Lecture 35

Question 1

MS etiology

Answer 1

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

Question 2

Pathophysiology of MS

Answer 2

increase IgG synthesis in the CNS of MS patients

Increase antibody titer to certain viruses

epidemiological data suggesting that childhood infection increases MS risk

Question 3

Epstein-Barr virus (EBV) may be involved in developing MS…

Answer 3

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)

Question 4

Relapsing-remitting MS (RRMS)

Answer 4

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

Question 5

Secondary progressive MS

Answer 5

less inflammation than RRMS

involves slowly progressive neurological decline and CNS damage, with little remission

Question 6

Primary progressive MS

Answer 6

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

Question 7

Clinically isolated syndrome (CIS)

Answer 7

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

Question 8

Progressive phase

Answer 8

involves cyto degeneration (loss myelin, axons, oligodendrocytes) occurs with a similar rate in the different forms of MS: THICK BLUE LINE IN GRAPH

Question 9

Clinical presentation

Answer 9

is determined by the combination of the underlying degeneration (uniform, progressive) AND the host’s immune reaction to it: dashed blue/orange lines

Question 10

Autoimmune phase

Answer 10

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

Question 11

Degenerative phase

Answer 11

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

Question 12

Autoimmune responses in MS

Answer 12

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

Question 13

Closer look at the autoimmune response of MS

Answer 13

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

Question 14

Remyelination (myelin repair)

Answer 14

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

Question 15

Astrogliosis

Answer 15

involves the invasion and propagation of astrocytes, resulting in the irreversible formation of gliotic plaques or scares

Question 16

Key steps in remyelination

Answer 16

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

Question 17

Demyelinated axons undergo remyelination or degeneration

Answer 17

SLIDE 16

Question 18

Rationale for MS therapies

Answer 18

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)

Question 19

Visualization of active MS brain lesions with gadolinium

Answer 19

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

Question 20

Guillain-Barre syndrome

Answer 20

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

Question 21

Guillain-Barre syndrome symptoms

Answer 21

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

Question 22

Guillain-Barre syndrome pathophysiology

Answer 22

autoimmune attack on peripheral nerves by circulating antibodies, resulting in demyelination

Question 23

Guillain-Barre syndrome treatment

Answer 23

ventilation

plasmapheresis

intravenous immunoglobulin adimistration