Immune-Mediated Pathogenesis in Multiple Sclerosis

Question 1

Define autoimmunity:

Answer 1

failure of an organism to recognize its own tissues as self, which can lead to an immune response against its own cells and tissues

Question 2

What is believed to be the drive of MS?

Answer 2

• MS is believed to be driven by autoreactive CD4 T cells with specificity for antigens expressed by oligodendrocytes, which comprise myelin
  
  • Myelin basic protein (MBP)
  • Myelin oligodendrocyteglycoprotein (MOG)
  • Proteolipidprotein (PLP)

Question 3

• What leads to the pathogenesis of MS?
• Describe the pathogenesis of MS:

Answer 3

• Myelin specific T cells get activated in the periphery and cross the blood-brain-barrier (BBB)
  
  • Reactivated in the CNS, which initiates events leading to the pathogenesis of MS
• Pathogenesis:
  
  • Activation and expansion of autoreactive CD4 T cells
  • Breakdown of the BBB
  • Infiltration of immune cells into the CNS
  • Demyelination/remyelination
  • Gliosis
  • Axonal/neuronal degeneration

Question 4

Describe the activation and expansion of autoreactive CD4 T cells:

Answer 4

1. Proliferate
2. Secrete cytokines/chemokines
3. Upregulate cell death molecules:
   
   • TNF-a
   • FasL
   • TRAIL
4. Provide help to CD8 T cells

Question 5

• What is the blood-brain barrier (BBB)?
• What is allowed to pass through the BBB?
• What is necessary to form the BBB?

Answer 5

• Highly selective permeability barrier that separates circulating blood from the brain extracellular fluid in the central nervous system
• Allows passage of water, some gasses and lipid soluble molecules by passive diffusion, as well as selective transport of molecules such as glucose and amino acids.
• Astrocytes are necessary to form the BBB

Question 6

• Describe how the BBB can be broken down:
• How mast cells play a role in BBB breakdown?

Answer 6

• BBB barrier breakdown occurs by a variety of mechanisms:
  
  • Disturbance in the endothelial cells on the inside of the blood vessel
  • Oxidative stress
• Mast cells in the CNS tissue upon activation recruit neutrophils that alter vascular permeability
  
  • Chemokine production
  • Adhesive interaction with endothelial cells leading to degranulation
  • Reactive oxygen species (ROS)

Question 7

• CD4 T cells, as well as other immune cells, require the integrin ____ to migrate into the CNS
• How do CD4 T cells induce the production of chemokines by CNS resident cells?

Answer 7

• CD4 T cells, as well as other immune cells, require the integrin VLA-4 to migrate into the CNS
• CD4 T cells can secrete chemokines and induce the production of chemokines by CNS resident cells (astrocytes, microglial cells):
  
  • IL-17
  • IFN-g
  • TNF-a

Question 8

What are chemokines?

Answer 8

Direct chemotaxis of cells

• Four main subfamilies
• G protein coupled receptors
• Each immune cell subtype responds to a specific set of chemokines
• Immune cells express a number of different chemokine receptors
• Many chemokinescan bind to multiple receptors and many chemokine receptors can bind multiple chemokines

Question 9

• What occurs in areas of immune cell infiltration?
• What is the impact of neuronal cell death?
• What is the role of CD4 T cells?
• What is the role of CD8 T cells?

Answer 9

• Demyelination occurs in MS in areas of immune cell infiltration
  
  • T cells and macrophages as well as neutrophils and mast cells can damage myelin
• Neuronal death is thought to contribute to progressive MS and chronic disability
• CD4 T cells recognize myelin antigens bound to MHC class II,
  
  • not expressed by oligodendrocytes or neurons
• CD8 T cells, which recognize MHC class I
  
  • could kill oligodendrocytes and neurons in a MHC-dependent manner

Question 10

List the cytokines/chemokines involved in MHC-independent apoptosis:

Answer 10

1. IFN-γ
2. TNF-α
3. Fas
4. TRAIL

Question 11

Describe the role of IFN-γ in MHC-independent cell death:

Answer 11

• Can induce apoptosis
• Produced by both CD4 and CD8 T cells
• In some viral infections of the CNS, IFN-γ was shown play a role in demyelination

Question 12

Describe the role of TNF-α in MHC independent cell death:

Answer 12

• Binds to two receptors: TNFRI and TNFRII
  
  • TNFRI – thought to be required for disease initiation
  • **TNFRII **– thought to play a protective role
• TNF-α via TNFRI can induce apoptosis

Question 13

Describe the role of Fas in MHC-independent cell death:

Answer 13

• FasL is upregulated on activated CD4 and CD8 T cells
• Engagement of Fas via its ligand induces apoptosis in the Fas expressing cell

Question 14

Describe the role of TRAIL in MHC-independent cell death:

Answer 14

• Cytokine produced by many cell types
• Binds to two death receptors: DR4 (TRAL-RI) and DR5 (TRAIL-RII)
• Induces apoptosis

Question 15

What is used in MHC-dependent cell death?

Answer 15

Granzyme/perforin

Question 16

Describe the role of granzyme/perforin in cell death:

Answer 16

• Upon activation via MHC class I, CD8 cytotoxic lymphocytes release perforin and granzymes A and B
  
  • CD4 T cells can also kill by this mechanism
• Perforin
  
  • forms a pore in the target cell membrane
  • allowing ions and water to enter leading to cell death
• Granzymes
  
  • serine proteases that in combination with perforin enter the target cell cytosol and induce apoptosis

Question 17

What is excitotoxicity?

Answer 17

Process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate

Question 18

Describe the pathogenesis of excitotoxicity:

Answer 18

• High levels of glutamate can cause excitotoxicity by _allowing high levels of Ca²⁺ to to enter the cell _
• Ca²⁺ flux activates a number of enzymes that damage cell structures such as the cytoskeleton, membrane and DNA
• Cell death mechanisms include:
  
  • apoptosis and mitochondrial dysfunction
• Sources of glutamate include neurons:
  
  • astrocytes and immune cells
• Both oligodendrocytes and neurons could be damaged by glutamate excitotoxicity

Question 19

What is oxidative stress?

Answer 19

Imbalance between the systemic manifestation of reactive oxygen species (ROS) and a biological system’s ability to readily detoxify the reactive intermediates or to repair the resulting damage

Question 20

Describe how oxidative stress can lead to damage:

Answer 20

• Production of ROS and reactive nitrogen species (RNS) is very destructive
  
  • via the production of peroxides and free radicals
    
    • superoxide, nitric oxide, peroxynitrite
• Cell death can occur via apoptosis or necrosis
• Can result in mitochondrial dysfunction and endothelial cell activation
• Macrophages and neutrophils produce ROS

Question 21

• What is antibody-mediated cell death?
• What are 2 types?

Answer 21

• B cells become activated after cognate interactions with CD4+T cell resulting in their differentiation into antibody secreting plasma cells
• 2 types:
  
  1. Antibody-dependent cell-mediated cytotoxicity (ADCC)
  2. Complement-dependent cytotoxicity

Question 22

Describe Antibody-dependent cell-mediated cytotoxicity (ADCC):

Answer 22

• An effector cell of the immune system actively lyses a target cell whose membrane surface antigens have been bound by antibodies
  
  • NK cells, macrophages, neutrophils and eosinophils

Question 23

Describe Complement-dependent cytotoxicity:

Answer 23

• The complement system consists of a number of proteins in the blood that when stimulated initiates an amplifying cascade of protein cleavages leading to the assembly of the membrane attack complex on the cell surface causing cell lysis
  
  • Can be triggered by antibodies