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PHRM 845 > 35 MS > Flashcards

35 MS Flashcards

1
Q

MS - multiple sclerosis
- an immune-mediated ( ___ ) disorder involving destruction of the ___ that surrounds neuronal axons

sclerosis - refers to ___ that accumulate in the white matter

A
  • inflammatory
  • myelin sheath
  • scars
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2
Q

multiple refers to the numerous affected areas of the CNS producing multiple neurologic symptoms that build up
- no 2 MS patients will exhibit the same profile of symtoms
- a patient’s symptoms may vary markedly during different stages of the disease
- the most prominent symptoms in each patient are a reflection of the regions of the nervous system with the most severe damage

A
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3
Q

MS etiology: a potential role for viral infections

viral or bacterial infections may increase the risk of MS by activating autoreactive ___ cells in genetically susceptible individuals
- increased ___ synthesis in the CNS of MS patients
- increased antibody titers to certain viruses
- epidemiological data suggests that ___ infection increases risk

A

immune
IgG
childhood

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4
Q

MS etiology: a potential role for viral infections

Epstein-Barr Virus (EBV)
- sequence similarities between EBV and ___ result in activation of autoreactive ___ or ___ cells (molecular ___ )
- increased atibody titers to epstein-Barr nuclear antigen (EBNA) in MS patients
- individuals with a particular ___ phenotype have an increased risk of developing MS when they also have anti-EBNA antibodies ( ___ -___ interactions)

A
  • self-peptides,T, B, mimicry
  • HLA
  • gene-environment
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5
Q

Different clinical forms of MS

RRMS - ___ MS , 85% of cases
- relapses of neurological dysfunction lasting ___ or ___ and affecting the brain, optic nerves and or spinal cord
- ___ areas of damage are revealed by magnetic resonance imaging, generally (but not always) in the ___ matter
- initial symptoms disappear, but less ___ with each relapse
- most cases eventually enter SPMS

A
  • relapsing-remitting
  • weeks, months
  • multifocal, white
  • remission
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6
Q

Different clinical forms of MS

SPMS - ___ MS
- less ____ than RRMS
- involves slowly progressive neurological decline and CNS damage, with little ___

A
  • secondary progressice
  • inflammation
  • remission
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7
Q

Different clinical forms of MS

PPMS - ___ MS, 15%
- resembles SPMS at initial stage
- mean age of onset is ___ than RRMS, perhaps because inflammatory episodes of RRMS surpass the symptomatic threshold

A
  • primary progressive
  • later
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8
Q

Different clinical forms of MS

Clinically isolated syndrome (CIS)
- an initial episode of neurologic symptoms lasting over 24 hours
- involves ___ and ___ in the optic nerve, cerebrum, brainstem, or spinal cord
- most cases progress to MS

A

inflammation and demyelination

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9
Q

Different clinical forms of MS

progressive phase involved ___ (loss of myelin, axons, oligodendrocytes) and occurs with a similar rate in the different forms of MS

the overall clinical presentation is determined by the combination of the underlying ___ (uniform, progressive) and the host’s ___ reaction to it (intermittent, vaiable)

A

cytodegeneration
- degeneration, immune

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10
Q

Autoimmune and degenerative phases

auto-immune phase
- antigens released from the ___or cross-reactive ___ antigens are presented to B and T cells in the lymph nodes
- B and T cells with high-affinity receptors for these antigens are expanded and migrate to CNS sites where they re-encounter and are activated by their target ligands
- activated B and T cells then carry out immune functions (release of antibodies and cytokines) at the __ sites

  • it is unclear which of the two phases is the disease trigger
A
  • CNS, foreign
  • CNS
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11
Q

Autoimmune and degenerative phases

  • CNS damage is triggered by activated B and T cells or by other insults such as ___ or ___
  • antigens released from damaged sites in the ___ further prime immune cells in the periphery, thus completing a vicious cycle
  • it is unclear which of the two phases is the disease trigger
A
  • infection, stroke
  • CNS
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12
Q

Autoimmune respinses in MS

  • ___ cells that present CNS antigens activate ___ -cell responses in the peripheral lymphoid tissue
  • activated B and T cells proliferate/infiltrate the CNS (involves ___ mediated binding and penetration of the BBB)
  • after re-encountering their specific antigen in the CNS, ___ cells mature to plasma cells and increase ___ antibodies that target the antigen on expressing cells (neurons)
  • ___ cells interact with their target ligands on oligodendrocytes, neurons, or microglia on MHC molecules
  • T cell activatioin results in ___ release and ___ stimulation, leading to damage to the myelin sheath
A
  • dendritic, T
  • a4-integrin
  • B, IgG
  • T
  • cytokine, macrophage
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13
Q

A closer look at autoimmune responses in MS

1) ___ T cells engage oligodendrocytes via T-cell receptor/mHC class I interactions
2) T cells release ___ , ___ , ___ , and ___ (leading to oligodendrocyte destruction)
3) antibodies trigger the activation of ___ (C5-9 membrane complex) on oligodendrocyte membranes resulting in ___ formation and cell damage
4) macrophages recruited to inflammatory lesion release toxic agents: ___ and ___ species, ___
5) macrophages also harm the ___ via phagocytosis

A

1) CD8
2) IFN-g, TNF-a, perforin, and granzyme
3) complement, pore
4) oxygen, nitrogen, glutamate
5) myelin sheath

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14
Q

action potetnials in zones of demyelination

  • node of Ranvier = normal zone of ___
  • the node of Ranvier has voltage-gated ___ channels that are essential for replenishing actions potentials
  • in demyelinated regions of axons in MS, the propagation of the action potential is ___
  • the amount of current generated at the node of Ranvier is insufficient to fully ___ the demyelinated region because current is lost through the membrane
A
  • demyelination
  • Na
  • slowed
  • depolarize
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15
Q

Repair via remyelination

remyelination involves the recruitment of ___ to the lesion and the differentiation of these cells into myelin-producing ___
- typically fails in MS because of a lack of ___ or failure for them to differentiate

___ involves the invasion and propagation of astrocytes resulting in the irreversible formation of gliotic plaques or scars

A

OPCs
oligodendrocytes
oligodendrocytes
astrogliosis

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16
Q

remyelination

  • demyelination (loss of myelin and ___ ) results in the activation of ___ and ___
  • once activated, they release pro-migratory factors and mitogens that recruit ___ to the lesion and stimulate their proliferation.
  • ___ eliminate the myelin debris
  • differentiation occurs via a process involving axon engagement and myelin sheath formation.
  • ____ is the key step where remyelination fails in MS
A
  • oligodendrocytes
  • microglia, astrocytes
  • OPCs
  • macrophages
  • differentiation
17
Q

demyelinated axons undergo remyelination of degeneration

remyelination fails in MS because of ongoing ___ . and demyelinated axons and neurons undergo degeneration

A

inflammation

18
Q
A

D) A and B

19
Q

Rationale for MS therapies

immunomodulatory therapies
- interference with T or B cell ___
- inhibitions of T or B cell ___ and ___ into the CNS
- inhibition of ___ mediated binding and penetration of the BBB, ___ breakdown of the BBB

rescue strategies
- ___ (agents that facilitate OPC recruitment or promote OPC differentiation)

A
  • activation
  • proliferation, movement
  • a4-integrin, enzymatic
  • remyelination
20
Q

Gadolinium

gadolinium is a contrast agent for MRI analysis
- penetrates the brain in regions where the BBB is ___
- MS lesions that exhibit enhancement after administration are considered ___ lesions
- over time, lesions observed by gadolinium enhanced MRI may grow or recede depending on how active the disease process is

A
  • compromised
  • active
21
Q

Guillain-Barre syndrome

  • acute, ___ neuropathy
  • preceded by a GI or respiratory ___ in about half of patients

symptoms
- weakness that begins in distal muscles and lower extremities, ascends to proximal muscles and upper extremities
- can progress to total ___ with death from respiratory failure in days
- progression peaks at 10-14 days

A
  • inflammatory
  • infection
  • paralysis
22
Q

Guillain-Barre syndrome

pathophysiology
- autoimmine attack on ___ nerves by circulating ___ , resulting in demyelination

treatment
- ventilation
- plasmapheresis (to eliminate auto - ___)
- IV immunoglobulin administration

prongnosis
- slow recovery (months to a year)
- fatalities can result from respiratory failure or ___
- most surviving patients recover completely, and the remaider have minor ___ deficits

A
  • peripheral, antibodies
  • antibodies
  • infection
  • motor
23
Q

Genetic influences of MS risk

  • about 5% of cases are familial
  • risk is highest in twins and siblings, lower in children and half siblings
  • these observations point to an exposure to some common ___ factor in childhood
  • alernatively, they suggest a role for one or more ___
  • ___ mode of ___ - genomic screens suggest that > 50 genomic regions may be linked to MS
A
  • environmental
  • genes
  • polygenic, inheritance
24
Q

Genetic influences of MS risk

genes linked to MS encode the following immune-related proteins:
- ___ : HLA DR15/DR6
- interleukin ___ receptor
- interleukin ___ receptor

A
  • MHC
  • 2a
  • 7a
25
Q

Clinically isolated syndrome (CIS)

  • initial episode of neurologic symptoms lasting more than ___ hours
  • involved ___ and ___ in the optic nerve, cerebrum, cerebellum, brainstem, or spinal cord (one or more foci)
  • ___ bands in cerebrospinal fluid (CSF)
  • most cases progress to MS
A
  • 24
  • inflammation, demyelination
  • oligoclonal
26
Q

Marbug variant of MS

  • agressive form of MS involving a high degree of ___
  • may resemble a brain tumor (high load of ___ ) in a brain scan
A
  • inflammation
  • lesions
27
Q

Different clinical forms of MS

___ phase involves cytodegeneration (loss of myelin, axons, oligodendrocytes) and occurs with a similar rate in the different forms of MS

see thick blue line in graphs

A

progressive

see thick blue line in graphs

28
Q

Different clinical forms of MS

the overall clinical presentation is determined by the combination of the underlying ___ (uniform, progressive) and the host’s ___ reaction to it (intermittent, variable)

see dashed blue/orange lines on graph

A

degeneration, immune

29
Q

pathophysiology of MS

___ results in a redistribution of voltage-gated ___ channels
- in healthy neurons, ___ channels are located under the myelin sheath in internodal regions, wherease ___ channels are predominantly found in the nodes of Ranvier
- in demyelinated axons, Na channels now accumulate in ___ regions from which they were previously excluded
- dysregulated ___ channel expression may play a role in disrupting the ___ properties of the axon and in neurondegeneration

A

demyelination, Na
- K, Na
- internodal
- Na, conductive

30
Q

demyelinated axons can undergo ___
- myelin sheaths that result from remyelination are ___ and ___ , but allow for partial functional recovery

A

remyelination
- thinner, shorter

31
Q

Patho of MS

1) ___ T cell MHC class I interaction leads to ___ / ___ release
2) ___ release by glial cells activates ___ receptors
3) ___ - antigen interactions causes ___ activation and formation of membrane disrupting TCC
4) release of ___ from macrophages, microglia, and astrocytes leads to inflammation, neuro ___ / ___
5) ___ release by glial cells and ___ T cells lead to neuro ___ and ___
6) migration of neuronal ___ cells and OPCs to the lesion causes ___ of damaged neurons and oligodendrocytes

A

1) CD8, cytokine/granule
2) glutamate, NDMA
3) antibody, complement
4) cytokines, protection, degeneration
5) neurotrophin, CD4, protection, regeneration
6) stem, replacement

32
Q

opportunities for therapeutic intervention in MS

immune system targets
- T cell ___ /penetration of ___
- T cell / ___ interactions
- cytokines

targets involved in remyelination
- facilitate OPC ___
- promote OPC ___

A
  • binding, BBB
  • APC
  • recruitment
  • differentiation
33
Q

drug examples - immune system targets

T cell binding / penetration of BBB (2)

A
  • a4-integrin antibodies
  • IFN-B
34
Q

drug examples - immune system targets

T cell / APC interactions (2)

A
  • altered peptide ligands (APLs) such as copaxon
  • statins
35
Q

drug examples - immune system targets

cytokines (2)

A
  • antibodies specific for IL-23
  • osteopontin

PHRM 845 (62 decks)

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