Complement Activation Is Associated With Disease Severity in Multiple Sclerosis
Johanna Oechtering, Kerstin Stein, Sabine Schaedelin, Aleksandra Maleska Maceski, Annette Orleth, Stéphanie Meier, Eline A.J. Willemse, Ferhan Qureshi, Ingmar Heijnen, Axel Regeniter, Tobias Derfuß, Pascal Benkert, Marcus D’Souza, Marguerite Limberg, Bettina Fischer‐Barnicol, Lutz Achtnichts, Stefanie Mueller, Anke Salmen, Patrice H. Lalive, Claire Bridel, Caroline Pot, Renaud Du Pasquier, Claudio Gobbi, Heinz Wiendl, Cristina Granziera, Ludwig Kappos, Marten Trendelenburg, David Leppert, Jan D. Lünemann, Jens Kühle, for the Swiss MS Cohort Study
Abstract
BACKGROUND AND OBJECTIVES: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. METHODS: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. RESULTS: < 0.0001). DISCUSSION: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.