Aberrant Complement Activation Is Associated With Structural Brain Damage in Multiple Sclerosis
Johanna Oechtering, Sabine Schädelin, Kerstin Stein, Aleksandra Maleska Maceski, Lester Melie‐García, Pascal Benkert, Alessandro Cagol, Selina Leber, Riccardo Galbusera, Esther Ruberte, Wayne Hu, Ferhan Qureshi, Annette Orleth, Lilian Demuth, Eline Willemse, Ingmar Heijnen, Axel Regeniter, Tobias Derfuß, Bettina Fischer‐Barnicol, Lutz Achtnichts, Stefanie Mueller, Robert Hoepner, Patrice H. Lalive, Claire Bridel, Marcus D’Souza, Caroline Pot, Renaud Du Pasquier, Claudio Gobbi, Chiara Zecca, Heinz Wiendl, Johanna M. Lieb, Christina Lamers, Ludwig Kappos, Marten Trendelenburg, David Leppert, Cristina Granziera, Jens Kühle, Jan D. Lünemann, and the Swiss MS Cohort Study
Abstract
BACKGROUND AND OBJECTIVES: Levels of activated complement proteins in the CSF are increased in people with multiple sclerosis (MS) and are associated with clinical disease severity. In this study, we determined whether complement activation profiles track with quantitative MRI metrics and liquid biomarkers indicative of disease activity and progression. METHODS: Complement components and activation products (Factor H and I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a, and sC5b-9) and liquid biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], CXCL-13, CXCL-9, and IL-12b) were quantified in the CSF of 112 patients with clinically isolated syndromes and 127 patients with MS; longitudinal MRIs according to a standardized protocol of the Swiss MS cohort were assessed. We used multivariable models to analyze associations of the 12 complement parameters as individual independent variables and longitudinal brain volumes, T2-weighted (T2w) lesion volumes, contrast-enhancing (CELs) and paramagnetic rim lesions (PRLs), and molecular biomarkers as dependent variables, respectively. RESULTS: = 0.006) increased PRL incidence rates. C1q, C3a, and C4a were associated with higher GFAP levels, and CXCL-13, CXCL-9, and IL-12b analyses showed consistent patterns with strongest associations for C1q, followed by Ba, C3a, and C4a. DISCUSSION: Intrathecal complement activation is consistently associated with MRI metrics and liquid biomarkers indicative for MS disease activity and progression. Our results demonstrate that aberrant complement activation is strongly associated with structural brain damage in MS. Therapeutic targeting of the complement system might limit disability accumulation due to MS.