Systemic complement profiling in multiple sclerosis as a biomarker of disease state

Abstract

Background:There is increasing evidence of significant and dynamic systemic activation and upregulation of complement in multiple sclerosis (MS), which may contribute to disease pathogenesis.Objective:We aimed to investigate the pathological role of complement in MS and the potential role for complement profiling as a biomarker of MS disease state.Methods:Key components of the classical, alternative and terminal pathways of complement were measured in plasma and cerebrospinal fluid (CSF) of patients with MS in different clinical phases of disease and in matched controls.Results:Increased plasma levels of C3 (p<0.003), C4 (p<0.001), C4a (p<0.001), C1 inhibitor (p<0.001), and factor H (p<0.001), and reduced levels of C9 (p<0.001) were observed in MS patients compared with controls. Combined profiling of these analytes produced a statistical model with a predictive value of 97% for MS and 73% for clinical relapse when combined with selected demographic data. CSF-plasma correlations suggested that source of synthesis of these components was both systemic and central.Conclusion:These data provide further evidence of alterations in both local and systemic expression and activation of complement in MS and suggest that complement profiling may be informative as a biomarker of MS disease, although further work is needed to determine its use in distinguishing MS from its differential.

TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice

“…In this study, we focused on complement components previously shown to play a role in the pathogenesis of autoimmune brain disease. C3, C4 and C6 have been implicated in EAE, a model for multiple sclerosis [49–51]. Moreover, C3 and C4 have been reported to be involved in the pathogenesis of NPSLE [26, 52, 53].…”

Complement system biomarkers in epilepsy

“…This physiological process has also been implicated in pathological synapse elimination in the context of schizophrenia and dementia [37][38][39]. Increased levels of C1q and iC3b (classical complement pathway markers) were reported in human brain samples in focal cortical dysplasia [31], suggesting that aberrant complement activation occurs in patients with drug resistant seizures. Our current study suggests that dysregulation of the classical (C1inh, C4), alternative (FH, properdin, C3) and terminal (TCC) pathways also contribute to epilepsy pathogenesis.…”

“…Total protein concentration (µg/ml) was automatically calculated by reference to the standard curve using GraphPad Prism version 5 (La Jolla, CA, USA). Detection limits, working ranges and assay performance were determined as described [31], using serum from local healthy controls.…”

Plasma complement biomarkers distinguish multiple sclerosis and neuromyelitis optica spectrum disorder

“…We previously reported that plasma levels of Bb and TCC were not elevated in MS compared to controls, while C4a was elevated but only in acute relapse. 34,35 These data demonstrate that complement activation represents a fundamental difference between the two diseases; peripheral evidence of complement activation (impacting all pathways) is specific to NMOSD. We concur with the conclusion of Tuzun et al that NMOSD differs from MS "by predominance of complement system involvement".…”