibilities of how peripheral immune cells access the CNS?

BBB breakdown, subarachnoid space, and the blood CSF barrier, glymphatic system

In MS, what are 3 suspected antigens that may activate T cells?

myelin-related antigens, axo-glial molecules, EBV-related antigens

What evidence supports myelin basic protein as a possible autoantigen in MS

myelin reactive T-cells in MS patients

What evidence does not suggest myelin basic protein as a possible autoantigen in MS

myelin reactive T & B cells in healthy people

What 2 pieces of evidence support EBV as a possible autoantigen in MS?

Almost all MS patients are positive for EBV. EBV shares molecular sequence w/MBP

What is molecular mimicry?

immune response to pathogen cross-reacts w/similar host proteins

Is remission in MS likely to do passive decline of immune system?

no

What are Treg cells?

immune suppressing T-cells

Are Treg cells involved in remission

yes, downgrade immune responses

How do Treg cells impact other immune cells

release inhibitory cytokines, trigger apoptosis of immune cells, prevent immune cell activation, produce adenosine to inhibit cells

How might peripheral B cells be involved in MS?

produce pro-inflammatory cytokines → activate T cells → activate myeloid cells → relapse cascades

How might central nervous system B cells be involved in MS?

attract and activate T-cells and myeloid cells in CNS

What are 2 unusual things about B cells in MS patients?

high propensity to produce pro-inflammatory cytokines. Deficient in producing regulatory cytokines

how inflammation differs between from RRMS and primary or secondary progressive MS

RRMS: more relapses, active lesions, peripheral immune infiltration. Progressive: compartmentalized CNS inflammation, Tcells and plasma cells persistent in meninges, microglia/astrocyte driven injury

What are the meninges?

protective membranes around brain/spinal cord

What is meant by subpial?

beneath the pia matter/outermost cortical layer

What is the correlation between meningeal inflammation and subpial cortical injury in progressive MS

more inflammation = more subpial cortical injury

how are meningeal inflammation and subpial cortical injury in progressive MS hypothesized to relate to each other causally?

meningeal inflammation associated with extent of subpial cortical injury & more pro-inflammatory cytokines → meningeal immune cells could be contributing to CNS injury

In addition to immune cells, list 7 other factors involved in neuro-axonal degeneration in progressive MS.

Oxidative stress, Mitochondrial dysfunction, Accumulation of extracellular free iron, Loss of myelin trophic support, Hypoxia, Altered glutamate homeostasis, Proinflammatory environment