Pathology and Immunology of MS

1. Pathology and Immunology of MS

2. Central nervous system (CNS) • CNS- consists of brain and spinal cord • CNS connects to peripheral nervous system by 12 pairs of cranial nerves and 31 pairs of spinal nerves • It is a complex network of nerve cells; made up of cell body, dendrites, axon and myelin sheath • Role of CNS - to enable us to perceive our environment through senses of sight, smell, taste, hearing and touch. It also controls our body functions and co-ordinates movement

4. Frontal lobe Occipital lobe Cerebral cortex Personality Vision Co-ordination Vital functions Brainstem Cerebellum Spinal cord

5. The brain and spinal cord are referred to as the Central Nervous System, whilst the nerves connecting the spinal cord to the body are referred to as the Peripheral Nervous System.

6. Structure of CNS • Cerebral cortex • personality, memory and intellect • voluntary motor functions and sensory functions • Cerebellum • co-ordination, muscle tone, posture • Brainstem • vital functions (e.g. Respiratory and cardiac) • Spinal cord • millions of nerve fibres transmitting electrical information to and from the body, back to and from the brain.

7. The neurone • Neurone = single nerve cell • consists of a cell body, axon (long nerve fibre) and dendrites (filaments connecting to the next nerve) • transmits nerve impulses in the form of tiny electrical and chemical currents (action potentials) • Large bundles of neurons form ‘nerves’

8. Structure of a Neurone Dendrites Cell body Axon Node Myelin sheath Synapses Oligodendrocyte (myelin-producing cell)

9. Myelin • Fatty substance which insulates and protects the axon • Formed by oligodendrocyte cells. Each oligodendrocyte myelinates several axons • Enables transmission of nerve impulses faster and more efficiently along the nodes of Ranvier and along the nerve

10. MS Plaques • On T2 weighted MRI, plaques show as high signal • They are typically white ovoid/round lesions • Form close to blood vessels within the brain • Most commonly seen within the periventricular area of the brain, the corpus callosum, brain stem, cerebellum, optic nerves and spinal cord (Rog 2009) • The pattern of the plaque tends to follow the blood vessels-this is known as Dawson’s fingers and is characteristic of MS

11. The immune system • Protects the body from invading microorganisms and abnormal/foreign cells Composed of: • Mechanical barriers e.g. skin, mucous, blood-brain-barrier • Lymphoid tissue e.g. lymph nodes, spleen • White blood cells • Co-factors e.g. cytokines, complement

12. The immune system The immune response: • Innate: Non specific or broadly specific. Recognises and processes antigens • Adaptive: activated by contact with antigen, sets in motion a series of cellular and humoral mechanisms against the antigen

13. Innate, non-or broadly -specific

14. Antigens • Immune system has to recognise self from non self • Antigens are molecules capable of interacting with immune receptors • May or may not lead to immune response • Immune response more likely if antigen is: • Foreign • Large and/or complex structure • Present in large amounts

15. White blood cells • Phagocytes i.e. monocytes, macrophages, neutrophils • Lymphocytes - T and B cells • Accessory cells i.e. eosinophils, basophils, platelets

16. Macrophages • Large white blood cells • Properties include phagocytosis and antigen presentation to T-cells • Enzymes and cytokines (e.g. interleukin II) in cytoplasm granules help to ingest and destroy antigens • Located where organs interface with environment or bloodstream e.g. lungs, spleen, liver, bone marrow • Monocytes are similar cells which circulate in the blood

17. Neutrophils • Key in defence against bacteria • Produced by bone marrow, circulate in bloodstream • Account for about 50% of total white cells • Swallow and destroy bacteria (phagocytosis) • Not capable of specific antigen recognition

18. Lymphocytes • Key in defence against viruses and tumours • Account for about 20% of white blood cells • Can specifically recognise foreign molecules - antigens • No other cell can do this! • May be B or T lymphocytes • origin and function • Classified using cell surface markers (CD) e.g. CD4, CD8, CD20, CD52

19. T Lymphocytes • Mainly involved in cell-mediated immunity • 70% of total lymphocytes • Produced in foetal bone marrow, migrate to thymus • Activated when meet antigen • Subsets depending on function: • T helper - Th • T suppressor - Ts • T cytotoxic - Tc • T delayed hypersensitivity - Td

20. T Lymphocytes • T helper cells • Help B cells produce antibody • Most are CD4+ • Cytotoxic T cells • Can kill certain cells e.g. virus-infected or tumour cells • Most are CD8+ (some CD4+) • All T cells carry the T cell receptor(TCR) • Also express CD3, linked to TCR

21. T Lymphocytes • Carry immunological memory • Can live for months to years • Circulate actively through lymphoid system • T cell mediated immunity can be transferred by giving T cells to genetically compatible individuals • T cell-antigen interaction releases cytokines which can modify immune response e.g. interferons, TNF, interleukins

22. Oligondendrocytes • Produce myelin • Can regenerate and remyelinate axons once the inflammatory cascade of MS has resolved (Bruck 2003) • It is currently thought that they may produce a soluble factor which protects the nerve from nitric oxide • Oligodendrocyte loss is evident at early stages of MS

23. What happens in MS • MS occurs in genetically and/or environmentally susceptible individual • An initial trigger causes an auto immune reaction to occur. • Activated T cells move from the lymph glands outside the CNS into the blood stream • Activated T cells enter CNS through defective BBB • They express adhesion molecules which weakens the BBB • Cause a cascade of inflammatory events which lead to myelin being attacked and destroyed

24. What happens in MS • Once activated, T cells trigger an inflammatory cascade including the production of cytokines • Cytokines activate macrophages which directly attack and phagocytise myelin • Chemokines are also produced that recruit other inflammatory cells across the BBB • The inflammatory process also causes release of nitric oxide which causes further local damage

25. Axonal degeneration • Loss of axons happens early in the disease process • Axonal loss correlates with inflammatory activity (Dutta and Trapp 2007) • Demyelinated axons are at particular risk of immune activity and injury • Axonal loss shows up as low signal (dark) on MRI, this can also be called ‘black holes’ • Black holes correlate with permanent disability and cerebral atrophy • Permanent disability becomes evident once the threshold of axonal loss beyond which the CNS cannot compensate is reached (Bjartmar et al 2003)

26. T Lymphocyte - journey in MS • Crosses blood brain barrier • Begins to look for target antigen • Macrophages and endothelial cells present themselves • T lymphocytes clones and proliferates • On proliferation gamma and toxic cytokines are released: • These attack the oligodendroctyes and cause them to die-apoptosis

27. T Lymphocyte - journey in MS • Gamma attracts more T lymphocytes which activate macrophages releasing more toxins • Macrophages begin to phagocytose myelin • This causes more damage to blood brain barrier, further leakage, increased inflammation • Continues for days or weeks until Suppresser T cells and transforming growth hormone suppresses activity

28. Pathogenesis of MS

29. Demyelination and axonal degeneration

30. Pathology and clinical outcome Filippi et al., EJN 2001, 8:291-297

31. MRI in MS • Sensitive but not specific • Routinely used in diagnosis • Important in clinical trials but predictive value controversial • Aids and supports treatment decisions • Does not replace clinical assessment

32. Conventional MRI techniques Gadolinium enhancement • Marker of oedema/inflammation/BBB disruption T1-weighted (T1W) images • Hypointense lesions or “black holes” • Probable marker of tissue damage and axonal loss T2-weighted (T2W) images • Pathologically non-specific - Composite of inflammation and permanent damage • Poor to fair correlation with clinical activity FLAIR (fluid-attenuated inversion recovery)

33. Conventional MRI techniques T2 Burden of Disease T1 / Gd post-contrast Disease Activity T1 pre-contrast Black Holes

34. Lesion Evolution T1 Acute hypo T1 (6 mo) Chronic BH  Gd Acute Black Hole Permanent Black Hole

35. T1 “Black Holes” Chronic T1 hypointensity correlates with axonal loss Bodian axonal density 40% 1: strongly hypointense 50% 2: mildly hypointense 90% 3: slightly hypointense Brueck et al., Ann Neurol 1997; van Waesberghe et al., Ann Neurol 1999

36. Correlation between black holes and disability • Permanent Black Holes • Direct Evidence • Correlation exists between histopathological (axonal loss) and MRI- MTR-MRS (magnetization transfer, magnetic resonance spectroscopy) markers of Black Holes • Indirect Evidence • Clear association between MTR-MRI markers and their predictive values for disease progression or clinical disability in MS