Lecture 35 Flashcards
MS etiology
a potential role for viral infections
viral or bacterial infections may increase the risk of MS by activating autoreactive immune cells, leading to and autoimmune response in genetically susceptible individuals
Pathophysiology of MS
increase IgG synthesis in the CNS of MS patients
Increase antibody titer to certain viruses
epidemiological data suggesting that childhood infection increases MS risk
Epstein-Barr virus (EBV) may be involved in developing MS…
sequence similarities between EBV and self-peptides result in activation of autoreactive T or B-cells (MOLECULAR MIMICRY)
increased antibody titers to Epstein-Barr nuclear antigen (EBNA) in MS patients
individuals with a particular HLA phenotype have an increased risk of developing MS when they also have the anti-EBNA antibodies (GENE-ENVIRONMENT INTERACTIONS)
Relapsing-remitting MS (RRMS)
85% of cases
involves relapses of neurological dysfunction lasting weeks or months and affecting the brain, optic nerves and/or spinal cord
multifocal areas of damage are revealed by magnetic resonance imaging, generally (but not always) in the white matter
initial symptoms disappear, but less remission with each relapse
most cases of RRMS eventually enter a phase of SPMS
Secondary progressive MS
less inflammation than RRMS
involves slowly progressive neurological decline and CNS damage, with little remission
Primary progressive MS
15% of cases
resembles SPMS at the initial stage of the disease
mean of onset is later than RRMS (40 years vs. 30 years) perhaps because inflammatory episodes of RRMS surpass the symptomatic threshold
Clinically isolated syndrome (CIS)
FIGURE WILL BE ON EXAM* SLIDE 8
initial episode of neurological symptoms lasting > 24 hours
involves inflammation and demyelination in the optic nerve, cerebrum, cerebellum, brainstem or spinal cord
most cases progress to MS
Progressive phase
involves cyto degeneration (loss myelin, axons, oligodendrocytes) occurs with a similar rate in the different forms of MS: THICK BLUE LINE IN GRAPH
Clinical presentation
is determined by the combination of the underlying degeneration (uniform, progressive) AND the host’s immune reaction to it: dashed blue/orange lines
Autoimmune phase
antigens released from the CNS or cross-reactive foreign antigens are presented to B and T cells in the lymph nodes
B and T cells with high affinity receptors for these antigens are expanded and migrate to CNS sites where they re-encounter and are activated by their target ligands
activated B and T cells then carry out immune functions (release of antibodies and cytokines, respectively) at the CNS sites
Degenerative phase
CNS damage is triggered by activated B and T cells or by other insults such as infections, or stroke
Antigens released from damaged sites in the CNS further prime immune cells in the periphery, thus completing a vicious cycle
it is unclear which phase is the disease trigger
Autoimmune responses in MS
DENDRITIC CELLS that present CNS antigens activate T cell responses in the peripheral lymphoid tissue
Activated B and T cells proliferate and infiltrate the CNS (this involves a4-integrin-mediated binding and penetration of the BBB)
After re-encountering their specific antigen in the CNS, B-CELLS MATURE TO PLASMA CELLS and release IgG antibodies that target the antigen on expressing cells
T CELLS interact with their target ligands presented by oligodendrocytes, neurons, or microglia on MHC molecules
T cell activation results in cytokine release and macrophage stimulation, leading to damage in the myelin sheath
Closer look at the autoimmune response of MS
Macrophages recruited to the inflammatory lesion release toxic agents (reactive oxygen species, nitrogen species, and glutamate) that harm oligodendrocytes
macrophages also harm the myelin sheath by phagocytosis
Remyelination (myelin repair)
involves the recruitment of OPCs to the lesion and the differentiation of these cells into myelin-producing oligodendrocytes
remyelination typically fails in MS because the lack of OPCs or a failure of OPCs to differentiate
Astrogliosis
involves the invasion and propagation of astrocytes, resulting in the irreversible formation of gliotic plaques or scares
Key steps in remyelination
Demyelination results in the activation of microglia and astrocytes
Activated microglia and astrocytes release pro-migratory factors and mitogens that recruit OPCs to the lesion and stimulate their proliferation
Recruited OPCs differentiate into oligodendrocytes via a process involving axon engagement and myelin sheath formation.
OPC DIFFERENTIATION IS THE KEY STEP WHERE REMYELINATION FAILS IN MS
Demyelinated axons undergo remyelination or degeneration
SLIDE 16
Rationale for MS therapies
Immunomodulatory therapies
-interference with T-cells and B-cell activation
-inhibition of T-cell or B-cell proliferation, movement into the CNS
-Inhibition of a4-integrin-mediated binding and penetration of the BBB, enzymatic breakdown of the BBB
Rescue strategies:
-remyelination (agents that facilitate OPC recruitment or promote OPC differentiation)
Visualization of active MS brain lesions with gadolinium
patients receive an injection of gadolinium, a contrast agent for MRI
gadolinium penetrates the brain in region where the BBB is compromised
MS lesions that exhibit enhancement after intravenous administration of gadolinium are considered active lesions bc they are sites at which the BBB has broke down as a result of ongoing inflammation
Guillain-Barre syndrome
acute, inflammatory neuropathy
occurs in all parts of the world, affects children and adults of all ages and both sexes
preceded by GI or respiratory infection in about half of patients
Guillain-Barre syndrome symptoms
weakness begins in distal muscles and lower extremities ascends to proximal muscles and upper extremities
can progress to total paralysis with death from respiratory failure in days
progression peaks at 10-14 days
Guillain-Barre syndrome pathophysiology
autoimmune attack on peripheral nerves by circulating antibodies, resulting in demyelination
Guillain-Barre syndrome treatment
ventilation
plasmapheresis
intravenous immunoglobulin adimistration
