B cells & MS: see the clinical connection

Multiple sclerosis (MS) is characterised by ongoing disease activity, both clinical and subclinical, which can predict future disability and lead to permanent damage.1-3

Subclinical disease activity, which is revealed by MS lesions, may be assessed by magnetic resonance imaging (MRI). MS-associated lesions are a result of demyelination caused by lymphocytes, including B cells.4,5

B cells are important drivers of ongoing disease activity in MS.4,6

B Cells Are Present in MS

B cells are largely present in the central nervous system (CNS) of patients with MS, but are largely absent from the CNS of healthy controls.7,8

Frischer JM, et al. Brain 2009;132(pt 5):1175-89. Reused under Creative Commons license CC BY-NC 2.0 UK.
PPMS = primary-progressive MS; RRMS = relapsing-remitting MS; SPMS = secondary-progressive MS.
* Normal controls typically exhibit few B cells in the CNS.

B cells are drivers of disease progression in MS

  • Demyelinating lesions are a hallmark of disease activity in MS9
  • A CNS lesion is commonly characterised by indefinite margins, demyelination, and notably dense populations of many types of immune cells around a blood vessel, including T and B cells9
  • The appearance of new lesions can significantly increase the risk of disability progression, even in the absence of clinical relapses1
Image adapted from Rovira A, Alonso J, Cucurella G, et al. AJNR Am J Neuroradiol 1999;20(10):1939-45 © the American Society of Neuroradiology.

RRMS

  • Relapsing-remitting MS (RRMS) phenotypes can be described as either active or not active, with active disease characterised by MRI activity and/or clinical relapses10
  • In RRMS, MRI scans usually reveal multiple small periventricular lesions, resulting from focal inflammation5,11
  • CD20+ B cells are frequently found in the cerebrospinal fluid (CSF) of patients with all forms of MS.6 In patients with RRMS, elevated B-cell levels in the CSF correlate with an enhanced disease progression rate7
Image adapted from Castriota Scanderberg A, Tomaiuolo F, Sabatini U, Nocentini U, Grasso MG, Caltagirone C., from the Departments of Radiology and Neurology, IRCCS, S. Lucia, Rome, Italy; and from the Department of Neurology, University Tor Vergata, Rome, Italy. AJNR Am J Neuroradiol 2000;21(5):862-8 © the American Society of Neuroradiology.

PPMS

  • Primary progressive MS (PPMS) is part of the spectrum of progressive MS and is likely not pathophysiologically distinct from relapsing MS that has entered a progressive course10
  • On MRI, up to 42% of patients with PPMS (mean disease duration 3.3 years) have gadolinium-enhanced lesions13
  • The diffuse meningeal inflammation in PPMS is associated with demyelinating pathology that contains B-cell infiltrates and is linked to severe clinical progression14

Disease activity results from B and T cells crossing the blood brain barrier (BBB) into the CNS

In normal homeostasis, immune cell access to the CNS is limited but not prevented by the BBB.15

In the formation of an MS lesion, autoreactive immune cells, including activated B and T cells, transit from the bloodstream to the CNS and proliferate following an interaction with a target self-neuroantigen.15,16

The hypercellularity around the blood vessel indicates cell proliferation and the breakdown of the BBB due to the release of inflammatory cytokines from these autoreactive cells.9,15,17


B cells can contribute to the pathophysiology of MS

Once inside the CNS, B cells have the capacity to influence the underlying pathophysiology of MS through several key roles:

Artist conceptualization of inflammation and neurodegeneration within the CNS

  • Antigen presentation: Autoreactive B cells in the CNS present self-neuroantigens, which abnormally activate T cells and the T-cell proliferation response against neural tissue, resulting in autoimmunity4,6
  • Cytokine production: B cells in patients with MS produce more proinflammatory cytokines than in people without the disease.18 This increased production results in a reduced ability to regulate other immune responses18,19
  • Autoantibody production: Autoreactive B cells drive the production of autoantibodies against neural tissue, which contributes to injury.4 B-cell antibodies can also activate other immune cells, including macrophages and natural killer cells, to destroy tissue20
  • Ectopic lymphoid follicle-like aggregates: In progressive MS, accumulation of B cells, T cells, and follicular dendritic cells can form in the meninges.21,22 These aggregates are linked to microglial activation, local inflammation, and neuronal loss in the nearby cortex

References

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  • 8. Frischer JM, et al. Brain 2009;132(pt 5):1175–89.
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  • 12. Lublin FD, et al. Neurology 2014;83:1–9.
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  • 16. Hartung HP, et al. Handbook of Clinical Neurology 2014;122(3rd series):3–14.
  • 17. Palmer AM. Cardiovasc Psychiatry Neurology 2013;2013:530356.
  • 18. Bar-Or A, et al. Ann Neurol 2010;67(4):452–61.
  • 19. Duddy M, et al. J Immunol 2007;178(10):6092–9.
  • 20. Weber MS, et al. Biochem Biophys Acta 2011;1812(2):239–45.
  • 21. Serafini B, et al. Brain Pathol 2004;14(2):164–74.
  • 22. Magliozzi R, et al. Ann Neurol 2010;68(4):477–93.