Microglial cell and pyramidal neuron

How Multiple Sclerosis Affects the Brain

Multiple sclerosis (MS) is caused by immune cells attacking the central nervous system (CNS)–the brain and spinal cord. 

MS is a chronic neurodegenerative disease in which a person's immune system causes damage to the brain and spinal cord.1,2 It results primarily from damage to the myelin sheath: a protective, insulating layer surrounding the long, thread-like part of nerve cells called the axon. Axons transmit nerve impulses in the brain, and the myelin sheath enhances conduction.

Damage to the myelin sheath is called "demyelination”. MS can also cause axons to be cut off from the rest of the nerve, which alters conduction in that part of the brain.3,4 These degenerative processes can start early in MS, before symptoms are observed.5

Immune cells that cross the blood-brain barrier trigger inflammation and destroy brain tissue

White blood cells called B-cells and T-cells contribute to MS,  both independently and by interacting with each other.6,7,8,9,10,11 Antibody-producing B-cells, T-cells, and other immune cells can cross the blood–brain barrier and attack tissues in the brain and spinal cord.

B-cells also release substances called cytokines that trigger inflammation, both within the CNS and outside it. Scientists believe this inflammation contributes to MS.12

In more advanced MS, activated B-cells  and other immune cells can form clusters in the lining of the brain. This can contribute to disease progression.13

Immune activity in the CNS can be seen as lesions in the brain. Damaged axons in these lesions can be re-myelinated, become inactive without being remyelinated, or continue to degenerate (“smolder”).14

Immune cells in the brain respond to the injury, causing further damage

When neural tissues are destroyed, they produce debris that attracts the attention of immune cells that reside in the CNS, including microglia.15

Microglia can be beneficial: they patrol the CNS for plaques, damaged neurons, and pathogens that need to be cleaned out. In MS, what starts out as a protective function becomes a destructive one: the debris from demyelination causes microglia to go into overdrive.16 They trigger inflammation, contribute to myelin destruction, make it harder to create new myelin, and damage axons.17,18  

Cellular debris from demyelination attracts microglia
Demyelination (green) leaves debris in its wake. Microglia (pink)–immune cells that patrol the central nervous system–respond

Most current treatments target cells outside the brain

The blood–brain barrier protects the CNS and is extremely selective about what molecules may pass. Current therapies can limit unwanted T-cells and B-cells from entering the brain. Most MS treatments, for example antibody therapies, are designed to target cells outside the CNS, which can affect some activity inside the brain.19

However, as we understand more about MS and its processes inside the brain, we are learning about specific targets in the brain that have previously been inaccessible.

Scientists are investigating therapeutic molecules that could cross the blood–brain barrier

Creating an effective treatment that can cross the blood–brain barrier to act directly on immune cells in the CNS is a long-standing challenge in drug development. The therapeutic molecule must have certain chemical properties that allow it to evade the protective processes that exclude small molecules from entering the brain.

Some researchers have been developing potential new MS medicines that could cross the blood–brain barrier and directly affect targets in the CNS. One example is Bruton's tyrosine kinase (BTK), an enzyme inside certain immune cells that was recently discovered to play an important role in immune activities on both sides of the blood–brain barrier.20,21

BTK is critical to the activation for microglia, B-cells, and other immune cells that are implicated in the pathophysiology of MS.22 A treatment that could act on BTK within the brain may be able to calm the activity of microglia and other immune cells.

Immune cells affected by Bruton's tyrosine kinase (BTK) on both sides of the blood–brain barrier shown in color. BTK is critical to communication for microglia, B-cells, macrophages, mast cells, microglia, astrocytes, oligodendrocytesand their precursors, and other immune cells implicated in the pathophysiology of multiple sclerosis23,24,25,26

What's next at Sanofi?

Researchers at Sanofi are developing a BTK inhibitor that they believe may be able to cross the blood-brain barrier in humans. They hypothesize that, if the substance reaches the brain, it might be possible to modulate B-cells and microglia in the brain.

This is one of many approaches to MS treatment being explored at Sanofi.


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