Multiple Sclerosis Flashcards
epidemiology
multifactorical cause → genetic background + environmental triggers
age of onset: 15-45 - about 6% is early onset → study early stages
gender bias: 5:1 female to male ratio
common in Northern Europeans - immigration
not Mendelian inheritance → genome wide studies showed implication in HLA-DRB1-15:01 gene; MHC; IL2RA/IL7RA
risk factors
insufficient vitamin D
infections (EBV)
smoking
salt
Expanded Disability Status Scale
neurological exam to track progression
motor changes (not cognitive/sensory)
determine extent of disability
>6 requires assistance
clinical picture
- relapse-remitting: inflammation is focal with flares - spikes last weeks to months then return to baseline; possible residual symptoms between spikes → recovery decreases as patient ages (decline in repair systems)
- secondary progression: independent of focal inflammation; less fluctuations; increase in symptoms
variety of symptoms correspond to location of lesions in brain + spinal cord
Pathology
demyelination: immune system attacks myelin of cells and causes inflammation and damage → sclerotic lesions are ventricular (around ventricles) - primarily in white matter (shown with staining and MRI)
can lead to axonal degeneration (atrophy + death of neurons) → attempt at remyelination is often incomplete or complete axon transection → transection of fibres of corticospinal tract
decreased axonal density in plaques as a result of injury and inflammation → ventricles, optic nerves + tracts, corpus callosum
Experimental Autoimmune Encephalomyelitis
EAE can be produced in animals by myelin specific T cells
induced in animal model to understand pathogenesis
external immunization: inject myelin basic protein into mice → trigger immune response to produce disease-primed lymphocytes (B cells and T cells) through antigen presentation
injection of MBP-specific TH1 cells (lymphocytes) into tail vein of healthy mouse induces disease - the cells are primed to respond to disease = attack myelin in CNS and induce inflammatory response with similar pathology to MS
models of molecular mimicry
antigen presentation of virus (similar to endogenous MBP) to naive T cells causes expansion of virus-specific T cells and the expansion of cross reactive MBP-specific T cells → target endogenous molecule similar to antigen
both T cells will enter CNS, recognize MBP, and initiate inflammatory damage
immune response
recognition and presentation of foreign antigen → activation and proliferation of naive T helper 0 cells into T helper 1 and 2 cells
cell-mediated T-cell responses derived from T helper 1 cells; antibody-mediated responses derived from T helper 2 cells → activation of B cells
T cell differentiation
IL-2 and IFNy → TH1 cells
IL-23 → TH17 cells
IL-4 → TH2 cells
TGFb and IL-2 → Treg
differentiation occurs in the periphery → cross BBB into CNS - reactivated
T lymphocytes
reactivation in CNS
TH1 and TH17 secrete cytokines that activate microglia/astrocytes + macrophages → APC function + ROS/RNS production
inhibition of T eff cells (+ inflammatory cells) by anti-inflammatory cells → Treg and Breg - decrease pro-inflammatory
B lymphocytes
different roles: antigen presentation, cytokine activation, activating T cells, antibody production
Breg → limit pro-inflammatory
pathogenesis
microglia activation
inflammation
ionic imbalance + increased Na+ levels
demyelination
neuro-axonal degeneration
glutamate excitotoxicity
mitochondrial damage → energy failure
astrocyte activation
imaging to measure damage
MRI - inflammation
MRS - spectroscopy → injury demyelination
PET scan - microglial inflammation
acute MS lesions
axonal transection
interrupts flow of cell → causes swelling
immune-independent neurodegeneration
- mtDNA mutations + mitochondrial injury → ROS/RNS
(ROS/RNS can also cause mitochondrial injury) - demyelination → Fe3+ → oxidative stress
- glutamate excitotoxicity → Ca2+ influx; ionic imbalance
