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.

Figure 1.

Plasma levels of C3, C4, fH and C1 inhibitor were increased and plasma levels of C9 were decreased in MS patients compared with normal controls.

Figure 2.

Receiver operated characteristic (ROC) curve to predict the probability of MS compared to control subjects. Combined model C statistic 0.97. For the individual components of the model; C3 C statistic 0.67, C9 C statistic 0.14, C1inh C statistic 0.83 and fH C statistic 0.76.

Figure 3.

ROC curve to predict the probability of A-RRMS from S-RRMS. Combined model C statistic 0.73. For the individual components of the model; C9 C statistic 0.63, disease duration C statistic 0.53 and age C statistic 0.34.

Figure 4.

Plasma factor H levels post relapse. A reduction in plasma factor H is seen post relapse in 26 of 44 patients at 2-3 months and 30 of 44 patients at 5-7 months. Mean levels are significantly reduced at both time points (p=0.013 at 2–3 months and p=0.007 at 5–7 months).