Lecture 35 - Pathophysiology of Multiple Sclerosis

Question 1

Multiple sclerosis

Answer 1

an immune-mediated (inflammatory) disorder involving destruction of the myelin sheath that surrounds neuronal axons
sclerosis: refers to scars
(sclerae, also known as plaques or lesions) that accumulate in the white matter of MS patients

Question 2

MS etiology

Answer 2

a potential role for viral infections
Viral or bacterial infections may increase the risk of MS by activating autoreactive immune cells, leading to an autoimmune response in genetically susceptible individuals.
Evidence in support of this mechanism:
→ increased IgG synthesis in the CNS of MS patients
→ increased antibody titers 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. (EBNA mimics myelin basic protein that’s endogenous to us, autoimmine response leads to destruction of myelin sheath)
→ individuals with a particular HLA phenotype have an increased risk of developing MS when they also have anti-EBNA antibodies (this illustrates gene-environment interactions).

Question 4

Different clinical forms of MS

Answer 4

Clinical forms of MS differ in terms of patterns of symptoms and intensities of inflammatory response:
relapsing-remitting MS (RRMS)
secondary progressive MS (SPMS)
primary progressive MS (PPMS)
clinically isolated syndrome (CIS)

Question 5

Relapsing-remitting MS (RRMS): ~85% of cases

Answer 5

→ 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 6

Secondary progressive MS (SPMS)

Answer 6

→ characterized by less inflammation than RRMS
→ involves slowly progressive neurological decline and CNS
damage, with little remission.

Question 7

Primary progressive MS (PPMS): ~15% of cases

Answer 7

→ resembles SPMS at the initial stage of the disease.
→ mean age of onset is later than RRMS (40 years vs. 30 years), perhaps because inflammatory episodes of RRMS surpass
the symptomatic threshold.

Question 8

Clinically isolated syndrome (CIS)

Answer 8

→ an initial episode of neurologic symptoms lasting ≥ 24 h
→ involves inflammation and demyelination in the optic nerve,
cerebrum, cerebellum, brainstem or spinal cord (one or more foci)
→ most cases progress to MS

Question 9

Progressive phase involves

Answer 9

cytodegeneration (loss of myelin, axons, oligodendrocytes) and occurs with a similar rate in the different forms of MS

Question 10

The overall clinical presentation is determined by

Answer 10

the combination of the underlying degeneration (uniform, progressive) and the host’s immune reaction to it (intermittent, variable)

Question 10

MS consists of what phases

Answer 10

autoimmune and degenerative
It is unclear which of the two phases is the disease trigger

Question 11

Autoimmune phase

Answer 11

→ 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 12

Degenerative phase

Answer 12

→ CNS damage is triggered by activated B and T cells or by other insults such as infection, or stroke.
→ antigens released from damaged sites in the CNS further prime immune cells in the periphery, thus completing a vicious cycle.

Question 13

Autoimmune responses in MS

Answer 13

• dendritic cells that present CNS antigens (e.g. myelin basic protein) activate T-cell responses in the peripheral lymphoid tissue.
• activated B and T cells proliferate and infiltrate the CNS (this involves α4-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 to the myelin sheath.

Question 14

A closer look at autoimmune responses in MS

Answer 14

• CD8+ T cells engage oligodendrocytes via T-cell receptor/MHC class I interactions.
• cytokines released by T cells include IFN-γ, TNF-α, perforin, and granzyme (leading to oligodendrocyte destruction).
• antibodies trigger the activation of complement (C5-9 membrane complex) on oligodendrocyte membranes, resulting in pore formation and cell damage.
• macrophages (Mφ) recruited to the inflammatory lesion release toxic agents (e.g. reactive oxygen and nitrogen species; glutamate) that harm oligodendrocytes.
• macrophages also harm the myelin sheath via phagocytosis.

Question 15

What happens to action potentials in zones of demyelination?

Answer 15

• action potentials travel more rapidly in myelinated regions of axons because of the insulating effects of myelin.
• action potentials slow down, and current density (shown by the thickness of the arrows) builds up, in the node of Ranvier, a normal zone of demyelination.
• the node of Ranvier has voltage-gated Na+ channels that are essential for replenishing action potentials.
• in demyelinated regions of axons in MS, the propagation of the action potential is slowed down.
• the amount of current generated at the node of Ranvier is insufficient to fully depolarize the demyelinated region because current is lost through the membrane.

Question 16

Demyelinated regions can be repaired via

Answer 16

remyelination

Question 17

Remyelination

Answer 17

(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 of a lack of OPCs or a failure of OPCs to differentiate.

Question 19

Astrogliosis

Answer 19

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

Question 20

Remyelination involves OPC recruitment and differentiation

Answer 20

(a) Normal white matter contains myelinating oligodendrocytes, astrocytes, microglia, and OPCs.
(b) Demyelination (loss of myelin and oligodendrocytes) results in the activation of microglia and astrocytes.
(c) Activated microglia and astrocytes release pro-migratory factors and mitogens that recruit OPCs to the lesion and stimulate their proliferation. Macrophages eliminate the myelin debris.
(d) 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 21

Demyelinated axons undergo remyelination or degeneration

Answer 21

• Most demyelinated axons undergo remyelination via a process involving OPC recruitment and differentiation into new oligodendrocytes
• Myelin sheaths that result from remyelination are thinner and shorter than those generated during developmental myelination, but they allow for partial functional recovery.
• Remyelination fails in MS because of ongoing inflammation, and demyelinated axons and neurons undergo degeneration
• Images in panel ‘b’ are cross sections from rat cerebellar white matter showing myelinated axons, demyelinated axons, and remyelinated axons with thin sheaths

Question 22

Rationale for MS therapies

Answer 22

Immunomodulatory therapies
Rescue strategies

Question 23

Immunomodulatory therapies

Answer 23

• Interference with T-cell or B-cell activation (APC interactions)
• Inhibition of T-cell or B-cell proliferation, movement into the CNS
• Inhibition of α4-integrin-mediated binding and penetration of the
  BBB, enzymatic breakdown of the BBB

Question 24

Rescue strategies

Answer 24

Remyelination (agents that facilitate OPC recruitment or promote OPC differentiation)

Question 25

Visualization of active MS brain lesions with gadolinium

Answer 25

• patients receive an injection of gadolinium, a contrast agent for MRI analysis.
• gadolinium penetrates the brain in regions where the blood- brain barrier is compromised.
• MS lesions that exhibit enhancement after intravenous administration of gadolinium are considered ‘active’ lesions because they are sites at which the blood–brain barrier has broken down as a result of ongoing inflammation.
• over time, lesions observed by gadolinium-enhanced MRI may grow or recede depending on how active the disease process is.

Question 26

Guillain-Barré syndrome

Answer 26

• acute, inflammatory neuropathy
• occurs in all parts of the world, affects children and adults of all ages and both sexes
• preceded by a GI or respiratory infection in about half of patients
  peripherla demyelinating disodred as opposed to CNS like MS

Question 27

Guillain-Barré syndrome symptoms

Answer 27

→ weakness that 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
→ generally, progression peaks at 10-14 days

Question 28

Guillain-Barré syndrome pathophysiology

Answer 28

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

Question 29

Guillain-Barré syndrome treatment

Answer 29

→ ventilation (in cases of respiratory difficulty)
→ plasmapheresis (to eliminate auto-antibodies)
→ intravenous immunoglobulin administration

Question 30

Guillain-Barré syndrome prognosis

Answer 30

→ recovery is slow (months to a year)
→ fatalities can result from respiratory failure or infection
→ most surviving patients (95%) recover completely, and the remainder have minor motor deficits.

Question 31

Which of the following molecular phenomena is (are) thought to be less pronounced in SPMS compared to RRMS?

Answer 31

T cell priming in peripheral lymphoid tissue
infiltration of B cells in CNS