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The Role of the CNS and Periphery in MS and Disease Accumulation

Elements in the periphery and the CNS each have their own distinct roles and players in the onset and progression of MS1




MS has historically been considered a disease mediated by adaptive immune cells from the periphery (B cells and T cells)2

Our current understanding is that innate immune cells residing in the CNS (including microglia) potentially play a pivotal role in disease progression that results in disability accumulation

Periphery
  • B cells
  • T cells
  • Monocytes

 

CNS
  • Microglia
  • CNS-resident B cells
  • Astrocytes

 

CNS, central nervous system; MS, multiple sclerosis.

References

  1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  2. Hernández-Pedro NY, et al. Clin Dev Immunol. 2013;2013:413465. doi:10.1155/2013/413465

These form 2 pathways: acute neuroinflammation driven by peripheral B cells and the microglia-driven pathway inside the CNS involved in smoldering neuroinflammation1-3

How do you think the peripheral pathway is involved in MS?

PIRA, progression independent of relapse activity.

References

  1. Hernández-Pedro NY, et al. Clin Dev Immunol. 2013;2013:413465. doi:10.1155/2013/413465
  2. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  3. Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201

Acute neuroinflammation in MS is driven primarily by activated B cells in the periphery

 

 

 

 

Acute Neuroinflammation
  • Activation and proliferation of autoreactive/ self-recognizing lymphocytes (ie, B cells)
 
  • Infiltration of autoreactive lymphocytes across the blood-brain barrier (BBB)
  • Secretion of proinflammatory cytokines
  • Demyelination
  • Formation of acute lesions

 

 

CD4, cluster of differentiation 4.

References

  1. Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201

…Unlike smoldering neuroinflammation, which is primarily driven by microglia in the CNS1

 

 

 

  • Focal and diffuse microglial inflammation in the CNS1

Smoldering Neuroinflammation
  • Pathogenic microglia act at the edges of lesions causing them to slowly expand as chronic active lesions2,3
  • Smoldering neuroinflammation manifests as disability accumulation1

BTK, Burton’s tyrosine kinase.

References

  1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  2. Dal-Bianco A, et al. Acta Neuropathol. 2017;133(1):25-42.
  3. Keaney J, et al. J Neuroimmune Pharmacol. 2019;14(3):448-461. BTK, Burton’s tyrosine kinase.

The BBB is a selective layer protecting the CNS from external solutes, materials, and pathogens

 

 

The BBB selectively inhibits trafficking into the CNS

Crossing the BBB is a highly regulated process dependent on:

  • Solute size and charge
  • Selective active transport

mAb, monoclonal antibodies.

References

  1. Schreiner TG, et al. Biomolecules. 2022;12(4):538. doi:10.3390/biom12040538

BTK plays a pivotal role in both peripheral and CNS pathways in MS1,2

BTK expression is increased in lesion tissue in people with progressive MS7

References

  1. Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201
  2. Keaney J, et al. J Neuroimmune Pharmacol. 2019;14(3):448-461.
  3. Alu A, et al. J Hematol Oncol. 2022;15(1):138. doi:10.1186/s13045-022-01353-w
  4. Frisch ES, et al. Neurotherapeutics. 2021;18(3):1602-1622.
  5. Dal-Bianco A, et al. Acta Neuropathol. 2017;133(1):25-42.
  6. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  7. Geladaris A, et al. Int J Mol Sci. 2021;22(7):3461. doi:10.3390/ijms22073461

Comprehensive clinical management of MS includes targeting both smoldering and acute neuroinflammation1-3

Early control of disability accumulation in addition to relapses and acute lesion activity may improve long-term outcomes1,2

Do you agree or disagree with this? Why or why not?

References

  1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  2. Simpson A, et al. Curr Treat Options Neurol. 2021;23(7):19. doi:10.1007/s11940-021-00677-1
  3. Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201

Key takeaways

Elements in the periphery and CNS each have their own distinct roles and players in the onset and progression of MS1

  • B cells, located in the periphery, and microglia, located in the CNS, are the main drivers of MS2

Because it is located inside the BBB within the CNS, smoldering inflammation has been largely inaccessible to date1,3,4

BTK is involved in the activation of both B cells, as well as microglia1,5

  • For microglia, this may result in a shift from a homeostatic to pathogenic state4

Optimal management of MS includes controlling relapses, lesions, and disability progression caused by both acute and smoldering neuroinflammation1

  • Because microglia reside in the CNS, any potential treatment would need to cross the blood-brain barrier to affect them1,3,6

References

  1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  2. Hernández-Pedro NY, et al. Clin Dev Immunol. 2013;2013:413465. doi:10.1155/2013/413465
  3. Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201
  4. Correale J, et al. Mult Scler Relat Disord. 2021;56:103264. doi:10.1016/j.msard.2021.103264
  5. Frisch ES, et al. Neurotherapeutics. 2021;18(3):1602-1622.
  6. Lenz KM, et al. Front Immunol. 2018;9:698. doi:10.3389/fimmu.2018.00698
MAT-BH-2400661 V1 Dec 2024