MS and Neuroinflammatory disease Flashcards
What are the 4 types of MS?
benign MS; relapsing and remitting; secondary chronic progressive; primary progressive
In relapsing remitting MS what is a mrker of severity?
time between relapses
How is latitude related to risk of MS?
MS occurs with much greater frequency in higher latitudes away from the equator
What happens to an individuals risk of MS if they are born in an area of high risk then move to an area of low risk?
acquire a risk similar to that of new home IF move happens before adolescence
What ethnic groups is MS more frequent in?
Caucasians- especially northern European ancestry
What happens to the MS risk of a Pakistani person who moves to london as a hcild?
increases by 20 fold
What is the monozygotic twin concordance rate for MS?
30%
What are the environemntal factors thought to be invovled in MS pathogenesis?
infection; climate; sunlight; diet; stress
Which HLA is most expressed of hte HLA-II genes?
HLA-DR
What HLA allele is the biggest marker of MS risk?
HLA-DR15*01
What is the evidence seen in the CSF for immune involvement in MS?
oligoclonal immunoglobulin bands
What is the pharmacological evidence for immune involvement in MS?
immunsuppression works
What is the genetic evidence for immune involvement in MS?
GWAS inficates that multiple immune genes espeically HLA are RFs for MS
What is hte cellular evidence for immune involvement in MS?
presence of T cell infiltrates at the site of plaques; disease is mimicked by EAE in which T cells are necessary and sufficient to induce disease
What are autoreactive T cell responses in MS nad EAE seen against?
myelin peptides
How is EAE induced in mice?
combine spinal cord antigens with a strong adjuvant to induce a T and B cell repsonse
What are the main myelin proteins T cells target in MS?
myelin basic protein; proteolipoprotein; myelin oligodendorycte glycoprotein
Which cells target myelin proteins in MS?
CD4; CD8 T cells and B cells
What is the MOA of natalizumab?
antibody against a4 integrin preventing leukocyte getting though BB and infiltrating the CNS
What other diseases is natalizumba effective in?
crohns and UC
What was a main problem with natalizumab?
JC virus reactivation and progressive multifocal luekoencephalopthy
Where does the evidence that T cells may be involved in neurodegenerative disorders come from?
studies on alteration of T cells subsets in the peripehry of patients during disease
What suggests that T cells may have a role in clearing amyloid b plaques?
decline in those responses with ageining adn the absence of those responses in Alzhemiers; as well as in mice
What is the evidence for T cells in Parkinsons?
CD4 cells are observed in the substantia nigra
What is the neurodegeneration seen with EBV infection?
grey matter atrophy; encephalopathy and acute quadriparesis; anterior horn cell degeneration
What is the evidence for EBV involvement in MS?
in severe MS ectopic lymphoid follicles are found with B cells specific for EBV
Is the brain an immune priviledged site?
T cells patrol the meninges and secrete cytokines with impact on the brain; T cells can cross the BBB in the contect of trauma or pathology
When may tT cells in the brain be bad for you?
in stroke there an overall detrimental role for CNS T cells
When may T cells in the brain be good for you?
CNS T cells are protective in traumtic brain injury
Which type of T cell response is typicall beneficial in CNS injury?
Th2
What may T cell derived IFNy be beneficial for?
regulating neuronal connectivity and development of learning and social behavioural traits
What is seen on gross pathology of brain tissue with MS?
multiple sharply demarcatated plaques in the CNS white matter with a prediliction to the optic nerves and white matter tracts of hte periventricular regions; brain stem and psinal cord
What happens to oligodendrocyte numbers in MS plaques?
reduced
What are relapses of MS thought to be caused by?
the traffic of activated, myelin-reactive T cells into the CNS causing acute inflammation with associated oedema—responds to streoids
What self-limits the acute attacks of MS?
Tregs
How many relapsing remitting patietns develop secondary progressive disease?
80%
What does the insensitivity to immunotherapy over the disease timecourse suggest about the pathogenesis of MS?
there are acute inflammatory events early on with secondary induction of a neurodegenerative process refractory to immunologic interventio
What suggests that primary progressive MS is a very different disease to relapsing remitting?
no acute attacks and gradual clinical decline- associated wiht a lakc of response to any form of immunotherapy
What B cell repsonse confrims the role of B cells in MS pathogenesis?
there are antimyelin autoantibodes by ElISA in sera and CSF of patients with MS; in MS CNS plaque tissue antimyelin oligodendrocyte natibodes are found
What is a4 integrin also known as?
VLA-4
What is epitope spreading found in EAE?
injection of single myelin protein epitope into mice, T cells become activated against other epitopes of hte same protein
What does epitope spreading suggest about the tissue damage in the CNS?
epitope spreading required costimulation which suggests that the tissue damage creates an adjuvant in the CNS with high express ion of costimulatory moelcules
What suggests that MS is initiated by a microbial infection?
high frequency of activated myelin-reactive T cells in the cirulcation and CSF of patients with MS
What determines which cytokines are secreted by the T cell?
strength of the signal delvered through the TCR
How does the strength of hte signal through the TCR change the cytokine expression?
cell apparently meausres affinity in part by timing hte engagement between TCR and pMHC- with longer engagement a different complex forms with xeta chain phosphorylation increasing
How can the signal strength be manipulated pharmacologically to alter the cytokine expression of a T cell?
altered peptide ligands bind with low affinity to the TCR weaken the signal and can change cytokine rpogram from Th1 to Th2
What is a problem with altered peptide ligands?
some highly degenerate TCRs can recognise APLs as self-antigens and activate reactive T cells against the patient’s tissues: espeically if given at high doses
How is bet-IFN thought to work in MS?
alterations of different pathways including induction of IL-10 and blocking of T cell traffic by blocking metalloproteinases
What is secondary progressive MS characterised by?
not immune cell infiltration but by continual irreversible neurological decline, a reduction in brain volume and axonal loss
Why may reducing relapses not halt progressive disease
may require direct targeting of neurodegenerative processes occuring independently of immune attacks in later stages
What suggests that immune cells may be helping to drive a seemingly less inflammatory form of the disease?
CD20 B cell depleting drug has been reporting to lower rates of clinical and MRI ascertained progression of primary progressive
What are the possible mechanisms by which EBV may promotes MS development?
EBV-infected autoreactive B cells in the CNS producing autoantibodies and activating autoreactive T cells- molecular mimicry between EBV and myelin antigens or EBV cells in the periphery or CNS causing bystander activation
Which cells are most prominent in acute MS lesions?
macrophages and CD8 T cells
What is the difference between demylination in early relapsing remitting compared with late?
demyelination is largely localised to the focal lesions however over time T and B cell infiltration becomes more diffuse, axonal injury is more widespread and there is whtie and grey matter atrophy
What drives the inflammatory processes in the later stages of MS?
action of CNS-resident innate microglia ells
what are hte MOA for glatiramer acetate?
modulation of APCs, the Th1-Th2 axis and Tregs to inhibit effector function
Why do some patients become refractory to treatment with IFNb and glatiramer acetate?
neutralising antibodies
What is the MOA of mitoxantrone?
inhibits DNA synthesis and repair- reduces lymphocyte numebrs
How effective is natalizumab at reducing relaspe rates?
annual relapse rate dcrease of around 70%
What happens in PML?
acute oligodendrocyte destruction
What is the MOA of alemtuzumab?
binds CD52 expressesed on all leukocytes and promotes depletion of large proportions of T and C cells then leading to reconstitution with cells with a different repertoire
what is hte problem with alemtuzumba?
30-40% of treated patients develop other AI disoreders
What is the efficacy of autologous haematopoietic stem cell transplatation?
suppresses MS for 4-5 years in over 70% of patients
When is AHSCT primarily beneficial?
in young patients with active disease in which irreversible CNS damage has not occurred
What is the MOA of daclizumab?
antibody against CD25 preventing prolfieration of T cells, increases avaiability of IL2 to NK cells which then exert regulatory effects on T cells
What is neurodegeneration?
slow and progressive dysfunction and loss of neurons and axons in the CNS
what is a common feature of neurodegeneration?
chronic immune activation, especially of microglia
What is a protective role for the immune response in the CNS?
microglia clear debris after myelin damage, if impeded-delayed regeneration occurs; removes necrotic cells; limits neurotropic viral infections
What is immune privilege in the CNS?
it has developed strategies to limit the entry of immune elements as well as the emergence of immune activation in the tissue itself
What is a major difference between peripheral macrophages and microglia?
microglia have an opposing role- they limit inflammation
What is the function of atrocytes in the immune response?
suppress Th1 and Th2 activation, the proliferation and efector functions of activated T cells and can induce apoptosis in activated T cells
What role do neurons play in dampening hte immune repsonse?
many of the products such as neuropeptides and transmitters as well as neuronal membrane proteins all regulate inflammation; promote T-cell apoptosis through Fas-FasL;
How do neurons favour the differentation of Tregs?
produce TGFb
what happens to neurons once damaged?
their ability to maintain the protective sheild is reduced, allowing further insults
What suggests a role for TLR2 and TLR4 in neurodegeneration?
mice deficient in these TLRs exhibit reduced levels of pro-inflammatory cytokines and milder clinical disease following traumatic brain injury or MCA occlusion
Which diseases have increased TLR2 and TLR4?
parksinsons; stroke; ALS; increased in amyloid beta plaques in AD
How does amyloid beta activate microglia in vitro?
TLRs
What suggests a role for TLRs in MS
mouse knock out of TLR4 are resistent to EAE; TLR9 deficient mice devleop less inflammation less severe clinical disease
Why may TLRs play a beneficial role in AD?
aid uptake of amyloid beta and other aggregated proteins, promoting clearance from the CNS
what family of PRRs are highly expressed in EAE
NLRs
In which disorders are accelearted accumulation of advanced glycation end-products seen?
MS and AD
When is the receptor for AGE (RAGE) increased?
following oxidative stress; immune/ infalm repsonses
What happens when RAGE is engaged?
relase of proinflammatory cytokines and free radicals
How is RAGE related to MS?
expressed on oligodendrocytes and is a predictor of disease severity
Why are there attempts to target adenosine receptors in neurodegenerative disorders?
assumed to be beneficial in disease by both modulating inflammation and aiding neuroprotection
What is foudn in the CSF of SLE patients with neurological involvement?
inflamamtory cytokines and matrix metalloproteinases
What is seen in the brain disease with SLE?
gliosis; axonal death; basal ganglia abnormalities
What is the brain dsiease in SLE assocaited with?
IgG and C4 deposition of necrotic cells
What is the function of C1q and C3 during development in the brain?
markers of synapses destined for elimination by microglia-expressing C3 receptors
What indicates a broad role for complement in neuronal degeneration?
increased C1q and C3 is seen in the CNS with AD; SLE; ALS; huntingtons; MS; PD; cerebral ischaemic injury
What shows that there is an anti-inflammatory environment in the CNS making adaptive responses hard?
survival of foreign tissues grafts in the CNS
why is it apparent that antibodies are produced intrathecally in MS?
oligoclonal immunoglobulins are present in CSF not serum
why is difficult to implicate T cells directed to myelin or neuronal antigens in the blood as a casative factor in CNS disorders?
they are also foudn in the healthy control stubjects
In what diseases are alterations in the peripheral levels of CD4 and CD8 t cells seen?
AD; ALS; traumatic brain injury
What usggests taht neuronal damage in MS may be mediated by CD8 cells?
they outnumber CD4 cells and have shown to be in clsoe contact with neurons
What is a role for T cells in protection and repair in the CNS?
produce neuroprotective factors e.g brain-derived neurotrophic factor
When may autoimmune T cells be curcial for repair and regeneration?
they have been shown to augment the uptake of myelin by microglia during damage
Give an example of a virus which directly kills neurons as a reuslt of viral replciation and cell lysis?
poliomyelitis
Why is the CNS the ideal environemnt for viral latency?
immun-privileged status of hte CNS as well as post-mitotic state of neurons
what is the difference between the inside-out and outside-in models of EAE?
inside-out: when neuronal damage happens before myelin; whereas outside-in: myelin damaged bfore neurons
What mechanisms may neuronal death occur?
necrosis; apotosis; autophagy
When is necrosis observed in acute brain injury?
result of the release of glutamate, nitrix oxide; ROS and clacium
What is the dual role of glutamate?
plays a major role in brain development, but in excessive quantities induces neuronal death
Which neurodegenerative diseases have glutamate excitotoxicity implicated?
AD and PD
why are proinflammatory cytokines produced by microglia detrimental>
not acute detrimental to neurons, and even protectuv, may signal to the bbb recruiting adaptive immune system into the CNS
What is MS?
most common chronic, inflammatory demyelinating and neurodegenerative disease of the CNS in young adults
How is diagnosis of MS made?
demonstration of the dissemination of demyelinating lesions to different regions of hte CNS in space and over time
What showed that Th1 did not only drive MS?
When the p40 subunit was KO there was protection from EAE- thought to prove Th1 mediation, however when p35 subunit was KO, mice got KO, suggesting it could not be Th1, when p19 was KO there was protection—IL-23 was implicated and therefore Th17
What may account for the latitudinal gradient seen with MS?
distribution of HLA-DRB1 haplotype; environmental e.g low vitamin D levels
How has the female to male ratio of MS changed over time?
increased from a 2:1 ratio in the 50s to a 3:1 now
What does the increase in female to male MS suggest?
possible role for environemntal risk factors that mainly affect women: occupation; increased smoking; obesity; birth control and childbirth
What are hte most well established environmental risk factors for MS?
EBV infection in adolesecnce; tobacco exposure; lac of sun; low vit D and obesity during adolescence
What suggests a role for EBV?
upto 100% of patients with MS are seropositive; potentially molecular mimicry leading to generation of cross-reactive T cells and antibodies - direct causality has not been established
What is the main determinant of vitamin D levels?
sun exposure- especially UV-B radiation
What genes are implicated in MS?
HLA-DRB1; IL2 and IL7R- T cell activation and proliferation; TNF; genes involvedi n vit d metabolism
What causes the BBB breakdown in MS?
direct effects of pro-inflammatory cytokines and chemokines produced by resident cells and endothelial cells; indirect cytokine-dependent and chemokine leukocyte mediated injury
What is the result of the dyregulation of the BBB?
increases the trans-endothelial migration of activated leukocytes, including macrophages, T cells and B ells- increased inflammation and demyelination–oligodendrocyte loss, reactive gliosis and neuro-axonal degeneration
What are the active demyelinating lesions seen in early relasping remitting assocaited wtih?
heavy lymphocyte infiltration- CD8 T cells and CD20 B cells; activated microglia; macropahges; large reactive astrocytes
What is seen in the inactive lesions in primary and seoncdary progressive MS?
sharply circumscribed, hypocellular with well defined demyelination; reduced axonal density and reactive astrocyte gliosis
What is seen in the white matter aside fomr the typical focal lesions in MS?
disffuse inflammation (macrophage and lymphocyte infiltration and microglia activation) and neuro-axonal damage
Which areas of the brain is extensive cortical demyelination seen particularly in in MS?
forebrain and cerebellum
What has been suggested as the mechanism of clinical recovery after a relapse and a potential target for future therapies?
remyelination
What is seen in MS relapses?
infiltration of cells of the innate and adaptive immune systems into the CNS parenchyma
What is one potential cause of aberrant effector T cell activation in MS?
poorly functioning Tregs and resistance of CNS specific effector T cells to Treg regulation
What abnormalities in Tregs have been seen in MS?
decreased expression of FOXP3
What allows the immune cells access to the CNS?
after activation in the periphery, immun ecells upregulate cell surface moleucles- chemokine receptors and adhesion molecules which enables efficient tissue infiltration
How did a role for B cells in the devleopment of MS relapses become recognised?
impressive results of selective B cell targeting therapies in MS; oligoclonal bands in the CNS
What suggests an antibody independent role of B cells in MS?
reduction in relapse rate with anti-B cell therapies did not change the CSF immunoglobulin profile in patients
What is different about B cells in MS patients?
abnormal propensity to produce pro-inflammatory cytokines and are deficient in regulatory cytokines e.g IL-10
What causes neuronal apoptosis in MS?
acute or chronic oxidative stress promoted by innate and adaptive immune cell activation, mitochondrial dysfunction, loss of myelin support, altered glutamate homeostasis ; proinflammatory environment
What suggests a role for myelin-reactive T cell in MS?
increased frequency, stability and/or pro-inflammatory repsonse profliles of these patients
What suggests that the presence of autoreactive T ells is insuggicient to induce disease?
most healthy controls ahve autoreactive cells to the same myelin antigens
What molecule is EBV thought to miic?
myeline basic protein
What is the relationship between obesity and MS?
2/3 fold increased risk of MS, and negative effect on clinical and MRI outcomes
What is ocrelizumab?
huamnised anti-CD20
What is alemtuzumab?
anti-CD52
What is the most common autoimmune adverse event assocaited with alemtuzumab?
thyroid disease
What was the first disease modifying treatment for primary and secondary progressive MS?
mitoxantrone
What new drug has been shown to work in PPMS and SPMS?
anti-CD20 DMTs- espeically in patients with active inflammation
What are hte treatments for MS currently under development?
S1P inhibitors; antigen-specific therapies; other agnets with potential neuroprotective effects e.g simvastatin; phenytoin; drugs aimed at increasing remyelination- opicinumab
