The Alternative and Terminal Pathways of Complement Mediate Post-Traumatic Spinal Cord Inflammation and Injury

American Journal of Pathology, 2010 · DOI: 10.2353/ajpath.2010.100158 · Published: December 1, 2010

Simple Explanation

This study investigates the role of the alternative and terminal complement pathways in spinal cord injury (SCI). The complement system, part of the immune system, can cause inflammation and further damage after SCI. The researchers found that mice lacking a protein (factor B) in the alternative pathway were protected from SCI. This protection included reduced tissue damage, less inflammation, and improved recovery. Conversely, mice lacking CD59, which inhibits the terminal pathway, experienced worse injury and impaired recovery. This suggests that both pathways contribute to the harmful effects of complement after SCI.

Study Duration

21 days

Participants

Female C57BL/6 mice, 6-8 weeks old

Evidence Level

Not specified

Key Findings

1
Mice deficient in factor B (fB), a protein in the alternative complement pathway, were protected from traumatic SCI, showing reduced tissue damage, demyelination, and inflammatory cell infiltrate.
2
Treatment with an anti-fB monoclonal antibody (mAb) in wild-type mice resulted in improved outcomes similar to those observed in fB-deficient mice, suggesting a therapeutic potential for alternative pathway inhibition.
3
Deficiency of CD59, an inhibitor of the membrane attack complex (MAC), resulted in significantly increased injury and impaired functional recovery compared to wild-type mice, indicating a role for the terminal complement pathway in SCI pathology.

Research Summary

This study demonstrates that the alternative and terminal complement pathways play key roles in the pathophysiology of spinal cord injury (SCI). Mice deficient in factor B (fB), a component of the alternative pathway, showed improved outcomes after SCI. Treatment with an anti-fB monoclonal antibody (mAb) also resulted in improved outcomes, suggesting a potential therapeutic strategy. Conversely, mice deficient in CD59, an inhibitor of the terminal pathway, experienced worsened injury and impaired recovery. The findings suggest that the alternative pathway amplifies classical pathway-initiated complement activation, and that both alternative and terminal pathways contribute to inflammation and secondary neuronal damage after SCI.

Practical Implications

Therapeutic Target Identification

The alternative complement pathway is a potential therapeutic target for SCI.

Clinical Relevance

Selective inhibition of the alternative complement pathway may be less immunosuppressive than inhibiting all pathways at the C3 activation step.

Terminal Pathway Inhibition

Selective inhibition of the terminal pathway could potentially have even greater benefit over blocking complement at an early step in any pathway because the MAC plays a very limited known role in host defense.

Study Limitations

1
The study was performed on mice and may not fully translate to human SCI.
2
The weight-drop method was used which may not reflect the spectrum of human SCI.
3
The study focused on early time points after SCI (up to 21 days) and did not assess long-term outcomes.

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