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MM Test 3 > B6.044 Prework 2: MS Etiology and Pathogenesis > Flashcards

B6.044 Prework 2: MS Etiology and Pathogenesis Flashcards

1
Q

epidemiology of MS

A

2-3x more common in women
peak onset 20-40 years
350,000-400,000 affected in US
8-10,000 new cases yearly

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2
Q

risk factors for MS

A

genetics
environmental
acquired defects

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3
Q

gene with greatest association with MS

A

HLA-DR : 5x risk
HLA-A0301 : 2x risk
HLA-A0201: 0.6 x risk (protective)

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4
Q

disease causing effect of HLA-A3

A

no negative selection for T cells that react with PLP peptide in thymic medulla

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5
Q

classes of genes associated with MS

A

3 functional groups
immunological
neuronal
unknown functions

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6
Q

disease protective effect of HLA-A2

A

negative selection and induced apoptosis/ anergy of T cells that react with PLP peptide in thymic medulla

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7
Q

thymic function in immune tolerance

A

eliminate self reactive t cells
-thymocytes have high avidity interactions with APCs presenting self antigen resulting in their elimination (clonal deletion)

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8
Q

what type of antigens are CNS myelin antigens

A

tissue specific antigens (TSAs)

-not present in PNS myelin

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9
Q

what happens to myelin specific T cells that escape central tolerance

A

low avidity T cells

not sufficient strength during maturation to induce deletion

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10
Q

environmental factors that increase risk of MS

A

living at northern latitudes
low levels of vit D
toxins
diet

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11
Q

what happens if you move from northern to southern latitudes within the first 20 years of life

A

decreased risk of MS

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12
Q

hygiene hypothesis for MS

A

no exposure early in life due to clean environment results in an altered immune response to infection as a young adult

  • MS patients have a later time of infection with EBV, rubella, mumps and measles than matched controls
  • late infection with EBV provides a 3 fold increased risk of developing MS
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13
Q

molecular mimicry hypothesis for MS

A

immune response to a virus results in cross reactivity with a myelin antigen resulting in immune attack against myelin
-EBV shares epitopes with myelin basic protein

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14
Q

vitamin D effect on APCs

A

decreased MHC 2 expression, costimulatory molecules, DC maturation, and IL-12, IL-1 and TNFa
increased tolerogenic DCs, chemotactic and phagocytic capacity, and PGE2

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15
Q

vitamin D effect on T cells

A

decreased FasL expression, T cell proliferation, IL-12, IFNy, IL-2, and antigen specific T cell activation
increased IL-4, 5, 10 and Treg cells

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16
Q

vitamin D effect on B cells

A

decreased Ig production, proliferation, and differentiation

increased VDR expression

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17
Q

other immunologic effects of vitamin D

A

decreased IFNy secretion by NK cells, cathelicidin production by epithelial cells, and iNOS synthesis

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18
Q

general characteristics of MS pathology

A

immune cell activation and infiltration into the CNS
demyelination, axonal transection, neuronal degeneration
presence of multiple lesions, scars, or plaques in the CNS

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19
Q

effect of myelin/axon damage on AP propagation

A

slows or stops

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20
Q

myelin production

A

oligodendrocytes in CNS

Schwann cells in PNS

21
Q

what is myelin made of

A

multilamellar compacted lipid bilayer that wraps around the exon covering the intranode

22
Q

function of myelin

A

enables saltatory conduction
greatly increased conduction velocity of action potentials down the exons
reduces energy expenditure since less ATP is required to pump ions
conserves space

23
Q

how does myelin reduce energy expenditure

A

AP develops at nodes of Ranvier rather than having APs move sequentially along the axon (like in unmyelinated axons)

24
Q

how does myelin conserve space

A

for an unmyelinated axon to have faster conduction velocity, it must increase the diameter of its axon

25
Q

structure of myelin and its relationship to T and B cells

A

lipid rich structure
contains 2 major proteins that function as probable antigens in MS (only in CNS myelin, not in PNS)
1. myelin basic protein (T cell antigen)
2. myelin oligodendrocyte glycoprotein (B cell antigen)

26
Q

what are nodes of ranvier

A

spaces between myelin segments

generate APs on myelinated axons

27
Q

appearance of axonal transection due to immune mediated damage

A

axonal ovoids
bulb like sites
transported organelles accumulate at transection site due to survival of neuronal body

28
Q

disruption of saltatory conduction due to myelin damage

A

damaged myelin leads to loss of current
longer time to reach threshold for an AP
slows conduction velocity OR threshold isn’t reached at all and action potential fails to propagate

29
Q

how is AP propagation enables after demyelination

A

redistribution of Na+ channels over demyelinated section results in a continuous nerve impulse over that section
slower and less energy efficient

30
Q

where does inflammation occur in MS

A

perivascular and meningeal T and B cell inflammation

31
Q

what are Dawson fingers

A 
enhancing lesions (T2 hyperintensities) perpendicular to ventricles
present in the majority of MS patients
32
Q

etiology of Dawson lesions

A

due to inflammation around penetrating venules (perivenular inflammation)

33
Q

activation of T cells in MS

A
  1. CNS antigens either soluble or engulfed in APCs are drained to lymph nodes
  2. CNS antigen specific T cells are activated
  3. activated T cells exit lymph nodes to circulation
  4. T cells adhere and migrate across the BBB
  5. T cells are locally reactivated
  6. immune cells secrete inflammatory mediators
  7. immune mediators cause axonal damage and demyelination
34
Q

describe the process of epitope spreading

A

once in the CNS, autoreactive T cells initiate myelin destruction
in this process, myelin antigens are released, phagocytosed, processed, and presented within the CNS by peripherally derived DCs to naïve T cells (both of which can enter through a now compromised BBB)
in destruction of myelin, both PLP and MBP are released
NOW relapses can occur via T cell activation against PLP or MBP

35
Q

4 primary pathogenic mechanisms in MS`

A
  1. T cell infiltrates and macrophages induce tissue damage
  2. antibody and complement mediated damage against myelin and oligodendrocytes
  3. hypoxia damage due to impaired blood flow or impaired mitochondria
  4. genetic susceptibility to immune damage against oligodendrocytes/myelin
36
Q

what is glutamate toxicity

A

T cells and APCs like macrophages produce glutamate

glutamate is toxic to oligodendroglial cells and underlying axons

37
Q

what can be used to combat glutamate toxicity

A

stains inhibit secretion of metalloproteases and may block T cells from entering CNS

38
Q

what do antibodies against a4 integrin do

A

impair adhesion of T cells to BBB and prevent penetration

39
Q

what is the significant of white matter plaques in MS

A

demonstrate loss of myelin

40
Q

describe the character of gray matter lesions in MS

A

meningeal infiltrates composed of lymphocytes intermingled with stromal cells and macrophages
core of these lymphoid organs consists of B cells whose maturation is supported by FDCs, while the cortex consist of T cells and macrophages

41
Q

result of meningeal infiltrates

A

extensive microglia activation in underlying cortex and gray matter damage

42
Q

significance of meningeal and perivascular inflammation in PPMS

A

more severe lesions result in earlier death

43
Q

effect MS on cerebral blood flow, cerebral blood volume, and mean transit time

A

all decreased

44
Q

mitochondrial changes in MS

A

decreased activity
electron transport chain gene expression is decreased in parietal and frontal cortex
some studies show increased mitochondrial activity following relapse which may be a mechanism for repair or a source of ROS for further injury

45
Q

effect of iron in MS

A 
accumulates in CNS
leads to:
-decreased DNA repair
-increased oxidative stress
-increased MMPs
-increased proinflammatory cytokines
-increased extracellular glutamate
which further cause:
demyelination, axonal injury, neuronal stress, neurodegeneration, BBB leakage, and inflammation
46
Q

discuss the process of remyelination

A

facilitated by oligodendrocytes on axon
can induce some functional recovery
remyelinated axon sheaths typically thinner and shorter than original tho
sometimes remyelination fails altogether

47
Q

what is natalizumab

A

antibody against a4 integrin used in MS treatment

prevents T cell diapedesis into parenchyma

48
Q

risk associated with natalizumab

A

increased risk for progressive multifocal leukoencephalopathy due to the JC virus
common infection, but immunosuppression can lead to reactivation of dormant JC virus
fatal in 50% of cases

49
Q

when should you use disease modifying therapies in MS?

A

effective for relapsing remitting MS but not progressive MS

MM Test 3 (31 decks)

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