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The immunology of multiple sclerosis

Nature Reviews Immunology volume 22, pages 734–750 (2022)Cite this article

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Abstract

Our incomplete understanding of the causes and pathways involved in the onset and progression of multiple sclerosis (MS) limits our ability to effectively treat this complex neurological disease. Recent studies explore the role of immune cells at different stages of MS and how they interact with cells of the central nervous system (CNS). The findings presented here begin to question the exclusivity of an antigen-specific cause and highlight how seemingly distinct immune cell types can share common functions that drive disease. Innovative techniques further expose new disease-associated immune cell populations and reinforce how environmental context is critical to their phenotype and subsequent role in disease. Importantly, the differentiation of immune cells into a pathogenic state is potentially reversible through therapeutic manipulation. As such, understanding the mechanisms that provide plasticity to causal cell types is likely key to uncoupling these disease processes and may identify novel therapeutic targets that replace the need for cell ablation.

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Fig. 1: Common multiple sclerosis-associated features shared across the immune repertoire.
Fig. 2: Immune surveillance of the brain.
Fig. 3: Multifaceted roles of immune cells in brain pathology in multiple sclerosis.

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Authors and Affiliations

  1. Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Oxford University Hospitals, University of Oxford, Oxford, UK

    Kathrine E. Attfield & Lars Fugger

  2. Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

    Lise Torp Jensen

  3. Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    Max Kaufmann & Manuel A. Friese

  4. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Lars Fugger

Authors
  1. Kathrine E. Attfield
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  2. Lise Torp Jensen
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  3. Max Kaufmann
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  4. Manuel A. Friese
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Contributions

All authors contributed substantially to discussion of the content. K.E.A., L.T.J. and M.A.F. wrote the article. M.K. designed the figures. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Lars Fugger.

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Nature Reviews Immunology thanks B. Becher, T. Korn and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Relapsing–remitting MS

(RRMS). Fluctuations in multiple sclerosis (MS) disease activity involving periods of complete or partial symptom relief (remission) between clinical episodes (relapse).

Primary progressive MS

(PPMS). Clinical worsening of multiple sclerosis (MS) disease from onset, without periods of clinical improvement (remissions).

Natalizumab

Monoclonal antibody against the integrin very late antigen 4 (VLA4) that is used to treat patients with relapsing–remitting multiple sclerosis (RRMS).

Grey matter

Brain tissue that largely consists of unmyelinated, neuronal cell bodies.

White matter

Brain tissue that largely consists of myelinated neuronal axons.

Secondary progressive MS

(SPMS). Patients with relapsing–remitting multiple sclerosis (RRMS) will typically progress into a secondary progressive phase, in which clinical worsening persists without any periods of remission.

T follicular helper cells

(TFH cells). A specialist subset of CD4+ T cells that promote the generation of germinal centres within secondary lymphoid organs where they support B cell proliferation and their development into antibody-producing plasma cells.

Glatiramer acetate

An immunomodulatory drug used to treat relapsing–remitting multiple sclerosis (RMMS), consisting of synthetic polypeptides composed of four amino acids resembling myelin basic protein (MBP).

Unconventional T cells

T cells characterized by their ability to raise public responses to a wide range of antigens compared with the highly specific T cell receptor (TCR) repertoire expressed by conventional T cells.

NKT cells

A subset of CD1d-restricted T cells that express both T cell receptors (TCRs) and receptors of the natural killer (NK) cell lineage.

Innate lymphoid cells

(ILCs). Cells that differentiate from a common innate lymphoid progenitor through the expression of specific transcription factors, with most populations (excluding natural killer (NK) cells), subsequently residing within tissues where they contribute to immune defence and tissue homeostasis.

Fingolimod

A sphingosine-1-phosphate receptor (S1PR) modulator that prevents the movement of lymphocytes out of lymph nodes; used as a treatment for patients with relapsing–remitting multiple sclerosis (RMMS).

Clinically isolated syndrome

(CIS). A clinical event in which neurological symptoms, involving inflammation and/or demyelination in the central nervous system (CNS), last for a period greater than 24 h, which then either fully or partially resolves. CIS may precede the onset of other neurological diseases, including multiple sclerosis (MS).

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Attfield, K.E., Jensen, L.T., Kaufmann, M. et al. The immunology of multiple sclerosis. Nat Rev Immunol 22, 734–750 (2022). https://doi.org/10.1038/s41577-022-00718-z

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