35 MS Flashcards
MS - multiple sclerosis
- an immune-mediated ( ___ ) disorder involving destruction of the ___ that surrounds neuronal axons
sclerosis - refers to ___ that accumulate in the white matter
- inflammatory
- myelin sheath
- scars
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
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
immune
IgG
childhood
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)
- self-peptides,T, B, mimicry
- HLA
- gene-environment
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
- relapsing-remitting
- weeks, months
- multifocal, white
- remission
Different clinical forms of MS
SPMS - ___ MS
- less ____ than RRMS
- involves slowly progressive neurological decline and CNS damage, with little ___
- secondary progressice
- inflammation
- remission
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
- primary progressive
- later
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
inflammation and demyelination
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)
cytodegeneration
- degeneration, immune
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
- CNS, foreign
- CNS
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
- infection, stroke
- CNS
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
- dendritic, T
- a4-integrin
- B, IgG
- T
- cytokine, macrophage
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
1) CD8
2) IFN-g, TNF-a, perforin, and granzyme
3) complement, pore
4) oxygen, nitrogen, glutamate
5) myelin sheath
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
- demyelination
- Na
- slowed
- depolarize
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
OPCs
oligodendrocytes
oligodendrocytes
astrogliosis
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
- oligodendrocytes
- microglia, astrocytes
- OPCs
- macrophages
- differentiation
demyelinated axons undergo remyelination of degeneration
remyelination fails in MS because of ongoing ___ . and demyelinated axons and neurons undergo degeneration
inflammation
D) A and B
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)
- activation
- proliferation, movement
- a4-integrin, enzymatic
- remyelination
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
- compromised
- active
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
- inflammatory
- infection
- paralysis
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
- peripheral, antibodies
- antibodies
- infection
- motor
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
- environmental
- genes
- polygenic, inheritance
Genetic influences of MS risk
genes linked to MS encode the following immune-related proteins:
- ___ : HLA DR15/DR6
- interleukin ___ receptor
- interleukin ___ receptor
- MHC
- 2a
- 7a
