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Multiple Sclerosis From neuroscience to treatment Dr Rosie Jones The Brain Centre, Southmead Hospital Spring 2015 1 Characteristics of MS “Autoimmune mediated inflammation (causing damage) triggered by unknown factors in susceptible individuals and resulting in”: • • • • • • Patchy damage to myelin / loss of Oligodendrocytes (?) Failure of nerve conduction Axonal damage Axonal/nerve cell degeneration Reduced brain Volume Development of scarring In the CNS Spring 2015 MS Research Unit This session • Understanding MS – Demographics – Pathology • • • • Immuno-pathology Myelin damage Axonal damage Routes to designing treatment – Possible CNS repair mechanisms – Some examples of MS Symptoms Spring 2015 3 MS Demographics • Prevalence between 10/100,000 and 170/100,000 (around 100,000 in the UK , 3 million world wide) • Most common in temperate latitudes • 2:1 women:men • Diagnosed in early adulthood (teens to 30s, range “x” to 70 years) Childhood MS now acknowledged. • Familial (genetic) susceptibility + unidentified factors • Significantly more common in Caucasian populations • Multiple symptoms-sensory and motor • Progressive with or without relapses Relapse Remitting, Primary Progressive Secondary Progressive (RR PP SP) Spring 2015 4 POPULATION STUDIES Some examples of prevalence figures world-wide: UK 99-178/100,000 (Orkney 287/100,00?) France 50/100,000 Italy 35-50/100,000 USA 70-165/100,000 (New Mexico 22/100/000) Australia 11-40/100,000 New Zealand 24-77/100,000 Middle East 20 -50/100,000 (?) Spring 2015 5 Environment: MIGRATION STUDIES Studies of migration from high prevalence area to low prevalence area: • South Africa and Israel are both low prevalence areas. • Europeans migrating to these areas retain high prevalence risk unless they migrate before the age of 15 years. Spring 2015 6 Environment: EXPOSURE • Levels of sunlight/Vit. D – Temperate latitudes, lack of exposure to sun • Exposure to chemicals – Solvents, fuel pollution, smoking • Exposure to (viral) infections – Measles, hepatitis, herpes etc. Vaccinations • Exposure to stress/trauma – MS may occur/worsen after giving birth, physical injury traumatic life events • Dietary differences • High saturated fat levels-lack of polyunsaturated fats in diet. Spring 2015 7 MULTIPLE SCLEROSIS Spring Spring2012 2015 MS Research Unit 8 EDSS expanded disability status scale Spring 2015 9 Kurtzke JF (1983) Neurology 33 (11): 1444–52. Progression of Disability Occurrence, Extent of Severity MS Courses as Redefined by MRI SPMS Clinical Impairment MRI-Defined Plaque Burden Late RRMS Enhancements Early RRMS Time Spring 2015 Adapted with permission from Dr. J.S. Wolinsky. 10 Natural History of MS • Relapse remitting phase- intermittent clinical events 1 to 4/year - 5 to 20 years • Secondary progressive phase-few or no relapses, steady progression in disability levelling off by about 20 years after diagnosis • Primary progressive – steady increase in disability with or without relapses. • Severe - very rare. Fast progression to wheelchair/bed-bound/death in 3 to 10 years Spring 2015 11 Pathology Development of an MS Plaque Inflammation, Demyelination Axonal damage Spring 2015 1 Characteristics of MS pathology “Autoimmune mediated inflammation resulting in”: • Damage to/loss of myelin/or loss of Oligodendrocytes? • Axonal damage • Axonal degeneration • Loss of brain bulk Spring 2015 13 Myelin and Nerve Conduction Spring 2015 14 Demyelination: Myelin and Oligodendrocytes in the CNS • Myelination in the CNS is by Oligodendrocytes-(peripheral nervous system myelin is produced by Schwann cells-not present in CNS and not affected by MS) • Each Oligodendrocyte produces myelin extensions that wrap around several nerve axons • What happens to Oligodendrocytes in MS? Spring 2015 15 OLIGODENDROCYTES Oligodendrocyte in culture (Immunofluorescence for galactocerebroside) Spring 2015 16 Brain Imaging Spring 2015 17 PATHOLOGY Not all aspects of MS pathology are understood • Blood brain barrier disruption- immune cells move into CNS. • Complex inflammatory responses • Localised CNS damagedemyelination, axonal damage Spring 2015 18 Pathology Local infiltration of inflammatory cells across blood vessel walls requires: • Adhesion to blood vessel epithelium • Transit across blood vessel wall • Migration into local brain tissue Spring 2015 19 Spring 2015 20 Evidence that MS is an Autoimmune disease. Immune activity overview • Activated T lymphocytes appear in the blood and CSF. Reactive to myelin proteins e.g. *MOG or MBP • Activated T cells and macrophages seen in MS plaques • Increased CD4+ (helper) to CD8+ (suppresser) T cell ratio. • Local IgG production seen in CSF-action of B cells? Possible antibody candidates:*MOG (oligodendrocyte glycoprotein), MBP (myelin basic protein), viral infection? Spring 2015 21 William Lindsey and Jerry Wolinsky • Spring 2015 22 Spring 2015 23 Immune markers Increased circulating levels of immune markers of immune activity during MS exacerbations observed including: • • • • • T cell activation markers Markers of macrophage activation Markers of cellular adhesion Markers of extracellular matrix breakdown Markers of inflammatory cellular amplification Spring 2015 24 T cell activation markers Markers of T Helper cell (Th-1) activation • Activated T helper cells release IL-2 (soluble IL-2 receptors detected) • IL-4 is associated with T cell activation • Interferon-gamma (INF) is associated with T cell activation • Macrophage activation follows. aTNF IL=interleukin, TNF = tumour necrosis factor, INF=interferon Spring 2015 25 Macrophage activation Macrophage demyelination in vitro is mediated by tumour necrosis factor-(TNF a) and Interferon (INF) • TNFa is increased in MS during relapse • INF and TNFa act synergistically to heighten immune responses • TNFa damages Oligodendrocytes in vitro Beta interferon, INF, counteracts the influence of TNFaand INF Spring 2015 26 Aims of Disease Modifying Drugs DMDs are designed to break a key link or links in the presumed pathway to tissue destruction in active disease Links include • Immune cell activation (PB, CNS other?) • Immune cell adhesion and migration (BBB) • Immune cell clonal expansion (PB or CNS) • Immune cell/cytokine cycle amplification Spring 2015 27 William Lindsey and Jerry Wolinsky • Spring 2015 28 Autoreactive T Cells Danger Signal or Trigger T T T Activation, Differentiation, Clonal Expansion T T Adhesion/Attraction T Periphery Transmigration T BBB B Antibodies IFN- T APC CNS APC M NO TNF-a Local Reactivation Release of Cytokines; Recruitment of M T TNF-a Demyelination and Axon Loss Spring 2015 Adapted with kind permission from Prof. R. Hohlfeld. 1 The Dual Nature of Inflammation in MS Pro-inflammatory and Neurotoxic Factors Th1 cytokines TNF-a IL-1 Nitric oxide Reactive oxygen species Glutamate Antibodies and complement Cell-mediated neurotoxicity TISSUE DAMAGE Spring 2015 Anti-inflammatory and Neuroprotective Factors Th2 cytokines TGF- IL-1 Neurotrophic factors – BDNF – NGF – NT-3 – CNTF – GDNF TISSUE PROTECTION 30 Aims of Disease Modifying Drugs DMDs are designed to break a key link or links in the presumed pathway to tissue destruction in active disease Links include • Immune cell activation (PB, CNS other?) • Immune cell adhesion and migration (BBB) • Immune cell clonal expansion (PB or CNS) • Immune cell/cytokine cycle amplification Spring 2015 31 Clonal cell expansion-promotion of cellular reactivity? Mechanisms for clonal expansion of autoreactive immune cells and cellular amplification/restriction unclear • Following BBB breach other cells follow: In MS plaques T cells and macrophages • Macrophage activation: e.g. TNFa,macrophage inflammatory proteins • Pro-inflammatory cytokines detected in lesions – TNFa, INf-,IL-2,IL-6,Il12. Spring 2015 32 Treatments based on modifying immune function • Some tested disease modifying agents – Beta interferon- (betaseron betaferon, Avonex) – Glatiramir acetate (Copaxone, copolymer 1) – Natalizumab (Antegren)-affects adhesion molecules – Campath H (Alemtuzumab) acts against CD52 lymphocytes – Cell proliferation modulation? – Stem cells?? Spring 2015 33 BBB Action of Adhesion Molecules Peripheral circulation Basement membrane Matrix degrading enzymes e.g. matrix metallo-proteinases T cells express adhesion molecules e.g. LFA-1 VLA-4 CNS Blood vessel Blood vessels express Adhesion molecules e.g. E-Selectin LFA- Leukocyte function associated antigen-1 VLA Very late antigen-4 Spring 2015 34 Current drug trials Cladribine Oral x5x2mo Depletes resting and dividing lymphocytes Lymphocytes and monocytes Alemtuzumab ivx5dx 12mo CD52+ Lymphocytes Ablation lymphocytes and monocytes Rituximab Ivx2 rep CD20+B lymphocytes Depletes naïve and memory B cells Aticept sc BlysS and APRIL Affects B lymphocyte activation Daclizumab ivxmo CD25+ Lymphocytes Expansion of CD2 56 and NK clones – takes out activated l’cytes Fingolimod Oral daily SIP Receptors Sequesters lymphocytes in lymph tissue Laquinomod Oral 3xd Enhances Th11 responses Immunomodulatory Teriflunomide Oral daily Blocks pyrmidine synthesis immunomodulatory BG00012 Oral 3xd Enhances Th11 responses imunomodulatory Spring 2015 35 Clinical outcome of some DMDs • Reduction in number of relapses in early RR MS • Reduction in new MRI (enhancing) CNS lesions in early RR MS • Reduction in progression of disease by 9 to 12 months • Changes broadly reverse when treatments stops. Spring 2015 36 Current treatments • Inflammatory phase-steroids • Non–acute phases – General immunosuppressant agents – Possible non-drug immuno-suppressants • e.g. diet, lifestyle changes • Statins? Spring 2015 37 Damage to axons and nerve cells Spring 2015 1 Myelin damage and axonal loss in MS Spring 2015 39 Fate of axons and nerve cells It is now clear that axonal loss and damage are major features of MS • Presence of NAA (N-acetyle aspartate) in MR spectroscopy • Loss of brain bulk • Increasing disability • Alterations in physiological measures Spring 2015 40 Neuronal/axonal damage Axonal damage thought to be secondary to myelin damage. Loss of trophic support or direct injury to axon BUT In some models of MS axonal damage appears early with or without evidence of demyelination. AND Reduction in CNS bulk continues in absence of demyelination episodes (e.g. Progressive MS) Spring 2015 41 Possible causes of axonal loss Damage by • Proteases • Inflammatory cytokines • Nitric oxide • Glutamate/Glutamine Evidence of up-regulation of all these possible mechanisms seen in active MS. Spring 2015 42 Possible mechanisms of repair Spring 2015 1 Remyelination Remyelination requires: • Viable myelin making cells (oligodendrocytes) • Intact nerve processes • Suitable environment for cellular survival and activation Spring 2015 44 Oligodendrocyte - development Oligodendrocyte (OD) progenitor OD precursor Pre-OD Adult OD progenitor ? Immature OD Mature OD Spring 2015 45 Features of Oligodendrocytes • Progenitor cells +ve for 04 mabs. Present throughout CNS. Undifferentiated. • Precursor cells +ve for Galacto-cerebroside (GalC). Earliest OG specific marker to be expressed. Large pale nucleus. • May produce myelin processes. • Mature cell +ve for myelin oligodendrocyte glycoprotein MOG. Small dense nucleus. Spring 2015 46 Possibilities for promoting remyelination • • • • Stimulate cell activity/differentiation Block progenitor cell inhibitory factors Block agents that kill myelin-making cells Transplant new OG cells-stem cells Spring 2015 47 Oligodendrocytes and myelin Extensive remyelination does not occur despite presence of intact axons and GalC+ve cells in the same lesion area. • GalC +ve cells do not appear to mature into MOG +ve cells to form new myelin – Cells appear quiescent. Die before they can mature? • GalC and MOG +ve cells appear to be destroyed in long term plaques – MOG+ve (mature) cells are destroyed selectively • Possibilities for treatmentstimulate cell activity/differentiation block inhibitory/cytotoxic factors Induce/transplant new OG cells? Spring 2015 48 Nerve cell repair Loss of axonal capability to repair may be : • Intrinsic-no mechanism in mature CNS • Due to Nogo-A mediated damage-Block or ablate. • Lack of access to or response to nerve growth factors • Hostile cytotoxic soup-too many factors to control Neurotrophic support may be developed e.g. CNTF ciliary neurotrophic factor. Spring 2015 49 Stem cells Can stem cells be used to effect repair in MS? • Types of possible stem cells – Resident/introduced oligodendrocyte precursor cells. • Used in early repair? Depleted? – Embryonic stem cells • ethical and cross reactivity issues. Tumours – Other stem cells-e.g. haematopoietic • Autologous and relatively easy to obtain Spring 2015 50 C. What is known about adult stem cell differentiation? Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. Spring 2015 51 Symptoms in MS Multiple symptoms both motor and sensory • Muscle weakness, fatigue, stiffness (spasticity) contracture • Sensory changes pain, burning/ tightness/numbness. Vision. Joint position. • Loss of motor control-ataxia tremor • Continence problems • Cognitive changes • Other behavioural and mood changes Spring 2015 52 Physical fatigue Neuromuscular fatigue and weakness Illustrated as change in force output with time. Loss of force may be due to central or peripheral (muscle) fatigue. Spring 2015 12 10 8 6 4 2 0 0 10 Force Control 20 30 Force MS 53 Neuromuscular Fatigue in MS Spring 2015 54 Symptom Treatment • Spasticity. Muscle stiffness and spasmsloss of central inhibition of spinal motoneurones. Baclofen • Loss of bladder control spinal lesions block descending and ascending pathways. Urine retention is most dangerous-can lead to kidney damage. • Pain. Neuropathic pain, very difficult to treat. Pain from muscle contractures. Spring 2015 55 Fatigue Statements • “Fatigue is one of the worst symptoms” “Having to use a wheel chair is a big change but it’s not as bad as the fatigue”. • -”like having a really bad ‘Flu” “You feel weak and unable to get about. It comes on without warning and is one of the hardest things to deal with” Spring 2015 56 Mental Fatigue • • • • • Runs out of steam Cannot make effort May need to rest or sleep May feel depressed or frustrated Usually worse when hot or under stress Spring 2015 57 Mental Fatigue • • • • Loss of concentration Ability to think through/solve problems Reduced motivation Over whelming need to rest or sleep Affects up to 90% of people with MS Spring 2015 58 Intention Tremor Definition-An increase in tremor amplitude towards the termination of a visually guided goal-directed movement. • 30% of the MS population are estimated to have upper limb tremor • Causes dependence in daily activities • Subjects with severe tremor have a high level of disability and loss of independence. Spring 2015 59 Figure of 8: Control subject Spring 2015 60 Example of figure of 8 data collection (severe tremor) Spring 2015 61 62 Measurement of Tremor • Second example: reach-retrieve (functional) test