Multiple Sclerosis Flashcards
what is MS
identified in 1868 by jean-martin charcot
patches of lesions in brain + sc
2-150 people/100,000
20-40yrs onset, 2x common in women
severity/type symptoms ranges widely
degen cns
autoimmune
types of ms
relapsing-remitting MS = 70-85%
primary progressive MS = 10-15%
secondary progressive MS = developed in 50% of RR-MS after 20 yrs
progressive-relapsing = rare, <5%
symptoms of MS
motor = muscular spasms, weakness, poor coordination, balance
fatigue = heat sensitivity
neuro symptoms = vertigo, pins/needles, neuralgia, visual disturbances
incontinence, constipation
neuropsychological = mem loss, depression, cog difficulties
describe the pathogenesis of MS = 1st and 2nd steps
- inflammatory insult = ROS, infiltrating myeloid cells, microglia
oligodendocyte lysis (t cells) autoantibodies (b cells) - demyelination = death oligodendrocytes
describe the pathogenesis of MS = 3rd + 4th cells
- remeylination = resolving inflam, opc/npc infiltration, recruitment + differentiation -> relapse
- exhaustion = in progressive form of disease, nutrient starvation, loss glial bidirectional support -> remission
describe the stage of pathogenesis causing permanent disability
- axonal transection/neuron death = metabolic toxicity, loss glial support for growth factors + nutrients
describe the pathogenesis from loss of cns myelin
demyelination -> thinning myelin -> ap failure -> axonal degradation -> loss function -> oligodendrocyte loss->
potential remyelination
involvement immune system
how is ms diagnosed
multiple neuro episodes characterisitc of ms
length time b/1st -2nd episode = indicator of disease progression
mri visualise gadolinium enhancing lesions, BBB breakdown, demyelination plaques
CSF tested for signs of inflam
autopsy histopath confirm
what triggers MS
breakdown in immune tolerance
antigens from cns derived from myelin sheath exposed to t/b cells
cd4+ t cells (TH1, Th17) create cytokines and reactivated by microglial cells when get into cns = cytokines like ifng, il17 => promote inflammation + breakdown BBB =.cells of innate immune system recruited to cns
ALSO cd8+ activation can become cytotoxic
b cells make antibodies
antibody secreting cells secreting antibody
proinflammatory mediators released by cells of innate immune system
RESULTING IN demyelination of axons in cns
etiology of MS - genetics
familal predisposition - 15-20x risk if 1st degree relative
presence of other autoimmune disease inc risk
females more susceptible
concordnace is higher in monozygotic twins
low incidence in africans, japanese, chinese
describe etiology of MS - environmental
smoking, diet, sun exposure, latitude, viral infections
how do genetic and env factors interact
susceptibility genes = inc likelihood of failure self tolerance = self reactive lymphocytes not deleted = >peripheral circ => env trigger activate => antigen pressenting cells act t cells => inflam + autoimmune disease
describe genes that cause ms
c variant inc risk
over 200 genes associated
HLA-DRB1 = highly polymorphic, odds ratio 3.5
+ other immune system genes, vit D metabolism/function + other genes
describe how migration impacts risk ms
greater latitude = greater risk
migration before 15 yr from high->low prevalence dec risk
migration before 15 yr from low -> high prevalence in risk
describe MS and vit D
multiple genes in vit D pathway are MS risk genes
prevalence of MS = higher/faster progression w/low vit D
relapse common winter
vit D might not help
vit D effects immune system = influences exp MHC-II, cytokine exp + inhibit t cell act + inc prod immunosuppressive factors in CNS
describe viral triggers of MS
epstein barr (EBV), human herpes virus-6 (HHV-6)
95% normal people infected w/EBV
but 99.9% MS sufferers EBV+ … causes infectious mononucleosis
serum levels of neurofilament light chain = biomarker of neuroaxonal degeneration, inc only after EBV seroconversion
suggests EBV is leading cause of MS in genetically susceptible individuals
what are the frontline therapeutics for MS
corticosteroids treat acute attacks
plamaphoresis for severe acute attacks
b-interferon = cytokine therapy, alter t cell exp, MHC-II exp, red relapse but side effects = flu like symptoms, + injection site reaction + liver damage
amino acid copolymer, unknown mech action, deviates pro inflam thi responses to th2
dimethyl fumarate = small molecule, anti infla, act nrf2, red oxidative stress = suppress inflam
describe secondlinetherapies for MS: natalizumab, rituximab, ocrelixumab
natalizumab = monoclonal anitbody against a4 integrin. reduce relapse,
side effects = allergy, inc infection, progressive multifocal leukoencephalopathy
rituximab + ocrelizumab = monoclonal antibodies against cd20 exp on b cells = deplete b cells, effective for relapsing + progressive MS.
side effects = immunosuppresion, suscepitbility to infect, infusion/allergic reaction
describe secondline therapies for MS: daclizumab, fingolimod, cladribine
daclizumab = monoclonal antibody agisnst cd56, activated NK cells, kill autoreactive T cells in relapsing MS
fingolimod = antagonist of sphigosine-1 phosphate ree. sequester lymphocytes in lymphoid organs, effective for relapsing-remitting
cladribine = synthetic deoxyadenosine analogue, cytotoxic to lymphs, progressive MS, maybe not safe after 2 yrs
describe 3rd line treatments for MS = mitoxanatrone, alemtuzumab, autologous HS transplant
mitoxanatrone = chemo, inhibits dna synth + inhinits lump proliferation + cytotoxic. slow 2ndrt prog MS, reduces relapse rate in RRMS.
side effects - immunosuppression, hair loss, nausea, cardiac effects
alemtuzumab = monoclonal antibody, targets CD52, lysis mononuclear cells that express cd52. potential immunosuppressive side effects
autologous HSC transplant = patients hematopoietic stem cells harvested from bone marro. patient undergoes radiotherapy to cill circulating immune cells, reinfuced with HSCs to reconstitute immune system
what is the prevailing view of MS pathogenesis
triggers causes inflam in brain => BBB permeable to leuks + blood proteins
=> T cells for CNS antigens acct in peripheral lymphoid tissues, reecounter antigen present on microglia/dendritic cells in brain
=> inflam brain bc mast cell, complement, antibodies + cytokines
=> demyelination neurons
thought th1 were key
then discovered th17
describe experimental autoimmune encephalomyelitis (EAE)
mice immunised w/neuropeptides in adjuvant
mice ascending paralysis, remission in PLP model
dependant on cd4+ T cells which invade CNS
TH17 drives pathology
describe EAE histopath
similar to histopath of mS
recruitment of lueks = brown staining
H+E staining associated with loss cns myelin
pros of using eae for studying ms
good model of cd4T tcell mediated CNS autoimmune responses
simple, reproducible
immune response is similar CNS cpoments that t cells from ms patients respond to
clin and path = similar
therapeutics (some) work for both
cons of using eae for MS
not ms
not all therapeutics work in both
requires immunisation
animal ethics
doesnt moedl progressive/nin-autoimm aspects
different bc not majorly involving B cells, cd8+ cells, respond against astrocytes
can we prevent recruitment of pathogenec subset of t cells into cnss?
fingolimod, natalizumab inhibit leuk recruitment
need more selective targets
chemokine superfamily - gpcr, specific to specific tcells
ccr2+, ccr6 profile enriches pathogenic th17 cells
