Multiple Sclerosis

• Autoimmune demyelinating disease


  Affecting the brain and spinal cord with a wide range of symptoms
• Immune-mediated process


  1. Causes an abnormal immune response

  2. Attacks the myelin sheath that insulates nerve axons in the brain, spinal cord, and optic nerves
• Demyelination


  • Can occur anywhere in the CNS
  • Leads to nerve damage
  • Determines the physical symptoms
• Symptoms


  • Vision problems – blurred
  • Problems controlling bladder
  • Problems moving limbs
  • Sensation problems
  • Problems with balance and coordination
  • Numbness and tingling in different parts of the body
  • Muscle stiffness and spasms
  • Problems with thinking, learning and planning
• Diagnosis


  15-60 years – most common cause of disability in younger adults
• 2x common in women than men and 3x more between 50-59yrs
• Condition


  Lifelong with a slight reduction in life expectancy by 5-10yrs but this gap is getting smaller due to increasing levels of care, intervention and treatments
• There is no cure only controlling symptoms
• Underlying causes


  • Viral infection?
  • Genetic
  • Environmental
• Systems involved


  • Motor
  • Sensory
  • Visual
  • Autonomic
• Types of MS


  • Clinically isolated syndrome
  • Relapsing remitting MS
  • Secondary progressive MS
  • Primary progressive MS
  • Progressive relapsing
• Relapsing remitting MS


  90% cases most common form of MS, with episodes of new symptoms or worsening of existing symptoms followed by periods of partial or complete recovery (remission)
• Secondary progressive MS


  RRMS may progress and transition to this stage, with a constant steady state of demyelination, gradual worsening of symptoms and disability, with or without relapses
• Primary progressive MS


  Steady increase in disability without distinct relapses or remissions
• Progressive relapsing MS


  Characterised by a steady decline in symptoms with occasional relapses, progressive demyelination and disability with relapses but NO remission
• Relapses


  Occur due to increased level of inflammation leading to further demyelination, disrupting neuronal signalling in the CNS
• Remissions


  Can last for several years at a time, experiencing relief from their MS symptoms
• Immune systems involved


  • Adaptive immune system
  • Innate immune system
• Adaptive immune system


  Slower/delayed but more specific, brings specific responses against pathogens or foreign antigens, consisting of lymphocytes – T cells and B cells
• Innate immune system


  Rapid response but less specific, first line of defence against pathogens and foreign antigens, consisting of dendritic cells, macrophages, neutrophils, mast cells, natural killer cells and innate lymphoid cells
• T and B cells cannot cross the BBB
• The adaptive and innate immune systems are upregulated in MS
• Molecular Mimicry Hypothesis


  Certain bacteria or viruses posses proteins that are structurally similar key proteins on myelin, so when infection occurs, T cells specific to these proteins cross-react with these similar proteins present on myelin attacking its own tissues
• MBP


  Accounts for 30% of the protein in the myelin sheath, prime target for immune attacks
• BBB


  • Formed by endothelial cells lining blood vessels in the CNS, regulating passage of molecules and cells between the blood and the brain
  • Becomes compromised in MS, allowing immune cells to enter
• Autoantigens


  Present in the CNS which attract B and T cells, probably present on the myelin sheath
• Proinflammatory cytokines and chemokines

  T cells secrete these, which activate other immune cells and contribute to CNS inflammation
• Autoimmune cell recruitment


  T cells recruit other immune cells like plasma cells and macrophages to the CNS, exacerbating inflammation and tissue damage
• Myelin destruction and neurodegeneration

  Demyelination occurs when immune system attacks the myelin sheath, causing the neurological symptoms
• T cells responding to MBP have been found to be in higher levels in the blood of MS individuals, indicating their involvement
• Macrophages


  Immune cells promoting the pro-inflammatory response of T cells and B cells and execute tissue damage in the CNS
• Microglia


  Immune cells in the CNS acting as the primary immune defence, microglial activation might be one of the initial events that develop lesions in MS
• Downstream pathway


  1. Activation of microglia and macrophages lead to production of ROS and nitric oxide NO, causing mitochondrial dysfunction

  2. Impaired mitochondrial activity – oxidative stress through increased ROS, exacerbating tissue damage and neuronal injury

  3. Mitochondrial dysfunction – contributes to demyelination, apoptosis of oligodendrocytes and the degeneration of axons

  4. Reduced ATP production due to mitochondrial dysfunction increases Ca2+ within neurons, exacerbating neuronal death and neurodegeneration
• Mitochondrial DNA deletions in cortical neurons and iron accumulation within oligodendrocytes are other contributors to oxidative stress in neurons induced by inflammation and mitochondrial dysfunction in MS
• Environmental triggers


  • Epstein Barr Virus
  • Human Herpes Virus HHV-6
  • Smoking higher risk of MS
• Higher incidence rate of MS further from the equator


  Due to low vitamin D levels seen in MS patients because of less sun exposure
• In autoimmune diseases its usually a caused by a combination of environmental and genetic causes
• Susceptibility genes


  • HLA DR-2
  • Biologically female XX chromosome
• HLA DR-2


  Mutation within this gene HLA-DRB1*15:01 allele (present on antigen-presenting cells) when exposed to a particular type of antigen e.g. from EBV or HHV-6 they develop this immune reaction that is exaggerated, increasing individuals susceptibility in combination with environmental factors
• Increased risk, the closer the relation to the individual with MS