week 8 part 1 Flashcards
1
Q
What is multiple sclerosis ?
A
Demyelinating disease of the central nervous system which include the brain and the spinal cord
autoimmune disease
polygenic - over 200 different genes that have been identified that are associated with susceptibility
2
Q
What is myelin?
A
protective sheath that surrounds the axon of neuron allowing them to quickly send electrical impulses
3
Q
What is myelin produced by?
A
oligodendrocytes - group of cells that supports the neuron
4
Q
When does demyelination happen?
A
when the immune system attacks and destroys the myelin which makes communication between neurons break diown
5
Q
What does demyelination cause?
A
sensory, motor and cognitive problems
6
Q
What is the most important gene?
A
HLADRB1*1501
7
Q
What is HLADRB1*1501?
A
a Class II member of the major histocompatibility complex (MHC)
8
Q
Who is more likely to be affected by MS?
A
- females
2. It is around 1-3
9
Q
What does MS have?
A
Graphical distribution
It is more common further away from the equator
10
Q
What does MS relate to?
A
Vitamin D responsiveness
11
Q
What are some of the most common risk factors for multiple sclerosis include?
A
- Genetics
- Certain Infections
- Smoking
- Obesity
- Environmental factors
- Certain autoimmune diseases
- Age, sex, race
12
Q
What do individuals with MS have?
A
- Epstein Barr Virus infection
13
Q
When a disease manifests itself what does it manifest as?
A
Relapsing remitting diseases
14
Q
What is secondary progressive MS?
A
Many people who are initially diagnosed with relapsing remitting MS find that, over time, their MS changes so that there are fewer or no relapses but disability is increasing.
15
Q
Why is there different residuals signs and symptoms?
A
As a consequence of losing myelin and axons and neurons and synapses
16
Q
What does the symptoms you will get depend on?
A
Where in the nervous system the attacks occur
17
Q
In MS brain, where are the lesions observed?
A
Paraventricular lesions
Lesions around the ventricles
18
Q
What are lesions associated with?
A
- De-myelination
2. Astrocytic scarring
19
Q
Where are the active lesions located?
A
Perivascular areas
Occur around the blood vessels
Contain lymphocytes and monocytes
20
Q
What are the features of active lesions?
A
- Foamy macrophages
- Myelin losses
- Hypertrophi astrocytes
- Perivascular infiltrates
21
Q
What are chronic active lesions?
A
- Large, grey lesions - inactive centre but show an outer hyperceullar rim - contain foamy macrophages
- Myelin remnants are seen in the macrophages
- Hypertrophic astrocytes are often present in the rim
- Oligodendrocytes numbers are depleted, increased or normal
- Perivascular lymphoid infiltrates are present
22
Q
What are macrophages full off?
A
Lipid
23
Q
What are shadow plaque?
A
If the inflammatory process is arrested at an early phase, plaques are partially remyelinated
24
Q
What are consequences of chronic inactive lesions?
A
- Complete myelin loss
- Loss of oligodendrocytes
- Few or no inflammatory cells
- Gliotic
- Surrounded by ‘normal’ white matter
- The lesions are clearly hypocellular
25
What are repairing lesions?
1. Myelin replacement
2. Thinner myelin
3. Smaller internode length
26
What is pathology of MS?
1. Characterised by multifocal lesions - MS plaque
2. in the acute phase - activated mononuclear cells - including lymphocytes, microglia and macrophages destroy myelin
3. Myelin debris are picked up by macrophages and degraded
4. At early stage - macrophages contain myelin fragments
5. later stage - they contain proteins and lipids from chemical degradation of myelin
6. with time gliosis develops
7. Plaques reach a burned-out stage - demyelinated axons traversing glial scar tissue
8. Remaining oligodendroyctes attempt to make new myelin
9. If the inflammatory process is arrested at an early phase, plaques are partially remyelinated (shadow plaque)
27
In more advanced lesions, why is remyelination ineffective?
Gliosis creates a barrier between myelin producing cells and their axonal targets
28
what is Experimental autoimmune encephalomyelitis?
animal model of brain inflammation
It is an inflammatory demyelinating disease of the central nervous system (CNS)
29
What is MS?
Immune mediated
30
How does EAE work?
immunization with myelin proteins or peptides induces the migration of activated autoreactive T cells across the blood-brain barrier and into the CNS;
31
What are killing oligodendrocytes which is causing the demyelination?
perivascular lesion around blood vessels, these are secreting toxin factors
32
What was the first drug to affect progressive MS?
Ocrelizumab
33
When do we get an accumulated risk of opportunity infections?
When the drugs are not specific and is targeting large parts of immune response
34
When do you have a risk of malignancy?
constantly depressing your immune system
Cannot take live vaccines
35
What is pulsed immunotherapies?
Non-continuous administration
Get treatment over a week or month
36
What are non-selective Immunotherapy?
Gets rid of adaptive and innate immune system
37
What are semi-selective Immunotherapy?
Doesn't target immune system so much
38
What is the escalation approach?
• You can take low efficacy drugs with low side effects and if the disease breaks through you switch to a higher efficacy drug which higher side effects
39
What is Glatiramer acetate
Modulates TH1 and TH2
Preventing and suppressing experimental autoimmune encephalomyelitis (animal model of MS)
Diverts TH1 cells to TH2 cells that suppress inflammatory responses and activate Tregs in the periphery
40
What does Di-methyl furmarate target?
NRF2
modulates anti-oxidative respinse
Exert a neuroprotective effect in patients with multiple sclerosis by activating the Nrf2 transcriptional pathway
41
What does Teriflunomide inhibit
1. pyramadine
2. stop DNA replication - stop proliferation of cells
3. Inhibits the proliferation of B and T cells
4. Exerts anti-inflammatory properties by inhibiting IFN-gamma producing T cells
5. Oral administration - reduce relapse rate, MS lesions and decreased disability progression D
42
How does Fingolimod work?
Attaches to surface of certain white blood cells
Retain within the body's immune system
less lymphocytes get into blood stream and fewer reach the central nervous system
potential for immune attack on cells of brain and spinal cord is reduced
43
What is Natalizumab associated with?
increased risk of opportunistic infection and progressive multifocal leucoencephalopathy (PML) caused by JC virus
1. Humanised monoclonal antibody against the cellular adhesion molecule alpha-4 integrin
2. Administered intravenously once a month which reduces activated T cells within the CNS, resulting in anti-inflammatory responses and hence neuroprotective effect
3. Approved by FDA in 2004 but was withdrawn due to 3 cases of rare brain Infection
44
Mechanism of Natalizumab?
– it blocks to cells binding to the vascular cell adhesion molecule 1 on the inflamed brain endothelia and therefore the cells cannot get into the brain and therefore cannot get disease
45
How does Cladribine work?
kills certain types of blood cells made by your immune system. These white blood cells (or lymphocytes) are called T and B cells.
it phosphorylates the adenosine cytokinase – integrates into the DNA and causes strand breaks and also goes into mitochondria and affects RNA
46
What does Daclizumab block?
Interleukin 2
1. Humanised monoclonal antibody against CD25, the IL-2 receptor expressed not he surface of T cells
2. Blocks IL-2 receptor on T cells, preventing the activation of T cells
47
What is Interleukin 2?
T cell growth factor
Anti-proliferative
48
What is percentage that CD4 T cells are depleted by?
80% throughout 2 years
49
What is MS?
T cell mediated disease
50
What does transgenic mice have?
CD52
51
What are immature B cells?
potentially auto-reactive
Re-populating in the absence of any CD8 regulation and CD4 T regulation
52
What is an effective treatment for relapsing MS?
Hematopoietic stem cell therapy
53
How does Hematopoietic stem cell therapy work?
1. Deplete the immune system
2. Liable to infection
3. Transplant CD34 positive stem cells
4. within 29-30 days create neutrophil which protect you against infection
54
What happens between 0.5 and 2% of people?
Die because of complications related to removing immune system
55
How long does it take for memory B cells to populate?
18 months - 4 years
56
What is diagnostic features of MS?
Memory B cell pool give rise to plasma blasts - plasma cells that could make oligo clonal bands
57
What is consistent with many autoimmune diseases?
B cell follicles
58
Where do you get extra B cell follicles within?
Arithritic joints
59
What are B cells that are accumulating in the CSF during active MS?
1. CD27+ memory B cells
| 2. Plasmablasts
60
What are B cells accumulating in the CNS parenchyma?
1. CD27+ memory B cells
| 2. Plasmablasts/plasma
61
What may B cell structures be associated with?
Disability
62
What does EBV proteins activate?
Immune risk gene
63
What induces memory B cells?
EBNA3
64
How does the Espar Bar viruses infect B cell?
1. CD21
| 2. HLA-DR
65
When do you get a higher viral load?
Autoimmune risk genes
66
What do Memory B cell up-regulate?
CD8 T cell
Becomes APC
67
What does lesion show?
Higher prevalence of EBV reactivity
68
What do T cells provide?
Trophic support for pathogenic B cells to mediate MS
69
What do memory B cells present?
antigen to pathogenic T cells to mediate MS
70
What may cause B cell autoimmunity?
Repopulation of Immature B cells in the absence of effective CD4 and CD8 T regulation
71
What is progressive MS not responsive to?
Immunotherapy
72
What is MS?
Length dependent axonopathy
73
How is MS assessed?
Mobility scale
74
What has an effect on progressive MS?
1. Ocrelizumab
| 2. Slowed the rate of loss down by 24%
75
What happens as a consequence of de-myelination?
You get re-distribution of ion channels that maintain the neurological function
76
What does too much glutamate cause?
Excessive calcium release
| cause nerve death
77
What are some consequences of de-myelination?
1. Mitochondrial problem (energy deficit)
2. Neuro-excitotoxicity
3. Problem with mitochdonrial movement
78
What happens in the presence of inflammation from glia?
1. Nitric oxide - causes problems for mitochondria
79
What does lactate influence?
Redox potential of the nerve and that can get blocked
80
What is the central driver for the progressive MS?
activated glia
produce cytokine e.g. IL=1, TNF
81
What do B cell follicles produce?
Antibodies
82
What is inflammation associated with?
1. Length-dependent nerve loss
| 2. Irreversible disability
83
What is Multiple Sclerosis?
Inflammatory and neurodegenerative from beginning to the end
84
What are symptoms of Multiple Sclerosis?
1. Blindness
2. Nystagmus
3. Fatigue
4. Pain
5. Tremor
6. Spasms and Spasticity
7. Bladder problems
8. Incontinence
9. Sexual problems
10. Cognitive deficit
11. Motor deficits
85
What do nature of the symptoms depend on?
Location of lesions within the neural circuitry
86
What is spasticity?
Velocity dependent stretch response
Based on the reflex arc
87
Spasticity
Muscle stiffness (Exaggerated stretch reflec)
88
What are used for Epileptic Seizures?
Standard anti-convulsant (1-8%)
89
What are used for neuropathic pain?
1. Voltage-gated sodium channel blockers
2. Carbazepine
3. Phenytoin
4. Gabapentin
5. Iamotrigine
6. Topiramate
90
What are used for depression?
1. Tricyclics (amitriptyline, desipramine)
2. SSRI (fluoxetine, paroxetine, sertraline)
3. SNARI (Venlafaxine), NARI (reboxitine)
91
What are used for ataxia and tremor?
1. Clonazepam (GABA A)
2. Propanolol (beta-blocker)
3. Gabapentin
4. Valproate
5. Physiotherapy-Gait modification walking aids
92
What causes nerve loss?
Adaptive inflammation
Demyelination
93
What promotes nerve loss?
Glial inflammation
