Immunopathogenesis of Multiple Sclerosis

Multiple sclerosis is an immune‐mediated disorder of the central nervous system characterised by focal demyelination, neuroaxonal injury and a progressive loss of neurological function. Its immunopathogenesis involves a complex interplay between adaptive and innate immune processes. Autoreactive T lymphocytes, in particular CD4+ and CD8+ subsets, breach the blood–brain barrier and initiate an inflammatory cascade that recruits B cells, macrophages and microglia. B cells contribute not only through antibody production but also via antigen presentation and cytokine secretion. Innate immune cells such as microglia adopt disease‐associated phenotypes that propagate local inflammation and tissue injury. Complement activation and metabolic dysfunction within infiltrating lymphocytes and resident glia further amplify damage to myelin and axons. Concurrently, failure of remyelination mechanisms, driven by oligodendrocyte precursor cells, underlies chronic lesion expansion and disability progression. Advances in high‐resolution imaging and spatial transcriptomics have begun to reveal lesion heterogeneity, ranging from actively demyelinating, rim‐enriched lesions to smouldering plaques. Understanding these pathogenic mechanisms has underpinned the development of therapies targeting lymphocyte trafficking, B cell depletion and molecular mediators of CNS‐intrinsic inflammation, with the ultimate aim of halting or reversing neurodegeneration in multiple sclerosis.

Research from Nature Portfolio

Recent studies have identified a novel lesion subtype characterised by broad myeloid rims rich in activated innate immune cells. Spatial transcriptomic analyses of post‐mortem tissue have revealed that these lesions exhibit inflammatory cytokine signatures, unfolded protein responses and apoptotic pathways linked to rapid clinical progression. A separate investigation into microglia nodules in multiple sclerosis has demonstrated that these clustered HLA-DR+ microglial aggregates possess heightened expression of lipid‐metabolism genes, complement components and immunoglobulin receptors. Some nodules were found to envelop partially demyelinated axons, suggesting an early stage of lesion formation. Together, these findings delineate CNS‐intrinsic inflammatory mechanisms and point to biomarkers for disease activity and potential targets for therapies aimed at the innate immune compartment.

Immunopathogenesis of Multiple Sclerosis publication trend

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

Technical terms

Broad rim lesions: A subtype of MS lesion marked by an outer zone of activated myeloid cells with pro‐inflammatory transcriptional profiles.

Microglia nodules: Clusters of activated microglial cells that may represent early foci of demyelination and axonal damage.

Spatial transcriptomics: A technology that maps gene expression within tissue sections, preserving spatial context of pathological features.

Experimental autoimmune encephalomyelitis (EAE): An animal model of MS induced by immunisation to study immune mechanisms and potential therapies.

Metabolic reprogramming: Alterations in cellular energy pathways, such as mitochondrial dysfunction, that affect immune‐cell function and inflammatory responses.

References

1. Broad rim lesions are a new pathological and imaging biomarker for rapid disease progression in multiple sclerosis. Nature Medicine (2025).
2. Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology. Cell (2024).
3. Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation. Nature Communications (2024).
4. Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions. Acta Neuropathologica (2024).
5. Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis. Journal of Neuroinflammation (2024).
6. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain and Behavior (2015).