Immunological Mechanisms in Multiple Sclerosis Pathophysiology and Therapy

Multiple sclerosis (MS) is driven by a complex interplay of adaptive and innate immune processes that breach central nervous system (CNS) immune privilege. Autoreactive CD4+ T cells, notably T helper 1 (Th1) and T helper 17 (Th17) subsets, infiltrate the CNS after blood–brain barrier disruption and orchestrate local inflammation through cytokine release and microglial activation. B cells contribute via antigen presentation, cytokine secretion and intrathecal immunoglobulin production, often localised within meningeal lymphoid‐like structures. Complement activation intensifies oligodendrocyte injury, while aberrant antibody responses against myelin proteins amplify demyelination. Single‐cell profiling has revealed compartmentalised immune landscapes in blood and cerebrospinal fluid (CSF), with expanded follicular helper T cells and specialised B‐cell subsets sustaining chronic inflammation. Therapeutic strategies have evolved from broad immunosuppression to targeted modulation, exemplified by monoclonal antibodies against CD20 and α4‐integrin, sphingosine 1‐phosphate receptor modulators, and emerging approaches to promote remyelination and immune tolerance. Integrating mechanistic insights with precision immunotherapy offers promise for both relapsing–remitting and progressive forms of MS, aiming to minimise neurodegeneration while preserving immune competence.

Research from Nature Portfolio

Integrated single‐cell transcriptomic analyses of paired blood and CSF leukocytes have uncovered a high diversity of CNS‐associated immune phenotypes. In MS patients, CSF exhibits an expanded population of follicular helper T cells that co‐localise with B cells in perivascular spaces, implicating local T–B cooperation in driving intrathecal antibody synthesis. A novel analytical framework identified cell‐type‐agnostic enrichment of B‐lineage and cytotoxic T‐helper programmes, suggesting that immune mechanisms in MS are highly compartmentalised. In murine models, blockade of these follicular helper signals reduced B‐cell infiltration and ameliorated disease severity, highlighting new targets for intervention.

Immunological Mechanisms in Multiple Sclerosis Pathophysiology and Therapy publication trend

The graph below shows the total number of articles in immunological mechanisms in multiple sclerosis pathophysiology and therapy across all publications each year (not limited to Nature Index journals).

Technical terms

T follicular helper (TFH) cells: CD4+ T‐cell subset specialised in supporting B‐cell maturation and antibody production within germinal centres.

Antibody‐secreting cells (ASCs): Differentiated B cells, including plasmablasts and plasma cells, responsible for producing and releasing immunoglobulins.

Oligoclonal bands: Discrete immunoglobulin G bands in CSF electrophoresis indicative of intrathecal antibody synthesis.

Complement‐dependent cytotoxicity: Immune mechanism whereby antibody binding activates the complement cascade, leading to cell lysis.

CD20: Surface antigen expressed primarily on B cells and a subset of T cells, targeted by monoclonal antibody therapies in MS.

References

1. Pathogenic myelin specific antibodies in multiple sclerosis target conformational proteolipid protein 1 anchored membrane domains. Journal of Clinical Investigation (2023).
2. Selective emergence of antibody-secreting cells in the multiple sclerosis brain. EBioMedicine (2023).
3. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nature Communications (2020).
4. Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity. Proceedings of the National Academy of Sciences of the United States of America (2023).