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. 2015 Apr 2;10(4):e0122048.
doi: 10.1371/journal.pone.0122048. eCollection 2015.

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

Affiliations

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

Shahin Aeinehband et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Levels of C3 in cerebrospinal fluid are increased in patients with MS and correlate with MRI lesions, clinical disability and levels of NFL.
CSF was obtained from 48 patients diagnosed with RRMS, SPMS or PPMS and 18 controls with other neurological/psychiatric diseases (OND). Protein quantification demonstrates increased levels of C3 in the CSF of MS patients compared to controls, with higher levels in patients with progressive disease, especially PPMS (A). Levels of NFL, a marker of neurodegeneration, are also increased in MS patients compared to controls (B). Patients with 9 or more MRI lesions at the time of sampling have significantly higher C3 levels (C) and a non-significant increase in NFL levels (D). C3 levels correlate with degree of clinical disability as assessed with EDSS (E), and NFL (F). * = p < 0.05; ** = p < 0.01; *** = p < 0.001.
Fig 2
Fig 2. BuChE activity, but not AChE activity, correlates with levels of C3 and NFL.
BuChE activity was not different between MS patients and controls at the group level, however, with a large spread within groups (A). A highly significant correlation between BuChE activity and C3 levels is evident (B). Also, BuChE activity correlated with levels of NFL (C) and demonstrates a close to significant trend for correlation to EDSS (D). Interestingly, AChE activity differs between MS patients and controls (E), but lacks correlation to C3 at the individual level (F). *p = < 0.05; ** = p < 0.01; *** = p < 0.001.
Fig 3
Fig 3. 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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