A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis
Open accessAbstract
Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans 1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state 4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.
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These prioritized genes were differentially expressed in MS brain lesion types relative to control white matter.
“These prioritized genes were differentially expressed in MS brain lesion types relative to control white matter26,27 (Supplementary Note, Supplementary Fig. 6).”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [27]
The section “MIMS and AIMS at the chronic active lesion edge” reports genes differentially expressed at that edge relative to control white matter. Extended Data Fig. 9 also maps a list of prioritized MS susceptibility genes, but does not establish that the citing document’s prioritized genes were differentially expressed across MS lesion types. (LLM, conf=0.78)
Experimental — accuracy not yet measuredMicroglia are a salient feature of white and gray matter lesions, representing a major part of ongoing compartmentalized inflammation induced by an initial inflammatory attack.
“Microglia are a salient feature of white and gray matter lesions, representing a major part of ongoing compartmentalized inflammation induced by an initial inflammatory attack (Absinta et al. 2021).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Absinta et al. 2021
The ‘MIMS and AIMS at the chronic active lesion edge’ section identifies inflamed microglia as a substantial immune-cell population in chronic active white-matter lesions, and Extended Data Fig. 4 describes frequent activated microglia at the lesion edge (page numbers unavailable). The paper does not establish the same finding for gray-matter lesions or show that the ongoing inflammation was induced by an initial inflammatory attack. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSignificantly higher expression of immunoglobulin receptors and complement components and their receptors in lesions with foamy microglia indicates increased immunoglobulin-mediated phagocytosis.
“In addition, we observed significantly higher expression of immunoglobulin receptors and complement components and their receptors in lesions with foamy microglia (Supplementary Fig. 6), indicating increased immunoglobulin-mediated phagocytosis11.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [11]
In “MIMS and AIMS at the chronic active lesion edge” (page not available), the paper links MIMS-foamy to myelin phagocytosis, but does not identify it as immunoglobulin-mediated. It reports elevated Fc-gamma receptors and complement components in MIMS-iron, with higher complement C1-complex expression than MIMS-foamy. The citing authors’ expression comparison is their own observation; the source does not establish the proposed mechanism for their foamy-microglia lesions. (LLM, conf=0.85)
Experimental — accuracy not yet measuredReclustering of microglia in the Absinta et al. dataset revealed three microglia clusters across five different MS conditions.
“Reclustering of microglia revealed three microglia clusters across five different MS conditions (Fig. 4 E and F and Dataset S7).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [38]
The Abstract describes subclustering of the dataset, and the section ‘MIMS and AIMS at the chronic active lesion edge’ identifies two inflamed microglial subclusters alongside homeostatic microglia. However, the five sampled tissue settings include normal white matter from neurologically healthy controls, so the source does not support calling all five ‘MS conditions.’ The citing paper’s reclustering is its own analysis, not a result reported by Absinta et al. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn the Absinta et al. dataset, microglial cluster 0 exhibited elevated MAFB expression alongside concurrent expression of microglial markers of activation, including APOE, GPNMB, BHLHE40, and C1QC.
“Among these, cluster 0 exhibited elevated MAFB expression (Fig. 4 G and H) alongside the concurrent expression of microglial markers of activation, including APOE, GPNMB, BHLHE40, and C1QC (Dataset S7).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [38]
The ‘MIMS and AIMS at the chronic active lesion edge’ section lists APOE in an inflamed microglial cluster, and ‘C1q critically mediates microglia activation’ says C1QC is expressed mainly by MIMS (page numbers unavailable). Our copy does not establish elevated MAFB in cluster 0 or concurrent expression there of APOE, GPNMB, BHLHE40, and C1QC; searches for those genes and cluster 0 did not resolve that specific claim. (LLM, conf=0.79)
Experimental — accuracy not yet measured
In the Absinta et al. dataset, microglial cluster 0 primarily consisted of microglia from the edges of chronic active lesions.
“Importantly, cluster 0 primarily consisted of microglia from the edges of chronic active lesions, which are characterized by ongoing inflammatory activity.”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [38]
The ‘MIMS and AIMS at the chronic active lesion edge’ section reports inflamed microglia at those edges, and Extended Data Fig. 4 describes frequent activated microglia there. Our copy does not identify these cells as ‘cluster 0’ or show that cluster 0 primarily consists of cells sampled from those edges; the cluster-specific part of the claim is unsupported. (LLM, conf=0.81)
Experimental — accuracy not yet measuredLPC remyelination DAMs remained enriched for inflammatory genes (Il1b, Cxcl9, Cd69), complement components (C1qa, C3), and hypoxia/glycolysis-associated genes (Mt1, Slc2a1).
“Interestingly, LPC remyelination DAMs remained enriched for inflammatory genes (Il1b, Cxcl9, Cd69), complement components (C1qa, C3), and hypoxia/glycolysis-associated genes (Mt1, Slc2a1), suggesting a continued pro-inflammatory microglial state during LPC remyelination stages (Fig. 5i)13,31–36.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [13]
In “MIMS and AIMS at the chronic active lesion edge” (page unavailable), the paper reports inflammatory IL1B expression and complement C1-complex genes, including C1QA, in microglia from chronic active MS lesions. It does not report gene enrichment in LPC remyelination DAMs or establish the listed Cxcl9, Cd69, C3, Mt1 and Slc2a1 signature during LPC remyelination. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLPC remyelination DAMs suggest a continued pro-inflammatory microglial state during LPC remyelination stages.
“Interestingly, LPC remyelination DAMs remained enriched for inflammatory genes (Il1b, Cxcl9, Cd69), complement components (C1qa, C3), and hypoxia/glycolysis-associated genes (Mt1, Slc2a1), suggesting a continued pro-inflammatory microglial state during LPC remyelination stages (Fig. 5i)13,31–36.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [13]
The 'MIMS and AIMS at the chronic active lesion edge' section (page unavailable) describes microglial enrichment for genes regulating inflammatory responses, and 'C1q critically mediates microglia activation' links C1q to reactive microglia in MS lesions and EAE. These findings support an inflammatory microglial state in those settings, but the cited paper does not establish that LPC remyelination DAMs remain pro-inflammatory during LPC remyelination stages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFeatures present in less than five cells were removed and only high-quality cells were retained, i.e. singlets with more than 200 features and a maximal percentage of mitochondrial RNA content of 15% for scRNA-seq data and 5% for snRNA-seq data.
“Features (genes) present in less than five cells were removed and only high-quality cells were retained, i.e. singlets with more than 200 features and a maximal percentage of mitochondrial RNA content of 15% for scRNA-seq data70 and 5% for snRNA-seq data25,64 (Supplementary Data 2).”
From CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis (2024) · cites this paper as [25]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA subset of microglia defined as 'microglia inflamed in MS' (MIMS) is characterized by neurodegenerative programming, with transcriptional programming overlapping with disease-associated microglia.
“A subset of microglia has been defined as “microglia inflamed in MS” (MIMS) that are characterized by neurodegenerative programming, where the transcriptional programming overlaps with disease-associated microglia (35).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [35]
MIMS-iron have an expression profile suggesting a role in antigen presentation and direct inflammatory damage at the edge of lesions.
“and MIMS-iron, which have an expression profile suggesting a role in antigen presentation and direct inflammatory damage at the edge of lesions (35).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [35]
MIMS-foamy have an expression profile related to foam-cell differentiation, lipid storage, response to lipoprotein particles, and regulation of inflammatory response, suggesting involvement in myelin phagocytosis and clearance.
“Two subsets have been described: MIMS-foamy, which have an expression profile related to foam-cell differentiation, lipid storage, response to lipoprotein particles, and regulation of inflammatory response, suggesting that these cells are involved in myelin phagocytosis and clearance (35);”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [35]
MRI provides high spatial resolution images of the brain but is not inherently sensitive to microglia.
“MRI provides high spatial resolution images of the brain; however, it is not inherently sensitive to microglia (35).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [35]
RNA sequencing identified two distinct microglia clusters in chronic active MS lesions: those involved in myelin phagocytosis and clearance, characterized by upregulation of genes involved in lipid metabolism, and those involved in antigen presentation, characterized by upregulation of genes such as MHC class II, ferritin complex, immunoglobulin Fc-γ receptors, and complement component C1 complex.
“Subsequently, RNA sequencing identified two distinct microglia clusters in chronic active MS lesions: those involved in myelin phagocytosis and clearance, characterized by upregulation of genes involved in lipid metabolism, and those involved in antigen presentation, characterized by upregulation of genes such as the major histocompatibility complex (MHC) class II, ferritin complex, immunoglobulin”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [35]
These included lysosomal enzymes ASAH1, LIPA, CTSA, CTSG, CTSZ, PLA2G15 and PPT1, part of the CLEAR network, as well as PLA2G7.
“Notably, these included the lysosomal enzymes ASAH1, LIPA, CTSA, CTSG, CTSZ, PLA2G15 and PPT1, enzymes part of the Coordinated Lysosomal Expression and Regulation network60, as well as PLA2G7, previously associated with atherosclerotic plaques61 and with the LAM48 and MIMS-foamy microglial states11.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [11]
There was considerable overlap between the Micro_D profile and previously reported microglial states, such as MIMS-foamy, amyloid-associated microglia in Alzheimer's disease and lipid-associated macrophages in obesity.
“There was considerable overlap between the Micro_D profile and previously reported microglial states, such as the MIMS-foamy state reported in ref. 11, amyloid-associated microglia in Alzheimer’s disease43,46,47 and lipid-associated macrophages (LAMs) in obesity48 (Extended Data Fig. 8).”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [11]
Iron rim lesions are characterized by a persistent rim of iron-laden microglia/macrophages and are strongly associated with ongoing tissue damage and lesion expansion.
“These lesions are characterized by a persistent rim of iron-laden microglia/macrophages and are strongly associated with ongoing tissue damage and lesion expansion.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [11]
One hallmark of progressive MS is the presence of slowly expanding demyelinating lesions with smoldering inflammation at their borders, often characterized by iron rims.
“One hallmark of progressive MS is the presence of slowly expanding demyelinating lesions with smoldering inflammation at their borders, often characterized by iron rims6,7,11,13,69.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [11]
Reanalysis of another snRNA-seq dataset from Absinta et al. corroborated coexpression of TREM2 and MAFB in microglia.
“Reanalysis of another snRNA-seq dataset from Absinta et al. (38) corroborated coexpression of TREM2 and MAFB in microglia (SI Appendix, Fig. S9 E–H).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [38]
Human Mg_D strongly expressed genes previously used to describe 'foamy' microglia, such as lipid storage genes LPL and PPARG and the lysosome gene CTSL.
“Human Mg_D strongly expressed genes previously used to describe ‘foamy’ microglia, such as lipid storage genes LPL and PPARG and the lysosome gene CTSL, supporting a role for these cells in clearance of myelin debris13.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [13]
Human Mg_D cells have a role in clearance of myelin debris.
“Human Mg_D strongly expressed genes previously used to describe ‘foamy’ microglia, such as lipid storage genes LPL and PPARG and the lysosome gene CTSL, supporting a role for these cells in clearance of myelin debris13.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [13]
The two predominant modules for MG4 were MS-associated and MIMS-foamy.
“The two predominant modules for MG4 were ‘MS-associated’23 and ‘MIMS-foamy’25 (Fig. 5C).”
From CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis (2024) · cites this paper as [25]
In the Absinta et al. dataset, MAFB was not detected in microglia from the core of chronic lesions.
“MAFB was not detected in microglia from the core of chronic lesions, where the damage to myelin is more extensive and less active, with less inflammation compared to the edges of the lesions (Fig. 4 E and F and Dataset S7).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [38]
The Extended Data passage describes microglia in the lesion core, but does not report whether MAFB was detected in them. Searches of our copy for MAFB and for lesion-core microglial gene expression found no passage establishing the claimed absence. (LLM, conf=0.72)
Experimental — accuracy not yet measuredIn the Absinta et al. dataset, MAFB was not detectable in neurons.
“Conversely, MAFB was not detectable in neurons.”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [38]
The Methods section on human single-nucleus RNA sequencing describes the dataset and its neuronal nuclei, but does not report whether MAFB was detectable in neurons. Searches for “MAFB” and “MAFB not detectable in neurons” found no passage addressing that result. The claim cannot be verified from our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredB2M has been shown to be upregulated in other MS datasets.
“Interestingly, B2M was not significantly upregulated by MOLs in any MS lesion type, however it has been shown to be upregulated in other MS datasets11–13.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [13]
The Extended Data Fig. 6 passage describes reanalysis of other MS datasets, but does not report B2M expression. Searches for B2M and beta-2 microglobulin found no passage in our copy establishing that B2M was upregulated. (LLM, conf=0.70)
Experimental — accuracy not yet measured
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“5i) 13,31 – 36 .”
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- Authors
- Absinta, M., Maric, D., Gharagozloo, M., Garton, T., Smith, M. D., Jin, J., Fitzgerald, K. C., Song, A., Liu, P., Lin, J.-P., Wu, T., Johnson, K. R., McGavern, D. B., Schafer, D. P., Calabresi, P. A., & Reich, D. S.
- Affiliations
- National Institutes of Health (US)
- Johns Hopkins University (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Absinta, Martina
- Reich, Daniel S.
- ORCID
- Venue
- Nature
- Published
- 2021-09-08
- Volume
- 597
- Issue
- 7878
- Pages
- 709-714
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8719282
- OpenAlex
- W3197136220
- Cited by
- 768
- References
- 19
- Citations by year
- 2026: 139 · 2025: 173 · 2024: 192 · 2023: 148 · 2022: 100 · 2021: 14 · 2020: 1
- FWCI
- 77.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (ZIA NS003148)
- National Institute on Aging (R01AG068281)
- National Institute of General Medical Sciences (T32GM136577)
- National Institute of Neurological Disorders and Stroke (R35NS097303, R01NS117533, ZIANS003119, R01NS041435, R01NS082347)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- microglia, astrocytes, lymphocytes, demyelination, white matter lesions, paramagnetic rim lesions, neurodegeneration, experimental autoimmune encephalomyelitis, single-nucleus RNA sequencing, glial phenotype, microglial activation, neuroinflammation
- MeSH terms
- RNA-Seq, Animals, Astrocytes, Brain, Encephalomyelitis, Autoimmune, Experimental, Female, Humans, Inflammation, Lymphocytes, Magnetic Resonance Imaging, Male, Mice, Inbred C57BL, Middle Aged, Multiple Sclerosis, Complement C1q, Microglia, Mice, Transcriptome, White Matter
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