Image of stained glass showing brain affected by multiple sclerosis

Multiple Sclerosis Mechanism of Disease

A Closer Look at MS Pathogenesis

Inflammation and Neurodegeneration

The pathogenesis of multiple sclerosis (MS) involves a complex and dynamic interplay between the immune system and central nervous system (CNS) resident cells, including neurons and glial cells.1 These mechanisms contribute to the acute inflammation and diffuse neurodegeneration that characterize MS.1,2

View references on Mechanism of Disease.

The Role of Glial Cells in Multiple Sclerosis

A Network of Support Cells for the CNS

A Closer Look at Cell Function

Neuroglia are a network of cells in the brain and spinal cord that support the central nervous system by maintaining homeostasis, producing myelin, and protecting neurons from outside attack.1,3,4

Glial cells include astrocytes, microglia, and oligodendrocytes.1

  • Astrocytes provide synaptic support, neuronal guidance, and maintain the blood-brain barrier3
  • Microglia have an important role in inflammatory and immune responses including clearing cellular debris and repairing tissues4
  • Oligodendrocytes create the myelin sheath that helps insulate axons and allow for efficient conduction of nerve impulses1

Glial Cell Activation

Glial cells are activated when immune cells, including T cells, cross the blood-brain barrier and set in motion a chain of cellular reactions.5-8

  • Cytokine Secretion: once inside the central nervous system, autoreactive T cells secrete proinflammatory cytokines1,8-10
  • Glial Activation: in response to these proinflammatory cytokines, resident glial cells, such as microglia and astrocytes, become activated3,8-10
  • Axonal Demyelination: activated microglia and astrocytes produce additional proinflammatory cytokines, such as TNF-α, NO, and IL-6, which play a key role in demyelination and axonal injury3,4,6,8,9
  • Oligodendrocyte Loss: inflammatory activity also results in the extensive loss and apoptosis of oligodendrocytes, which are no longer able to repair and replenish damaged myelin sheaths1,3,4

Glial Cell Activity in the Pathogenesis of MS1,3-10

Picture of Glial Cell Activity in the Pathogenesis of MS
Adapted from Duffy SS, Lees JG, Moalem-Taylor G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int. 2014;2014:285245. Reprinted with permission. ©2018 Hidawi Publishing Corporation. All rights reserved.

View references on the Role of Glial Cells.

Migration and Activation

The Biology and Signaling of Sphingosine-1-phosphate (S1P) Receptors

A Range of Biological Functions

A quick overview of the biological mechanisms in multiple sclerosis (MS).

Summary of Key Points

1. Lymphocyte Migration in MS

  • In MS, autoreactive T and B lymphocytes cross the blood-brain barrier and cause neurological damage5
  • Before invading the central nervous system (CNS), autoreactive lymphocytes must first leave lymph nodes and move into circulation11
  • This may be a pivotal control point in MS. Focusing on the complex mechanisms that drive lymphocyte migration may be key to understanding MS12
A graphic showing lymphocyte migration in multiple sclerosis

2. S1P and the Role of S1P Receptor-1 in Lymphocyte Migration

  • One of those mechanisms involves the signaling of S1P receptors12,13
  • S1P binds to a family of five S1P receptors—S1PR1 through S1PR512
  • S1PR1 is expressed on the surface of lymphocytes and directs their migration from lymph nodes into circulation13-15
A graphic showing role of S1P receptor-1

3. Diverse Biological Functions of S1P Receptors

  • In addition to lymphocyte migration, S1P receptors are involved in other biological functions16
  • S1PR1, S1PR2, and S1PR3 are broadly expressed in cells of the immune system, cardiovascular system, and CNS17,18
  • S1PR4 expression is limited to the immune system, while S1PR5 is found primarily in the CNS17,19
A graphic showing diverse biological functions of S1P receptors

4. Role of S1P Receptors in the Cardiovascular System

  • In the cardiovascular system, activation of S1PR1 on cardiac myocytes of the sinoatrial node can cause a reduced heart rate16
  • S1PR2 causes coronary artery smooth muscle to contract20
  • S1PR3 is expressed on Purkinje fibers and can alter conduction along the atrioventricular node, leading to cardiac arrhythmias and complete heart block21
A graphic showing that S1P1 can cause a reduced heart rate

View references on Migration and Activation.

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