Multiple Sclerosis Flashcards
Multiple Sclerosis
MS is an T-cell mediated autoimmune response against the myelin of the central nervous system. The disease is more common in females by a 3:1 ratio.
Clinical presentation
• Clinically Isolated Syndrome: This is referring to the first MS attack, however as this is only the first event and does not satisfy the McDonald diagnostic criteria, a diagnosis of MS cannot be given. • Relapsing Remitting: 90% of MS start out as a relapsing remitting disease, the features of this presentation are intermittent MS attacks with periods of stability in-between. • A recognisable pattern of deteriorating symptoms which develop over hours to days, followed by a recovery period taking days to weeks • Primary Progressive: Disease course shows a steady decline in functionality without bouts of attacks • Secondary Progressive: This happens in the end stages of MS. The disease course has a stepwise loss of function, brought about by each attack • Progressive Remitting: Loss of function with each attack with some recovery in ability but never completely
Symptoms
- Optic neuritis
- Transverse myelitis
- Brainstem syndromes
- Pure cranial nerve lesions
- Double vision and Nystagmus
- Facial palsy/ numbness
- Ataxia
- Dysarthria
Paroxysmal syndromes
- Lhermitte’s phenomenon (bending of neck send a shock down arms and legs. This is causes by the haptic rubbing of exposed nerves)
- Trigeminal neuralgia
- Uhthoff’s phenomenon (Raise in body temperature leads to features of MS)
Diagnostic Criteria
2010 McDonald Diagnostic Criteria:
MS is characterised as having clinical lesions that are disseminated in space and time.
- To have dissemination in space a patient must have more than one T2 lesion in at least 2/4 areas of CNS (cortical, periventricular, juxtacordial, infratentorial, spinal cord)
- To have dissemination in time there must be at least one baseline scan with a lesion and follow up scan with new lesion. These criteria can be satisfied with having simultaneous presence of a T2 lesion and a gadolinium enhancing lesion
In 2017 the McDonald Diagnostic Criteria made some additions:
- Oligoclonal bands in CSF as a surrogate for dissemination in space
- Fluid is taken from CSF and Serum for comparison by electrophoresis. If heavy chain of IgG are present in the CSF and unmatched in the blood serum, this indicates B-Cell activity localised to the brain.
- Addition of cortical lesions to dissemination in space criteria McDonalds Criteria for Primary Progressive MS
- One-year disease progression with evidence of dissemination in space - two lesions in different areas • +/- Oligoclonal Bands
Pathophysiology
Autoreactive T-cells escape inactivation and reside outside the CNS, by unknown mechanisms they are activated and migrate to the CNS.
• Hypothesis of their activation point to either molecular mimicry of MBP, 129 motifs from virus and bacteria match MBP, or previous CNS infections lead to MBP being exposed in the vessels
Autoreactive T-cells travel through the blood vessels till they reach the site of endothelium where glycoproteins are being expressed.
They bind with selectin and roll until they are anchored by integrin-ICAM interactions, the T-cells then squeeze through the walls via diapedesis and migrate down a cytokine gradient to the blood brain barrier.
T cells express CCR6 which bind to CCL20 of the choroid plexus epithelium, the interaction here promotes TH17 movement across the BBB. Once inside the subarachnoid space, APC’s present MBP to the T-cells and this initiates the immune response causing inflammation.
DEMYELINATION OCCURS BY TWO PATHWAYS:
- Autoantibodies from B-cells attract complement, macrophages and microglial cells.
- IL-3 secreted by T-cells recruit astrocytes and promotes macrophage recruitment
- Macrophages strip myelin from axons, generate reactive oxygen species, secrete TNF-alpha and protein-degrading enzyme.
Neuronal loss in MS
Early immune mediated axon transection: Caused by immune cells targetting myelin
Late non-immune mediated axonal degeneration
- To maintain speed of transmission mitochondria, must actively propagate action potentials over non-myelinated section of axon, the persistent Na+ influx causes the reversal of Ca2+ pumps.
- This leads to injury via cascade mechanisms (ROS, mt failure via replication and mutation) •
Smouldering compartmentalised immune mediated damage:
- Relapse mediated by microglia and B-cells
- Microglia activate both inside old lesions and ectopically outside them. CD20+ B Cells commonly aggregate in the deep sulcus in secondary progressive MS
RELAPSING REMITTING
EPITOPE SPREADING:
- Immune activation of a specific epitope can cause immune activation and inflammation causing immune responses to different epitopes in the inflamed area.
- This can be intramolecular (to subdominant or cryptic epitopes) or intermolecular (to whole new antigens). o In MS this means that an immune response to one antigen (e.g. MBP) can subsequently cause an immune response to another (e.g. MOG)
Various myelin proteins are autogenic, MBP, MOG, PLP, S100beta. Theories suggest this could be the reason behind the heterogeneity of the disease.
EAE MOUSE MODEL
Experimental autoimmune encephalitis, this is a model inflammatory demyelinating system in rodents. Rodents are sensitised by proteins from the myelin sheath by injection of myelin proteins into circulatory system. This activates T-cells and leads to the MS phenotype
Berer at al 2011
- “The commensal microbiota, in the absence of pathogenic agents, are important for triggering EAE.”
- Models of microbiome free mice were made, these were then exposed to myelin proteins in attempt to sensitise T-cells to the CNS.
- This process did not result in an EAE model, when the microbiome was introduced in these mice, the EAE model developed.
- Recruitment and activation of autoantibody B-cells is dependent on the availability of MOG
Friese et al. 2008
- HLA class I and CD8 T-cells may also have significance in triggering EAE, especially with respect to the first bout of disease → epitope spreading
- Done by using transgenic mice which express HLA-A3 and myelin specific T-cell receptors (from patients with MS)
- The authors showed that the early bout of disease is mediated by 2D1-TCR+CD8+ T cells, but that the later manifestations were due to a unique type of epitope spreading.
- The 2D1-TCR and HLA-A3–expressing transgenic mice developed autoreactive T cells that were specific for a myelin protein (myelin oligodendrocyte glycoprotein) different from the inducing one (PLP) and restricted by MHC class II molecules. The findings suggest that disease can initially be triggered by CD8+ autoreactive T cells and then later evolve to a CD4+ mediated process.
- Expression of the HLA-A2 molecule greatly reduced not only the number of 2D1-TCR+CD8+ T cells but also their peptide responses and cytokine secretion. The decrease in the number of 2D1-TCR+CD8+ T cells was due to HLA-A2– mediated negative selection in the thymus and, in the periphery, the downregulation of the 2D1-TCR.
Ousman et al 2007
Protective role of αB-crystalline:
- Anti-apoptotic and neuroprotective functions
- Target of CD4 T-cell immunity
- Reduces cleaved caspase-3 in astrocytes (anti-apoptotic)
- Regulator of inflammatory pathways
Management for MS
First line: INTERFERON BETA TERIFLUNOMIDE
Second line: NATALIZUMAB ALEMTUZUMAB
Interferon Beta
MoA: Interferon beta is a naturally occurring polypeptide predominantly produced by fibroblasts.
Its anti-inflammatory effects are largely believed to result from the inhibition of T-lymphocyte proliferation, a shift of cytokine response from an inflammatory response to an anti-inflammatory profile, and reduced migration of inflammatory cells across the blood–brain barrier
Side effects: Most patients (50%–75%) experience flu-like symptoms, including muscle aches, fever, chills, headache and back pain, that usually appear 2–8 h after an injection and resolve within 24 h.
Liver enzymes may be elevated and bone marrow function may be depressed, which warrants periodic surveillance of liver function and blood counts before starting therapy and every 6 months thereafter o Interferon beta treatment may induce formation of specific neutralizing antibodies (NABs).
Teriflunomide
MoA: Teriflunomide is an immunomodulatory agent that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, required for de novo pyrimidine synthesis.
This leads to reduced proliferation of dividing cells that need de novo synthesis of pyrimidine to expand. The therapeutic effect in MS is not fully understood but it is probably mediated by a reduced number of circulating lymphocytes
Side effects: Common adverse events include upper respiratory tract infection, urinary tract infection, paraesthesia, diarrhoea, nausea, hair thinning, alanine aminotransferase increase, reduction in blood leucocytes and increase in blood pressure. o Teriflunomide treatment should be stopped if liver transaminase levels increase three times above upper normal levels.
Natalizumab
MOA: largely through preventing adherence of activated leucocytes to inflamed endothelium, thus inhibiting the migration of inflammatory cells into the CNS.
SE: Risk of developing Progressive multifocal leukoencephalopathy PML.
This is a potentially life-threatening CNS infection of oligodendrocytes by the JCV. Therefore all patients receiving natalizumab should be screened for previous JCV infection.
The risk for PML in JCV-negative patients is low and is probably associated with recent seroconversion or a false negative test.
Amongst the JCV-positive patients the risk of developing PML is influenced by treatment duration and previous immunosuppressive treatment.
Natalizumab treatment may induce an immune response, with the formation of persistent NABs
