Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis
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Updated: Mar 13, 2026
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Published on: May 31, 2024
Iliana Michailidou1, Daphne M P Naessens1, Simon Hametner2
1Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, Amsterdam, 1105, The Netherlands.
Abstract:
Microglial clusters with C3d deposits are observed in the periplaque of multiple sclerosis (MS) brains and were proposed as early stage of lesion formation. As such they should appear in the brain of MS donors with acute disease but thus far this has not been shown. Using postmortem brain tissue from acute (n = 10) and chronic (n = 15) MS cases we investigated whether C3d+ microglial clusters are part of an acute attack against myelinated axons, which could have implications for disease pathogenesis. The specificity of our findings to MS was tested in ischemic stroke cases (n = 8) with initial or advanced lesions and further analyzed in experimental traumatic brain injury (TBI, n = 26), as both conditions are primarily nondemyelinating but share essential features of neurodegeneration with MS lesions. C3d+ microglial clusters were found in chronic but not acute MS. They were not associated with antibody deposits or terminal complement activation. They were linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production. C3d+ microglial clusters were not specific to MS as they were also found in stroke and experimental TBI. We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons. As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease. GLIA 2017;65:264-277.
Insights
Microglial clusters with C3d deposits are not involved in acute multiple sclerosis (MS) attacks. These clusters appear in chronic MS and other neurological conditions, suggesting a role in clearing damaged axons rather than causing new lesions.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglial clusters with C3d deposits are found in multiple sclerosis (MS) lesions.
- These clusters were hypothesized to represent early stages of MS lesion formation.
- Previous studies have not confirmed their presence in acute MS cases.
Purpose of the Study:
- To investigate the presence and role of C3d+ microglial clusters in acute and chronic MS.
- To determine if these clusters are specific to MS or also occur in other neurological conditions.
- To elucidate the potential contribution of C3d+ microglial clusters to MS pathogenesis.
Main Methods:
- Analysis of postmortem brain tissue from acute and chronic MS patients.
- Examination of brain tissue from ischemic stroke and experimental traumatic brain injury (TBI) cases.
- Immunohistochemical staining for C3d, microglial markers, and axonal transport indicators.
Main Results:
- C3d+ microglial clusters were identified in chronic MS, but not in acute MS.
- These clusters were associated with slowly expanding lesions and impaired axonal transport.
- C3d+ microglial clusters were also observed in stroke and TBI, indicating a lack of MS specificity.
- No association with antibody deposits or terminal complement activation was found.
Conclusions:
- C3d+ microglial clusters are not indicative of an acute attack on myelinated axons in MS.
- These clusters are unlikely to drive new lesion formation in MS.
- They may represent a mechanism for clearing irreversibly damaged axons in chronic neurodegenerative conditions.
