Wednesday, 8 April 2015

Complement activation in MS

Complement levels correlate with spinal fluid neurofilament levels. #MSBlog #MSResearch

"Systems biology and biomarkers meet. The study below tests an hypothesis based on genomic studies linking complement, an inflammatory mediator of the innate immune system, to a downstream gene product called butyrylcholinesterase. The latter is an enzyme that breaks down the neurotransmitter acetylcholine. The hypothesis is that if complement is upregulated in MS by inflammation then so should the enzyme butyrylcholinesterase as they are close together in the genome. A simple way to think of this is that if you unwind and start reading the part of the genome, or DNA, that encodes the gene for complement, the so called transcriptional machinery is likely to read  past the complement gene and also read the butyrylcholinesterase gene that is downstream of the complement gene on the DNA strand. Interestingly, in individual MSers there was a correlation between complement component 3 (C3) levels and butyrylcholinesterase supporting their hypothesis."

"What is interesting is that there was a correlation between C3 levels and neurofilament levels, and disability, suggesting that C3, a marker of innate immunity, is involved in neuronal damage in MS."

"What is complement? Complement is a family of proteins that are responsible for damaging and killing foreign cells or microbes. In MS there is evidence that complement is part of the complex reaction that damages myelin producing cells and neurones. There are many ways to activate the complement cascade, but one way that has been shown to occur in MS is via antibody recognition of a target protein that then causes the antibody to expose a segment on its tail that is capable of recruiting and activating the complement cascade that eventually leads to killing of the relevant cell by the so called membrane attack complex (MAC). C3 is a major complement component and sits at the junction the so called classical, alternative and lectin-induced complement pathways (see image below). There have been numerous studies showing antibody and complement activation in acute MS lesions. What is not known is what antigen is responsible for the antibody binding in MS. If we knew that then we would be one step closer to finding the cause of MS."

"I like this study because it is hypothesis driven and also supports using spinal fluid neurofilament levels (my favourite biomarker) as a marker of damage in MS; another reason why we need to fully recruit for the PROXIMUS trial to see if we can use NF as a response marker in neuroprotection trials."

Aeinehband et al. Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis. PLoS One. 2015 Apr 2;10(4):e0122048.

Background: Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. 

Methods: We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from MSers (n = 48) and non-inflammatory controls (n = 18). 

Results: C3 levels were elevated in MSers compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in MSers with ≥9 cerebral lesions on magnetic resonance imaging and in MSers with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. 

Conclusion: In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

1 comment:

  1. What are the target cells for MAPs in the CNS? If they interact with neurons, what is the effect on ion flow and membrane potential?


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