May 1, 2015

Researchers link the complement system, an integral part of the body’s immune network, to multiple sclerosis disease progression


Multiple Sclerosis (MS) is a disease in which the body’s immune system attacks the central nervous system (CNS).  Understanding why and how the immune system malfunctions is therefore vital to better understanding the disease and developing new therapies. To date, researchers have made multiple breakthroughs, linking various aspects of the immune system to MS disease progression. A group of proteins, which make up part of the immune network called the complement system, boosts the immune system’s ability to efficiently and rapidly combat infection. Dysfunction of the complement system has been associated with numerous neurodegenerative diseases, and more recently, with MS. For example, complement system proteins were recently shown to reside within MS brain lesions. However, little is known whether the complement system’s activity is directly related to MS disease; its course and severity.

To address this possible relationship, a team of researchers from Sweden, led by Dr. Fredrik Piehl, focused on the protein C3, a marker for complement system activity, and butyrylcholinesterase (BuCHe), an enzyme previously shown to influence C3 activity following nerve damage. Their findings were published in the online journal PLoS ONE.

The Study

Cerebral spinal fluid (CSF) was collected from 48 participants with MS and compared to CSF samples from 18 control participants without MS. The MS group included 33 individuals with relapsing-remitting MS, 9 with secondary-progressive MS and 6 with primary-progressive MS.

Proteins of interest were isolated from CSF samples and measured. Researchers focused on three proteins: (1) the complement system protein C3, (2) the enzyme BuCHe, and (3) neurofilament light (NFL) protein, a molecule that is indicative of neurodegeneration (nerve damage) in MS. Protein levels were compared between MS and control groups, as well as within the MS group to determine if proteins levels were associated with degree of disability (assessed using the Expanded Disability Status Score (EDSS)), MS subtype, and total number of brain lesions as seen on magnetic resonance imaging.


The MS group had significantly higher levels of C3 protein – suggesting greater complement system activation – relative to the control group. The highest levels of C3 protein were found in individuals with 9 or more brain lesions and in those with the progressive form of the disease.

The researchers also observed higher C3 levels in individuals with greater neurodegeneration and increased disability, as evidenced by increased levels of neurodegeneration marker NFL and changes in EDSS.

In contrast, activity of BuCHe did not differ between the MS cohort and the control group. However, BuCHe activity did significantly correlate to both C3 and NFL levels within the MS group; i.e. when BuCHe activity increased, C3 and NFL concentrations followed suit.


The data builds on previous work, reinforcing a role for the immune complement system in MS. It further establishes a link between the protein C3 (and, by extension, the complement system) and (1) ongoing neurodegeneration (NFL levels), (2) the enzyme BuCHe (which was previously shown to influence C3 activity following nerve damage) and (3) degree of disability in MS. The findings also suggest that the complement system may have a prominent role in the more chronic or aggressive form of the disease as C3 was found to be higher in both the progressive groups and in individuals with 9 or more brain lesions.

However, as the authors note, the studies are preliminary and consist of a small group of participants, particularly the primary-progressive group that was made up of only 6 individuals. Despite its limitations, the study does support previous findings and raises questions worthy of further investigation. More work needs to be done to establish how the complement system is regulated in MS and whether its activation is a primary cause, or consequence, of the disease.


Aeinehband S et al. (2015). Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis. PLoS ONE. 10(4): e0122048