Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease of the central nervous system (CNS), which causes damage to myelin and axons, resulting in neurological symptoms such as partial loss of sight, paresthesias and ataxia.

Research Areas
Background
Literature

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease of the central nervous system (CNS), which causes damage to myelin and axons, resulting in neurological symptoms such as partial loss of sight, paresthesias and ataxia.

Approximately 2.5 million people worldwide suffer from MS, with prevalence varying by latitude. The average age for onset is 30 and the disease has a female to male ratio of 2:1. In most cases, MS is episodic (relapsing-remitting), with focal neurological symptoms and signs developing over hours to days and improving across weeks to months.

The frequency of relapses decreases with time, but there is a tendency to accrue progressive disability. Diagnosis is based on a clinical assessment, with magnetic resonance imaging (MRI) of the brain and spinal cord, and cerebrospinal fluid analysis also being used to support the diagnosis.

There are four main groups of MS:

  1. Relapsing-remitting: characterized by a series of remissions and relapses (~85% of MS suffers).
  2. Secondary progressive: this develops in patients who have suffered from relapsing-remitting MS. The symptoms either plateau or get progressively worse.
  3. Primary progressive: characterized by a continuous worsening of symptoms from the start.
  4. Progressive-relapsing: characterized by progressively worsening symptoms from the beginning. There are no remissions. This form affects ~5% of patients.

MRI scan of a MS brain

Multiple Sclerosis

Pathology of MS

MS hallmarks include CNS inflammation, demyelination and axonal degeneration. Autoreactive T cells are activated, migrate to the CNS and pass through the blood-brain barrier, leading to the degradation of the myelin sheath. Activation of CNS B cells and microglia are important steps in these processes, inducing local inflammation. Microglia also release reactive oxygen species (ROS) that cause neuronal damage, including mitochondrial injury, which in turn promotes protein misfolding in the ER.

Axonal injury occurs early on and progresses over time, disrupting action potential propagation and axon transport. As the axon becomes damaged, there is a redistribution of ion channels, including Nav1.2 and Nav1.6, ASICs and TRPM4, along demyelinated neurons to compensate for an ionic imbalance. This redistribution gradually promotes tissue damage. A range of mechanisms are upregulated to compensate for the axonal injury sustained during an MS attack, such as those mediated by the cannabinoid system. However, the accumulated damage eventually passes a tipping point, and the neuron suffers significant damage, resulting in cell death.

Genes and Environment

Polygenetic determinants of MS risk have been identified, in particular specific human leukocyte antigen haplotypes confer higher susceptibility. In addition, environmental factors such as exposure to infectious agents may modify this risk. Epidemiological studies confirm variations in the incidence of MS within and between countries and a latitudinal gradient with higher risk further from the equator. Latitude alone however fails to explain intra-regional differences, which may be better explained by ethnicity-related susceptibility and migration patterns. In keeping with an autoimmune basis to disease, HLA haplotypes, in particular DR2, have been identified as susceptibility factors. Epidemiological studies show an association between specific viral infections and MS risk. Epstein Barr virus exposure during an age-linked period of susceptibility is an emerging hypothesis as an environmental risk factor for MS. In addition, low vitamin D levels are linked to risk of relapse, and studies are assessing whether vitamin D replacement influences MS disease course.

MS Therapies

There are a broad range of immunomodulatory treatments that reduce relapse rates, but developing treatments effective in preventing long-term disability remains a challenge.

MS Drug Targets and Therapy*

There are many licensed drug treatments for relapsing-remitting Multiple Sclerosis, which reduce the burden of relapse. Interferon β-1b was the first of these, introduced in 1993 and is of modest efficacy. More effective agents often with a more significant adverse event profile have been developed, in particular the monclonal antibodies. Oral agents of modest efficacy and good tolerability such as dimethyl fumerate and teriflunomide, have further expanded our formularies.

Despite good progress there remains no significant randomized control trial evidence, showing that any of these therapies have significant impact on long-term disability.

Drug Target Effect
Interferon β Interferon receptor and STAT signaling pathways PLieiotropic - modulates various aspects of immune system
Glatiramer acetate Possibly MHC II on antigen presenting cells Hypothesised induction and activation of suppressor T cell population
Teriflunomide Inhibitor of mitochondrial dioorate dehydrogenease Reduces uridine synthesis
Impairs clonal expansion of activated lymphocytes
Dimethyl fumarate Ketch-like ECH-associated protein 1 Activates Nrf2 antioxidant response pathway
Natalizumab &alpha4 integrin receptor Impairs migration of activated autoreactive T cells in CNS
Alemtuzumab CD52 Peripheral B and T cell depletion
Modulates autoreactive immune response

*Adapted from the MS poster, written by Dr Wilkins and Dr Ibitoye 2016

Literature for Multiple Sclerosis

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Multiple Sclerosis

Multiple Sclerosis Poster

Multiple sclerosis (MS) is an autoimmune disease that is characterized by focal demyelination and axon degeneration in the central nervous system. This poster summarizes the neurobiology and current therapies of MS.