…migrate nPDGF promotes motility nchemorepellent, netrin naxonal following nstop signals in ECM ?? plus actions of neurotransmitters
… myelinate and enstheath ndepends on axonal signals u neurotransmitters u NCAM and u N-cadherin
Summary nAstrocytes u metabolic partner u control blood supply u regulate synaptic efficacy u axonal/synaptic outgrowth nOligodendrocytes and Schwann cells u myelinate axons Now onto: a third kind of glial cell: microglia
Microglia narise from macrophages outside CNS nswitch from resting to active state nphagocytic nmigratory (chemotaxis)
Gliosis nform scar tissue u astrocytes and microglia involved ischaemia → glu release → TNF → … u HIV infects microglia → release of chemokines → …
Summary nAstrocytes u metabolic partner u control blood supply u regulate synaptic efficacy nOligodendrocytes and Schwann cells u myelinate axons nMicroglia u immune elements of CNS u with astrocytes generate gliosis Now onto: what happens in MS ?
MS nMultiple sclerosis ndemyelinating disease u CNS nrecognised by Jean Martin Charcot in 1868 nsymptoms u initally weak movement, blurred vision u later bladder dysfunction, fatigue nrelapses in 85% nIgG levels high
MS Lesions nblue: myelin dye nbrown HLA antibody (marks MHC microglia) n NAWM – normal appearing white matter
Loss of myelin from OL B: lesions in corpus callosumA: signals in white matter relapses associated with new lesions
Long time scale nlesion in 2008 gives relapse in 2018 u anti-inflammatory treatments u over 2-3 years interferon reduced # people who had second attack by ~30% n15 years after diagnosis u < 20% not affected in daily living u 60 % need assisted walking u 75% not employed
Epidemiology 1.2 : 1000 – in UK about 85000 people are affected
Genetics nidentical twins 20-30% nfraternal same-sex twins 2-5% nAfrican Americans less susceptible than Caucasian Americans n HLA-DRB1 gene on chromosome 6p21
Environmental factors nmay have protein like myelin n Chlamydia pneumoniae u in vitro infects microglial cells, astrocytes and neuronal cells [was not replicated] nEpstein-Barr virus as child u no causative explanation nSunlight (vitamin D), solvents, pollution, temperature, rainfall….
Animal model nexperimental allergic (or autoimmune) encephalomyelitis (EAE) (1935) nlymphocytes cross blood-brain-barrier (BBB) u express metalloproteinases (e.g. TACE, TNF-α-converting enzyme) -interferon blocks metalloproteinases u destroys membranes and allows more cells through BBB u T-cells activated by myelin F secrete cytokines ….
-interferon-1B -interferon levels go up just before relapses -interferon inhibits -interferon nFDA approved nreduced relapses from 69% of patients in 2 years to 55%
Glatiramer Acetate ncopaxone npolymer molecular mimic of a region of myelin basic protein nmay saturate HLA receptors nFDA approved
Choosing the right drug… nIs an expensive business: since ~2002, 5583 patients received interferon/glatiramer costing £350M nNICE recommended … should not be used in NHS because of doubts about their effectiveness and high price nMS Society etc. applied pressure for these drugs to be available nDept of Health created trial u cost £8000/patient/annum (+15% for extra nurses) u cost to be reduced if quality of life not satisfactory u MS Society withdrew support in 2009 when results were unsatisfactory nMS patients got high % of NHS budget and extra nurses
Natalizumab ntrade name Tysabri (£15k /annum / patient) u http://news.bbc.co.uk/1/hi/wales/7928456.stm nhumanized monoclonal antibody nagainst the cellular adhesion molecule α4-integrin nprevent cells crossing blood-brain barrier nassociated with PML (inflammation of white matter) u progressive multifocal leukoencephalopathy
New drugs ? noral drugs u immunosuppressive F Fingolimod Phase III trials (Oct. 2010) u cladribine F NICE expected to recommend in Aug 2011 ?
Remyelination nIn a lesion, loss of myelin/axonal damage major feature nremyelination normally seen, but blocked by glial scarring Rat model (ethidium bromide)
Remyelination… nred: demyelination nblue remyelination nvery variable between patients
What affects remyelination? nlack of OPCs ? nsignalling? in animal models, critical failure is due to macrophages not clearing myelin debris which contains inhibitors of differentiation.
Stem cell transplantation nsince 1995 nchemotherapy to kill T-cells ntransplant-related mortality up to 5% nreplace bone marrow to have fresh stem cells u http://news.bbc.co.uk/1/hi/health/7858559.stm http://news.bbc.co.uk/1/hi/health/7858559.stm
Summary nAstrocytes nOligodendrocytes and Schwann cells nMicroglia nMS u loss of myelin over long time scale u autoimmune disease u EAE model suggests invasion of CNS by T-cells, followed by inflammatory cascade u No effective treatment ???? ndemyelination or remyelination ???