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Updated: Aug 13, 2026
Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin
Published on: March 26, 2015
Complement and demyelinating disease: no MAC needed?
Scott R Barnum1, Alexander J Szalai
1Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sbarnum@uab.edu
Insights
The complement system
Area of Science:
- Neuroimmunology
- Complement System Biology
Background:
- The complement system's role in demyelinating diseases, like multiple sclerosis, is traditionally attributed to the Membrane Attack Complex (MAC).
- Previous understanding implicated MAC-mediated lysis of oligodendrocytes and neurons in disease pathogenesis.
Purpose of the Study:
- To investigate the specific roles of complement system components, particularly C3 and C5, in the pathogenesis of experimental autoimmune encephalomyelitis (EAE).
- To re-evaluate the contribution of the MAC versus other complement fragments in demyelinating disease.
Main Methods:
- Utilized genetically modified mouse models, including knockout mice for C3, C5, and their respective receptors, as well as transgenic mice with CNS-specific expression of C5a.
- Assessed the frequency and intensity of EAE development in these models compared to wild-type counterparts.
Main Results:
- Mice lacking C5 or the C5a receptor developed EAE with similar severity to wild-type mice, challenging the role of MAC.
- Mice lacking C3 or its receptors showed attenuated EAE, while CNS-specific C3a expression led to severe EAE.
- These findings indicate non-MAC-mediated mechanisms involving C3 fragments are crucial in EAE.
Conclusions:
- C3-derived fragments, not C5 and the MAC, are likely the primary drivers of complement-mediated pathology in EAE.
- This study reframes the understanding of complement's role in demyelinating diseases, highlighting C3a's pathogenic significance.
Abstract:
It has long been accepted that the complement system participates in the onset, evolution, and exacerbation of demyelinating disease, and it is widely suspected that this is accomplished mainly via destruction of nervous tissue by membrane attack complex (MAC)-mediated lysis of oligodendrocytes and neurons. However, recent studies using mutant mice indicate the MAC may not be so important. For example, mice lacking C5 and mice lacking the C5a receptor both develop experimental autoimmune encephalomyelitis (EAE) with the same frequency and intensity as their wild type counterparts. Also, transgenic mice that express C5a exclusively in the central nervous system (CNS) develop EAE that is not remarkably different from that in non-transgenic littermates. Since C5 is required for formation of the MAC, development of fulminant EAE in the absence of this complement protein demonstrates that non-complement-mediated mechanisms of CNS damage are operating. Paradoxically, mice lacking C3, mice lacking the C3a receptor, and mice lacking the complement receptor type 3 develop attenuated EAE, while mice that express C3a exclusively in the CNS develop severe and often fulminant EAE. Based on these newer data, we posit that C3-derived biologically active fragments, rather than C5 and the MAC, are central players in the pathophysiology of complement in EAE.
