- Article
- Source: Campus Sanofi
- 19 Sep 2025
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 |
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CNS |
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CNS, central nervous system; MS, multiple sclerosis.
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Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
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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

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How do you think the peripheral pathway is involved in MS?
PIRA, progression independent of relapse activity.
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Hernández-Pedro NY, et al. Clin Dev Immunol. 2013;2013:413465. doi:10.1155/2013/413465
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Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
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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
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Acute Neuroinflammation |
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CD4, cluster of differentiation 4.
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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
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Smoldering Neuroinflammation |
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BTK, Burton’s tyrosine kinase.
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Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
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Dal-Bianco A, et al. Acta Neuropathol. 2017;133(1):25-42.
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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
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mAb, monoclonal antibodies.
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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
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BTK expression is increased in lesion tissue in people with progressive MS7 |
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Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201
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Keaney J, et al. J Neuroimmune Pharmacol. 2019;14(3):448-461.
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Alu A, et al. J Hematol Oncol. 2022;15(1):138. doi:10.1186/s13045-022-01353-w
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Frisch ES, et al. Neurotherapeutics. 2021;18(3):1602-1622.
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Dal-Bianco A, et al. Acta Neuropathol. 2017;133(1):25-42.
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Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
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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
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Early control of disability accumulation in addition to relapses and acute lesion activity may improve long-term outcomes1,2 |
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Do you agree or disagree with this? Why or why not?
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Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
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Simpson A, et al. Curr Treat Options Neurol. 2021;23(7):19. doi:10.1007/s11940-021-00677-1
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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
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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
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Optimal management of MS includes controlling relapses, lesions, and disability progression caused by both acute and smoldering neuroinflammation1
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Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
-
Hernández-Pedro NY, et al. Clin Dev Immunol. 2013;2013:413465. doi:10.1155/2013/413465
-
Häusser-Kinzel S, et al. Front Immunol. 2019;10:201. doi:10.3389/fimmu.2019.00201
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Correale J, et al. Mult Scler Relat Disord. 2021;56:103264. doi:10.1016/j.msard.2021.103264
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Frisch ES, et al. Neurotherapeutics. 2021;18(3):1602-1622.
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Lenz KM, et al. Front Immunol. 2018;9:698. doi:10.3389/fimmu.2018.00698
MAT-BH-2400661 V1 Dec 2024