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Updated: Jul 3, 2025
Author Spotlight: Novel Assay for Studying B-Cell Responses in Multiple Sclerosis Research
Published on: December 1, 2023
Complement Activation Is Associated With Disease Severity in Multiple Sclerosis
Johanna Oechtering1, Kerstin Stein1, Sabine A Schaedelin1
1From the Department of Neurology (J.O., A.M.M., A.O., S. Meier, E.W., T.D., M.D.S., M.L., B.F.-B., C. Granziera, L.K., D.L., J.K.); Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB) (J.O., S.A.S., A.M.M., A.O., S. Meier, E.W., T.D., P.B., M.D.S., M.L., B.F.-B., C. Granziera, L.K., D.L., J.K.), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Switzerland; Department of Neurology with Institute of Translational Neurology (K.S., H.W., J.D.L.), University Hospital 4 Münster, Germany; Clinical Trial Unit (S.A.S., P.B.), Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; Octavebio Bioscience (F.Q.), Menlo Park, CA; Division of Medical Immunology (I.H.), Laboratory Medicine, University Hospital Basel, Switzerland; Medica Laboratory (A.R.), Zürich; Department of Neurology (L.A.), Cantonal Hospital, Aarau; Department of Neurology (S. Mueller), Cantonal Hospital St. Gallen; Department of Neurology (A.S.), Inselspital, Bern University Hospital and University of Bern; Department of Clinical Neurosciences (P.H.L., C.B.), Division of Neurology; Diagnostic Department (P.H.L.), Division of Laboratory Medicine; Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; Division of Neurology (C.P., R.A.D.P.), Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne; Neurocentre of Southern Switzerland (C. Gobbi), Multiple Sclerosis Centre, Ospedale Civico; Faculty of Biomedical Sciences (C. Gobbi), Università della Svizzera Italiana (USI), Lugano, Switzerland; Translational Imaging in Neurology (ThINk) Basel (C. Granziera), Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel; and Division of Internal Medicine (M.T.), University Hospital Basel and Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
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:
CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 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.
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