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.

References

  1. Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med. 2018;378(2):169-180
  2. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4):1180-1188
  3. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-285
  4. Lassmann H. Multiple Sclerosis Pathology. Cold Spring Harb Perspect Med. 2018;8(3):a028936
  5. De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 2010;74:1868-1876
  6. Nylander A, Hafler DA. Multiple sclerosis. The Journal of Clinical Investigation. 2012 Apr;122(4):1180-1188
  7. Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. The New England Journal of Medicine. 2018 Jan;378(2):169-180
  8. Li, R., Patterson, K.R. & Bar-Or, A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol 2018;19:696–707
  9. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:394-404. 2. 
  10. Lehmann-Horn K et al. Ther Adv Neurol Disord. 2013;6:161-173
  11. Krumbholz M et al. Nat Rev Neurol 2012;8:613-623
  12. Kunkl M, et al. T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis. Cells 2020;9(2): pii:E482
  13. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest 2012;122(4):1180-1188
  14. Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med. 2018;378(2):169-180
  15. Neumann H, Kotter MR, Franklin RJ. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain. 2009;132(Pt 2):288-295
  16. Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science 2013;339:156-161
  17. Franklin, R., ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 2008;9:839–855
  18. Franklin, R. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 2002;3:705–714 
  19. Freskgård P-O, Urich E (2017) Antibody therapies in CNS diseases. Neuropharmacology 2016;120: 38-55
  20. Brunner C, Muller B, Wirth T. Bruton’s tyrosine kinase is involved in innate and adaptive immunity. Histol Histopathol 2005;20:945-955
    Liang C, Tian D, Ren X, et al. The development of Bruton’s tyrosine kinase (BTK) inhibitors from 2012 to 2017: a mini-review. Eur J Med Chem 2018;151:315-26
    Weber ANR, Bittner Z, Liu X, et al. Bruton’s tyrosine kinase: an emerging key player in innate immunity. Front Immunol 2017;8:1454
    Hartkamp L, Radstake T, Reedquist K. Bruton’s tyrosine kinase in chronic inflammation: from pathophysiology to therapy. Int J Interferon Cytokine Mediat Res 2015;7:27-34
  21. Weber ANR, Bittner Z, Liu X, et al. Bruton’s tyrosine kinase: an emerging key player in innate immunity. Front Immunol 2017;8:1454
  22. Ito M, Shichita T, Okada M, et al. Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun. 2015;6:7360
  23. Werneburg S, et al. Immunity 2020;52:167-82.e7
  24. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541:481-487
    Ludwin SK, Rao VTs, Moore CS, Antel JP. Astrocytes in multiple sclerosis. Mult Scler 2016;22:1114-1124
  25. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707-717
  26. Franklin RJM, Goldman SA. Glia disease and repair — remyelination. Cold Spring Harb Perspect Biol 2015;7(7):a020594-a020594

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