Complement Activation: A Key Player in Multiple Sclerosis Severity
A recent study has shed light on the role of complement activation in multiple sclerosis (MS), revealing its association with disease severity. The study, published in *Neurology: Neuroimmunology & Neuroinflammation*, investigated complement components (CCs) and complement activation products (CAPs) in patients with MS, and how they relate to disease progression.
What is the Complement System?
The complement system is part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promotes inflammation, and attacks the pathogen's cell membrane.
Key Findings:
* Elevated Complement Activation in CSF: The study found increased levels of complement activation products (C3a, C4a, Ba, and Bb) in the cerebrospinal fluid (CSF) of patients with clinically isolated syndrome (CIS) and MS compared to symptomatic controls. This suggests that complement activation is happening within the central nervous system (CNS) in MS patients.
* Intrathecal IgM Production Matters: The increase in complement components was more evident in MS patients who also had intrathecal IgM production, meaning IgM antibodies were being produced within the CNS. IgM is known to be a strong activator of the classical complement pathway.
* Association with Disease Severity: Higher levels of complement activation products in the CSF correlated with:
* Increased Expanded Disability Status Scale (EDSS) scores at the time of lumbar puncture in CIS patients.
* Higher MS Severity Scores (MSSS) in the future for CIS/MS patients.
* Elevated neurofilament light chain (NfL) levels in CSF, a marker of neuroaxonal damage.
* Classical and Alternative Pathways: The study points to the activation of both the classical and alternative complement pathways in MS. The classical pathway is typically triggered by antibodies, while the alternative pathway can amplify the complement response.
* Compartmentalized Inflammation: The study suggests that complement activation is more pronounced in the CNS, as opposed to the bloodstream. Few differences were observed in plasma levels of complement components and activation products between MS patients and symptomatic controls. This highlights the concept of compartmentalized inflammation in MS, where the immune response within the brain and spinal cord differs from that in the rest of the body.
The Significance:
These findings support the idea that complement activation contributes to the pathology and progression of MS. By linking complement activation to disability scores (EDSS and MSSS) and neuroaxonal damage (NfL levels), the study strengthens the argument that the complement system is a key player in the disease.
Potential Therapeutic Implications:
The authors suggest that complement inhibition should be explored as a therapeutic target to potentially slow down disease progression and reduce disease severity in MS. Several preclinical studies in experimental autoimmune encephalomyelitis (EAE) models have shown that reducing complement activation can protect against neural tissue damage. Therefore, complement inhibition beyond the blood-brain barrier might be a novel therapeutic approach to attenuate disease severity in MS and might be one of the highly needed tools to combat ongoing smoldering progression.
Study Details:
* Participants: The study included 112 patients with CIS, 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease controls, and 44 symptomatic controls.
* Methods: Complement components and activation product levels were measured in CSF and plasma samples. Statistical analyses were performed to compare levels between groups and assess associations with clinical parameters.
* Follow-up: Patients with CIS/MS were followed for a median of 6.3 years.
Caveats:
One limitation of this study is the absence of MRI data. Future studies should aim to validate these results with MRI findings and investigate the effects of MS treatments on complement component and activation product levels over time.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Oechtering, J., Stein, K., Schaedelin, S. A., Maceski, A. M., Orleth, A., Meier, S., ... & Swiss MS Cohort Study. (2024). Complement activation is associated with disease severity in multiple sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 11(2), e200212.
