Lecture 35 - Pathophysiology of Multiple Sclerosis Flashcards
Multiple sclerosis
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
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 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
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. (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).
Different clinical forms of MS
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)
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 (SPMS)
→ characterized by less inflammation than RRMS
→ involves slowly progressive neurological decline and CNS
damage, with little remission.
Primary progressive MS (PPMS): ~15% of cases
→ 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.
Clinically isolated syndrome (CIS)
→ 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
Progressive phase involves
cytodegeneration (loss of myelin, axons, oligodendrocytes) and occurs with a similar rate in the different forms of MS
The overall clinical presentation is determined by
the combination of the underlying degeneration (uniform, progressive) and the host’s immune reaction to it (intermittent, variable)
MS consists of what phases
autoimmune and degenerative
It is unclear which of the two phases is the disease trigger
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 infection, or stroke.
→ antigens released from damaged sites in the CNS further prime immune cells in the periphery, thus completing a vicious cycle.
Autoimmune responses in MS
- 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.
A closer look at autoimmune responses in MS
- 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.
What happens to action potentials in zones of demyelination?
- 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.
Demyelinated regions can be repaired via
remyelination
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 of a 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 scars.
Remyelination involves OPC recruitment and differentiation
(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.
Demyelinated axons undergo remyelination or degeneration
- 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
Rationale for MS therapies
Immunomodulatory therapies
Rescue strategies
Immunomodulatory therapies
- 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
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 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.
Guillain-Barré syndrome
- 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
Guillain-Barré syndrome symptoms
→ 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
Guillain-Barré syndrome pathophysiology
autoimmune attack on peripheral nerves by circulating antibodies, resulting in demyelination
Guillain-Barré syndrome treatment
→ ventilation (in cases of respiratory difficulty)
→ plasmapheresis (to eliminate auto-antibodies)
→ intravenous immunoglobulin administration
Guillain-Barré syndrome prognosis
→ 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.
Which of the following molecular phenomena is (are) thought to be less pronounced in SPMS compared to RRMS?
T cell priming in peripheral lymphoid tissue
infiltration of B cells in CNS
