Lecture 5 Multiple Sclerosis
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- 1. Lecture 5 Multiple Sclerosis 1. Symptoms 2. Epidemiology 3. What causes MS ? 4. The major histocompatibility complex (MHC) 5. Possible etiology of MS: Molecular mimicry
- 2. Saltatory Conduction (1mm) (1-2 m) Transmission of action potentials along myelinated axons. An action potential jumps from node to node. Voltage-gated Na+ channels are present only at the nodes of Ranvier
- 3. Action potentials No Action potentials (Active current) (Passive current) Inward Na currents through the voltage-gated Na+ channels cause an action potential It regenerates the passive current to flow through the next segment of myelinated axon.
- 4. Multiple Sclerosis Results of Demyelination slower Normal Axon conduction time along the affected nerve Demyelinated Axon Degenerated Axon
- 5. Multiple sclerosis Characterized by patches of demelination in the brain and spinal cord, resulting in multiple neurological symptoms Autoimmune disorder of the CNS Symptoms Weakness and clumsiness Stiffness and gait disturbances Visual defects Mental defects, including lack of judgment, emotional liability, sudden weeping or laughter
- 6. MS: epidemiology Affects mainly Caucasians (N. Europe) Most common neurodegenerative disease of young adults (1 per 400) Average age at onset 28(f)/30(m) years. Female : male ratio = 2:1 Etiology Unknown Autoimmune attack (of T cells and B cells) against oligodendrocytes
- 7. What causes multiple sclerosis? Genes - many (polygenic) Example: the MHC genes (on chromosome 6) have been consistently linked with MS Sospedra 2005
- 8. What causes multiple sclerosis? Environmental agents molecular mimicry Viruses (measles, rubella, mumps, and the herpes viruses) Bacterial infections, dietary factors, exposure to animals, minerals, chemical agents, metals, organic solvents, and various occupational hazards. Sospedra 2005
- 9. What causes multiple sclerosis? Combination of Genes and Environmental agents Sospedra 2005
- 10. The major 6 histocompatibility complex (MHC) Class I, II, & III A cluster of genes encoding cell- surface antigen- presenting proteins
- 11. The major histocompatibility complex (MHC) Plays pivotal role in the immune system Contains 140 genes coding for class I, II, and III proteins Found on antigen-presenting cells (APCs) They display an epitope of a foreign antigen to T cells, via the T cell receptors (TCRs) T cells should ignore self peptides while reacting appropriately to the foreign peptides A subset of genes in MHC region implicated in MS
- 12. MHC Class II Found on specialized antigen-presenting cells (APCs) - macrophages Interact with CD4+ ("helper") T cells (Th). Antigen is digested in lysosomes An epitope is displayed by MHC-II Th cells divide rapidly and secrete small proteins called cytokines that "help" the immune response Secrete antibodies cytokines B cells Th2 Th1 Macrophages cytokines CD4+ ("helper") T cell (TH) Secrete cytotoxins The inflammation seen in MS appears to be largely due to an overactive Th1 response.
- 13. Possible etiology of MS: Molecular mimicry A foreign antigen initiates an immune response How is the CNS destroyed ? A self antigen (auto-antigen) mimics the foreign antigen The self protein is destroyed. Autoreactive Th1 cells activated outside the CNS by microbial antigens (cross-reactive with the self antigen myelin proteins).
- 14. Stages of MS 1. Inflammation 2. Partial recovery 3. Demyelination 4. Axonal degeneration 5. Permanent clinical disability
- 15. Blood Brain Barrier It is a physical barrier between the blood vessels and the central nervous system Controls the passage of substances from the blood into the CNS In MS the white blood cells can cross BBB Endothelium Basement membrane Astrocyte end feet
- 16. Inflammatory Phase Demyelination results from a defect of immune function 1. Initial infection (i.e. virus, bacteria, foreign antigen) 2. The antigen gets into the blood stream and is processed by macrophages (APCs) 3. Macrophages display the antigen with MHC molecules 4. The MHC displayed antigen can be recognized by special receptors on the surface of T cells (TCR)
- 17. Inflammatory Phase 5. Th1 cells are activated in the blood Bind to adhesion molecules on the BBB CNS surface of the BBB endothelium adhesion molecules Secrete chemicals called proteases that facilitate migration through the endothelial cells Proteases breakdown the BBB Th1 cells cross the BBB and enter the CNS Proteolysis (degradation) of myelin components.
- 18. Inflammatory Phase BBB 6. Th1 cells arrive in the CNS; may encounter local APCs (i.e. microglia) APC 7. The APCs display an epitope of a self-antigen (i.e. breakdown product of myelin) on MHC proteins - "mistaken identity 8. The Th1 cells are re- activated in the CNS
- 19. Inflammatory Phase 9. In the CNS: the activated Th1 cells secrete cytokines that stimulate microglial cells and astrocytes recruit additional inflammatory cells from peripheral blood (microphages, B cells) Production of more cytokines and antibodies Complement system production Demyelination Oligodendrocyte apoptosis Primary oligodendrocyte degeneration
- 20. Inflammatory Phase Homology between Foreign proteins (i.e. viral or bacterial epitope) and Self protein (myelin epitope) myelin basic protein - MBP, myelin oligodendrocyte glycoprotein - MOG, or myelin associated glycoprotein (MAG). Sospedra 2005
- 21. Molecular mimicry Certain amino acid positions in a peptide are more critical than others for the interactions (complete sequence matching is a rare event) Sospedra 2005
- 22. Partial recovery Voltage-gated Na+ Partial recovery due to an increase in channels the number of Na a high density channels along the clustered at the nodes demyelinated parts of the axon, of Ranvier partially restoring axon conduction