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Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

Aeinehband S, Lindblom RP, Al Nimer F, Vijayaraghavan S, Sandholm K, Khademi M, Olsson T, Nilsson B, Ekdahl KN, Darreh-Shori T, Piehl F - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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. 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 patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. 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.

No MeSH data available.


Related in: MedlinePlus

RRMS clinical relapse activity increase CSF NFL levels, but not BuChE activity or C3.RRMS patients in relapse (n = 16) as compared to patients in remission (n = 17). C3 levels were not affected by clinical disease activity in RRMS (A), while NFL levels were significantly higher after relapse (B). For BuChE activity there was a non-significant (p = 0.06) trend for an increase in patients with a relapse. * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
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pone.0122048.g003: RRMS clinical relapse activity increase CSF NFL levels, but not BuChE activity or C3.RRMS patients in relapse (n = 16) as compared to patients in remission (n = 17). C3 levels were not affected by clinical disease activity in RRMS (A), while NFL levels were significantly higher after relapse (B). For BuChE activity there was a non-significant (p = 0.06) trend for an increase in patients with a relapse. * = p < 0.05; ** = p < 0.01; *** = p < 0.001.

Mentions: In the RRMS group 16 patients had a clinical relapse within 3 months of sampling, while 17 were in remission. CSF levels of C3 were not different between the two groups (Fig 3). In contrast, and as expected, NFL levels were significantly increased in patients with a recent relapse. BuChE activity displayed a non-significant trend (p = 0.061) for an increase in patients with a relapse as compared to patients in remission (Fig 3).


Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

Aeinehband S, Lindblom RP, Al Nimer F, Vijayaraghavan S, Sandholm K, Khademi M, Olsson T, Nilsson B, Ekdahl KN, Darreh-Shori T, Piehl F - PLoS ONE (2015)

RRMS clinical relapse activity increase CSF NFL levels, but not BuChE activity or C3.RRMS patients in relapse (n = 16) as compared to patients in remission (n = 17). C3 levels were not affected by clinical disease activity in RRMS (A), while NFL levels were significantly higher after relapse (B). For BuChE activity there was a non-significant (p = 0.06) trend for an increase in patients with a relapse. * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383591&req=5

pone.0122048.g003: RRMS clinical relapse activity increase CSF NFL levels, but not BuChE activity or C3.RRMS patients in relapse (n = 16) as compared to patients in remission (n = 17). C3 levels were not affected by clinical disease activity in RRMS (A), while NFL levels were significantly higher after relapse (B). For BuChE activity there was a non-significant (p = 0.06) trend for an increase in patients with a relapse. * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Mentions: In the RRMS group 16 patients had a clinical relapse within 3 months of sampling, while 17 were in remission. CSF levels of C3 were not different between the two groups (Fig 3). In contrast, and as expected, NFL levels were significantly increased in patients with a recent relapse. BuChE activity displayed a non-significant trend (p = 0.061) for an increase in patients with a relapse as compared to patients in remission (Fig 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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. 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 patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. 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.

No MeSH data available.


Related in: MedlinePlus