Multiple Sclerosis
what are the characteristics associated with the Relasing/Remitting subtype?
*85% of patients begin in this stage (RRMS) this involves an abrupt onset of neurological dysfunction/flares that are followed by a complete or partial recovery
what are the ways that you can confirm a diagnosis of MS?
1. pattern of clinical episodes (acute onset and relapse) 2. MRI done, if there is no relapse, to view lesions 3. CSF analysis to find IgG banding due to IgG spikes in MS 4.somatosensory evoked potential
what are the 4 subtypes of MS?
1. relapsing/remitting 2.secondary progressive 3. primary progressive 4. progressive/relapsing
what are the microscopic characteristics of an MS lesion that are the mark of the acute/chronic inflammation that it causes?
1.Perivascular infiltrates: lymphocytes & mac 2. BBBdamage: leakage of plasma component (antibodies & complement) into brain 3. demyelination by mac/microglia/complement/antibody 4. destruction of oligodendrocytes 5. hypertrophy of reactive astrocytes: gliosis, scar formation 6.axonal damage/loss
what is the mechanism by which Tcell vaccination restores self tolerance? peptide based vaccination?
1.it induces CD8 cells to recognize autoreactive Tcells and kill them 2. giving synthetic antigen epitopes in combo with TCR-derived peptides influences tolerance and helps generate regulatory Tcells specific to the autoreactive TH1 cells
what are the charactersistics associated with the Secondary Progressive subtype?
It begins as RRMS and makes the change to a more progressive type by slowly worsening the baseline symptoms that occur between the attacks. partial recoveries continue to occur, however. *90% of RRMS patients become SP within 25 years
what is used to stain myelin?
Luxor Fase Blue
what are the genetic risk factors of MS?
MHC non-MHC genes gender
What is MS?
a demyelinating disorder of the CNS that causes patches of sclerosis in the brain and spinal cord
what does 'clinically silent' mean?
a lesion caused by MS will not lead to an immediate episode alone;
what is used to block Tcell migration across the BBB?
a neutralizing antibody agains VLA4 called Natalizumab (an alpha4beta1integrin); this helps the severity of MS symptoms
what is a remission?
a period following an acute clinical episode that is characterized by tissue repair, re-myelination, and adaptation
What is a clinical episode?
an abrupt onset of neurological dysfunction without any prediction of magnitude/frequency/location that is a reflection of multiple accumulated lesions on a single neural tract
What is a shadow plaque and what causes it?
areas of incomplete demyelination due to the body's attempt to heal the demyelination via directy re-myelination by oligodendrocytes
what is caused by the neurological dysfunction caused by MS?
attack/relaps chronic disability
where does the breakdown of self tolerance to CNS self antigens occur?
both in the central and peripheral tolerance!!!
what areas of the brain are most affected by MS?
cerebrum cerebellum optic nerve cerebellum and cerebellar pathways
why might a patient have difficulty controlling eye movement?
eye movement is controlled by cranial nerves (which my be affected, too) but likely because the cranial nerves go through the brainstem
what symptoms might occur if there are lesions in the cerebellum tract?
fine motor skill impairment resting tremor
why might genetic risk factors cause MS?
genetically predisposed individuals might have autoimmunity triggered as a result of failed intrinsic tolerance mechanisms or due to environmental triggers (ie: infection)
what causes vision-related symptoms to worsen?
heat (like from summer weather or a hot shower)
when are disease modifying treatments for MS most effective?
in early stages
what is the mechanism by which EBV-caused-inflamm leads to MS?
infection induces costimulators on APCs, those APC's present antigen to self-reactive Tcells and cause autoimmunity
what is caused by the lesions on the CNS?
inflamm demyelination neurodegeneration (axonal loss, gliosis)
what is an overt progression of disability (as it correlates to a clinical episode)?
irreversible tissue injury that exceeds the critical threshold beyond the ability to adapt and re-myelinate. this is a degenerative process that includes neurologic deterioration that is completely independent of ongoing smoldering inflammation. this degeneration is independent of the initial inflammatory process that caused the clinical episode
what are the characteristics associated with Progressive/Relapsing subtype of MS?
it begins as PP but will develop acute relapse periods and a period of recovery later on
why do many patients have depression/commit suicide?
it is an extremely difficult disease to deal with and often causes depression to be severe in patients
why is vitamin D related to the onset of MS?
it may be involved in the formation of tolerogenic semi-mature dendritic cells that promote the differentiation of regulatory Tcells that suppress those autoreactive TH1 cells
what are the environmental risk factors of MS?
latititude Sun/vitamin D Epstein Barr Virus
what is the mechanism by which peripheral tolerance causes EBV to lead to MS?
mature Tcells recognize self-antigen WITHOUT costimulators that would've been produced had there been an infection
what kind of problems occur if Gray brain matter becomes involved as MS progresses?
memory cognitive impairment
what are the characteristics associate with Primary Progressive subtype of MS?
slow worsening of the symptoms from the onset. there is a complete absence of episodes but instead a constant steady progression or the alteration b/t faster and slower periods of progression
what type of symptoms are caused by cerebellum-located lesions?
taxic gait
why do MS lesions have such distint borders?
the are due to an inflammatory response
why are plaques dynamic in the beginning?
the body attempts to repair the lesions by remyelinating in the beginning. this only affects oligodendrocytes because schwann cells are not in the CNS
what causes patients to suffer from different neurological symptoms when compared to other patients?
the location of the lesions on different specific neural tracts
what is a Scottoma?
the result of MS attacking the optical disk
what does it mean that plaques in the CNS can disseminate in 'space and time' ?
there can not only be multiple spots in multiple places, but in the beginning of MS, they can move around and increase....eventually they will become permanent, though.
why is MS considered a heterogenous disease?
there is a possible genetic association between different genes as well as a potential interaction/combination of the genetic factors and environmental factors because they are not mutually exclusive
what happens when a person in a near-equator latitude moves to a more northern one?
they increase their risk for MS (and vice versa)
what is another method for inducing encephalomyeltis in mice?
transfer of Tcells specific to myelin protein antigens *because Tcells actually carry MS, but antibodies do not. CD8 cells are clearly involved with causing the initial part of the disease
when will a clinical episode actually occur if lesions are clinically silent?
when a substantial # of lesions accumulate along a single neural tract.
what mediates the encephalomyelitis that was induced in the mice?
-TH17 and TH1 cells that were specific for myelin basic protein
what happened when scientists injected ground up spinal cord (including the Myelin proteins) into a mouse?
-encephalomyelitis similar to MS - paralysis of hind legs, then front legs
what are the injuries caused by demyelination?
-failure of saltatory conduction -nerve signal short circuits, causing wrong, bad, poorly communicated, or non-existant messages
what evidence supports the theory of genetic susceptibility to MS?
-familial recurrence rate is about 20% -recurrence rate is highest (30%) in monozygotic twins [though, no single mendelian trait for MS exists]
what are the myelin proteins that act as autoantigens?
-myelin basic protein -proteolipid protein (PLP) -Myelin Oligodendrocyte glycoprotein (MOG)
why is Epsetein Barr Virus considered a cause of MS?
-there have been increased levels of antibodies against EBV found in MS patients -the exposure to EBV in childhood was linked to higher MS risk -traces of EBV in postmortem brains of MS patients was found
1.what is sclerosis? 2. where does it occur? why?
1. "hardening"/plaques/lesions 2.white matter of the CNS; less likely in the grey matter (tho it does happen sometimes) because myelination of axons occurs in the white matter
what is the mechanism of immunopathogenesis of MS development?
1. Breach of self-tolerance: activation of autoreactive Tcells that act against the brain proteins MBP, PLP, MOG 2. compromisation of BBB causing diapedesis of those T's through the BB and into the brain 3. autoreactive T cells are reactivating when they re-encounter antigen on brain APC's 4. causing them to secrete cytokines (IFNgamma) and activate resident microglia 4. influx of immune cells into brain, such as mac, DC, and Bcells along with complement antibodies cause ACUTE INFLAMMATION 5. these immune cells cause a cumulative injury to the oligodendrocytes cause loss of neuronal function due to the demyelination
what are the mechanisms by which EBV might promote autoimmunity in MS?
1. EBV-caused inflammation 2. Molecular mimicry 3. peripheral tolerance
what are the three most common symptoms of MS?
1. Vision problems: blurred vision, loss of vision, optical pain 2. Fatigue 3. change in sensation
What is the difference between MS clinical episode/relapse and chronic progression?
1. clinical episode/relapse is an acute onset of conditions followed by a remission, which might again be followed by an acute relapse 2. Chronic progression is caused by a combination of disturbance (bad/wrong messages) due to demyelination as well as continuous chronic progressive axonal loss (neurodegeneration) with no remission periods
what are the non-MHC genetically-associated risk factors for MS?
1. cytokine pathways (IL2RA, CXCR5, IFNgR, TNFR, etc) 2. costimulators (CD40) 3. signal transduction molecules of immunological relevance (STAT3) 4. environmental factor related (vitamin D metabolic pathway)
what are the disease modifying treatments for MS?
1. inflam suppression via steroids or IFNgamma 2. suppression of T/B lymphocytes using a cytotoxic chemoagent like MITOXANTRON 3. blockage of Tcell activity by: ---blocking BBB crossing (via antil VLA4) ---blocking activation (anti IL2R, anti CD25 antibody) ---promotion of TH2 instead of TH1 (via Glatiramer acetates) 4.restoration of balance in self-tolerance by promotion of elimination of self-reactive Tcells (via Tcell vaccine)
what treatment is used for MS patients?
1. managment of acute attacks via steroids, etc 2. disease-modifying treatments 3. managment of MS effects via neurorehabilitation or chronic medical treatment of MS symptoms
what is the mechanism of Glatiramer acetates?
1. overloading MHCs to compete against myelin protein antigens for presentation to Tcells---->prevention of generation of TH1 cells that are autoreactive to myelin proteins 2. changes balance to more TH2 production; Glatiramer acetate-specific TH2's move to CNS and are reactivated by CNS antigens to make anti-inflamm cytokines and neurotropin so there is an increased recovery of damaged neurons
what is the best-known genetic association with MS?
HLA-DR B1: codes for beta-1 portion of MHC II 1. seroptype HLA-DR 15 is associated with early MS onset 2. inappropriate antigen presentation by altered MHCs likely leads to autoreactive CD4 cells
what is the mechanism by which molecular mimicry of EBV causes MS?
EBV produces a peptide antigen that look similar to self-antigens, thus, MHC's might present the similar-looking EBV peptide to active Tcells then activated Tcells attack simliar-looking self-antigens
what is used to attack Tcell activation?
Glatiramer acetates: they are random polymers made of four of the AAs that are found in MBP
