B6.044 Prework 2: MS Etiology and Pathogenesis Flashcards
epidemiology of MS
2-3x more common in women
peak onset 20-40 years
350,000-400,000 affected in US
8-10,000 new cases yearly
risk factors for MS
genetics
environmental
acquired defects
gene with greatest association with MS
HLA-DR : 5x risk
HLA-A0301 : 2x risk
HLA-A0201: 0.6 x risk (protective)
disease causing effect of HLA-A3
no negative selection for T cells that react with PLP peptide in thymic medulla
classes of genes associated with MS
3 functional groups
immunological
neuronal
unknown functions
disease protective effect of HLA-A2
negative selection and induced apoptosis/ anergy of T cells that react with PLP peptide in thymic medulla
thymic function in immune tolerance
eliminate self reactive t cells
-thymocytes have high avidity interactions with APCs presenting self antigen resulting in their elimination (clonal deletion)
what type of antigens are CNS myelin antigens
tissue specific antigens (TSAs)
-not present in PNS myelin
what happens to myelin specific T cells that escape central tolerance
low avidity T cells
not sufficient strength during maturation to induce deletion
environmental factors that increase risk of MS
living at northern latitudes
low levels of vit D
toxins
diet
what happens if you move from northern to southern latitudes within the first 20 years of life
decreased risk of MS
hygiene hypothesis for MS
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
molecular mimicry hypothesis for MS
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
vitamin D effect on APCs
decreased MHC 2 expression, costimulatory molecules, DC maturation, and IL-12, IL-1 and TNFa
increased tolerogenic DCs, chemotactic and phagocytic capacity, and PGE2
vitamin D effect on T cells
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
vitamin D effect on B cells
decreased Ig production, proliferation, and differentiation
increased VDR expression
other immunologic effects of vitamin D
decreased IFNy secretion by NK cells, cathelicidin production by epithelial cells, and iNOS synthesis
general characteristics of MS pathology
immune cell activation and infiltration into the CNS
demyelination, axonal transection, neuronal degeneration
presence of multiple lesions, scars, or plaques in the CNS
effect of myelin/axon damage on AP propagation
slows or stops
myelin production
oligodendrocytes in CNS
Schwann cells in PNS
what is myelin made of
multilamellar compacted lipid bilayer that wraps around the exon covering the intranode
function of myelin
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
how does myelin reduce energy expenditure
AP develops at nodes of Ranvier rather than having APs move sequentially along the axon (like in unmyelinated axons)
how does myelin conserve space
for an unmyelinated axon to have faster conduction velocity, it must increase the diameter of its axon
structure of myelin and its relationship to T and B cells
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)
what are nodes of ranvier
spaces between myelin segments
generate APs on myelinated axons
appearance of axonal transection due to immune mediated damage
axonal ovoids
bulb like sites
transported organelles accumulate at transection site due to survival of neuronal body
disruption of saltatory conduction due to myelin damage
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
how is AP propagation enables after demyelination
redistribution of Na+ channels over demyelinated section results in a continuous nerve impulse over that section
slower and less energy efficient
where does inflammation occur in MS
perivascular and meningeal T and B cell inflammation
what are Dawson fingers
enhancing lesions (T2 hyperintensities) perpendicular to ventricles present in the majority of MS patients
etiology of Dawson lesions
due to inflammation around penetrating venules (perivenular inflammation)
activation of T cells in MS
- CNS antigens either soluble or engulfed in APCs are drained to lymph nodes
- CNS antigen specific T cells are activated
- activated T cells exit lymph nodes to circulation
- T cells adhere and migrate across the BBB
- T cells are locally reactivated
- immune cells secrete inflammatory mediators
- immune mediators cause axonal damage and demyelination
describe the process of epitope spreading
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
4 primary pathogenic mechanisms in MS`
- T cell infiltrates and macrophages induce tissue damage
- antibody and complement mediated damage against myelin and oligodendrocytes
- hypoxia damage due to impaired blood flow or impaired mitochondria
- genetic susceptibility to immune damage against oligodendrocytes/myelin
what is glutamate toxicity
T cells and APCs like macrophages produce glutamate
glutamate is toxic to oligodendroglial cells and underlying axons
what can be used to combat glutamate toxicity
stains inhibit secretion of metalloproteases and may block T cells from entering CNS
what do antibodies against a4 integrin do
impair adhesion of T cells to BBB and prevent penetration
what is the significant of white matter plaques in MS
demonstrate loss of myelin
describe the character of gray matter lesions in MS
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
result of meningeal infiltrates
extensive microglia activation in underlying cortex and gray matter damage
significance of meningeal and perivascular inflammation in PPMS
more severe lesions result in earlier death
effect MS on cerebral blood flow, cerebral blood volume, and mean transit time
all decreased
mitochondrial changes in MS
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
effect of iron in MS
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
discuss the process of remyelination
facilitated by oligodendrocytes on axon
can induce some functional recovery
remyelinated axon sheaths typically thinner and shorter than original tho
sometimes remyelination fails altogether
what is natalizumab
antibody against a4 integrin used in MS treatment
prevents T cell diapedesis into parenchyma
risk associated with natalizumab
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
when should you use disease modifying therapies in MS?
effective for relapsing remitting MS but not progressive MS
