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
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
- 24
- inflammation, demyelination
- oligoclonal
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
- inflammation
- lesions
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
progressive
see thick blue line in graphs
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
degeneration, immune
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
demyelination, Na
- K, Na
- internodal
- Na, conductive
demyelinated axons can undergo ___
- myelin sheaths that result from remyelination are ___ and ___ , but allow for partial functional recovery
remyelination
- thinner, shorter
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
1) CD8, cytokine/granule
2) glutamate, NDMA
3) antibody, complement
4) cytokines, protection, degeneration
5) neurotrophin, CD4, protection, regeneration
6) stem, replacement
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 ___
- binding, BBB
- APC
- recruitment
- differentiation
drug examples - immune system targets
T cell binding / penetration of BBB (2)
- a4-integrin antibodies
- IFN-B
drug examples - immune system targets
T cell / APC interactions (2)
- altered peptide ligands (APLs) such as copaxon
- statins
drug examples - immune system targets
cytokines (2)
- antibodies specific for IL-23
- osteopontin
