Multiple Sclerosis

Question 1

what is MS

Answer 1

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

Question 2

types of ms

Answer 2

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%

Question 3

symptoms of MS

Answer 3

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

Question 4

describe the pathogenesis of MS = 1st and 2nd steps

Answer 4

1. inflammatory insult = ROS, infiltrating myeloid cells, microglia
   oligodendocyte lysis (t cells) autoantibodies (b cells)
2. demyelination = death oligodendrocytes

Question 5

describe the pathogenesis of MS = 3rd + 4th cells

Answer 5

3. remeylination = resolving inflam, opc/npc infiltration, recruitment + differentiation -> relapse
4. exhaustion = in progressive form of disease, nutrient starvation, loss glial bidirectional support -> remission

Question 6

describe the stage of pathogenesis causing permanent disability

Answer 6

5. axonal transection/neuron death = metabolic toxicity, loss glial support for growth factors + nutrients

Question 7

describe the pathogenesis from loss of cns myelin

Answer 7

demyelination -> thinning myelin -> ap failure -> axonal degradation -> loss function -> oligodendrocyte loss->
potential remyelination
involvement immune system

Question 8

how is ms diagnosed

Answer 8

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

Question 9

what triggers MS

Answer 9

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

Question 10

etiology of MS - genetics

Answer 10

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

Question 11

describe etiology of MS - environmental

Answer 11

smoking, diet, sun exposure, latitude, viral infections

Question 12

how do genetic and env factors interact

Answer 12

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

Question 13

describe genes that cause ms

Answer 13

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

Question 14

describe how migration impacts risk ms

Answer 14

greater latitude = greater risk
migration before 15 yr from high->low prevalence dec risk
migration before 15 yr from low -> high prevalence in risk

Question 15

describe MS and vit D

Answer 15

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

Question 16

describe viral triggers of MS

Answer 16

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

Question 17

what are the frontline therapeutics for MS

Answer 17

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

Question 18

describe secondlinetherapies for MS: natalizumab, rituximab, ocrelixumab

Answer 18

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

Question 19

describe secondline therapies for MS: daclizumab, fingolimod, cladribine

Answer 19

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

Question 20

describe 3rd line treatments for MS = mitoxanatrone, alemtuzumab, autologous HS transplant

Answer 20

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

Question 21

what is the prevailing view of MS pathogenesis

Answer 21

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

Question 22

describe experimental autoimmune encephalomyelitis (EAE)

Answer 22

mice immunised w/neuropeptides in adjuvant
mice ascending paralysis, remission in PLP model
dependant on cd4+ T cells which invade CNS
TH17 drives pathology

Question 23

describe EAE histopath

Answer 23

similar to histopath of mS
recruitment of lueks = brown staining
H+E staining associated with loss cns myelin

Question 24

pros of using eae for studying ms

Answer 24

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

Question 25

cons of using eae for MS

Answer 25

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

Question 26

can we prevent recruitment of pathogenec subset of t cells into cnss?

Answer 26

fingolimod, natalizumab inhibit leuk recruitment
need more selective targets
chemokine superfamily - gpcr, specific to specific tcells
ccr2+, ccr6 profile enriches pathogenic th17 cells