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Complement Activation Profiles Predict Clinical Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated
Javier Villacieros-Álvarez1, Jan D Lunemann1, Maria Sepulveda1
1From the Neurology-Neuroimmunology Department (J.V.-Á., V.F., A.V., M. Castillo, M. Comabella), Multiple Sclerosis Center of Catalonia, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Research Institute; Autonomous University of Barcelona (M. Comabella), Spain; Department of Neurology with Institute of Translational Neurology (J.D.L.), University Hospital Münster, Germany; Neuroimmunology and Multiple Sclerosis Unit (M.S., S.L., Y.B.), Hospital Clinic de Barcelona; Fundación INCE (Iniciativa para las Neurociencias) (A.V.-C.), Madrid, Spain; Neurology Unit (A.D., S.M.), Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Italy; Neuroimmunology Program (S.L., Y.B., T.A.), Neurology Service, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona; Girona Neuroimmunology and Multiple Sclerosis Unit (G.Á.B., L.R.), Neurology Department, Dr. Josep Trueta University Hospital and Santa Caterina Hospital; Neurodegeneration and Neuroinflammation research group (G.Á.B., A.Q.-V., L.R.), IDIBGI, Girona-Salt; Department of Medical Sciences (G.Á.B., L.R.), Faculty of Medicine, University of Girona; and Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS) (A.Q.-V., L.R.), Red de Enfermedades inflamatorias (RD21/0002/0063), Instituto de Salud Carlos III, Madrid, Spain.
Insights
Complement factors (CFs) show diagnostic and prognostic value in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Serum CFs distinguish MOGAD from MS and AQP4-NMOSD, while CSF CFs predict relapse and disability.
Area of Science:
- Neuroimmunology
- Complement System Biology
- Biomarker Discovery
Background:
- The role of the complement system in MOGAD is not fully understood.
- Diagnostic and prognostic biomarkers for MOGAD are lacking.
- Complement factors (CFs) are investigated for their potential in MOGAD.
Purpose of the Study:
- To investigate the diagnostic and prognostic value of CFs in MOGAD patients.
- To compare CF levels in MOGAD, MS, and AQP4-NMOSD.
- To evaluate the association of CFs with relapse and disability outcomes in MOGAD.
Main Methods:
- Multicentric retrospective cohort study.
- Inclusion of patients with MOGAD, MS, and AQP4-NMOSD with paired serum and CSF samples.
- Measurement of CFs using multiplex ELISA and statistical analyses for diagnostic and prognostic evaluation.
Main Results:
- Serum C3a, C4a, and C3a/C3 ratio effectively discriminated MOGAD from MS and AQP4-NMOSD (AUCs 0.95 and 0.88, respectively).
- CSF complement levels, particularly C4 and C4a/C4 ratio, were associated with relapse risk and frequency in MOGAD.
- Elevated CSF SC5b9 levels correlated with increased disability (EDSS ≥ 3.0) in MOGAD patients.
Conclusions:
- Serum and CSF levels of complement factors demonstrate significant diagnostic and prognostic utility in MOGAD.
- These findings support the potential of complement inhibitors as a therapeutic strategy for MOGAD.
- CFs represent promising biomarkers for MOGAD diagnosis and outcome prediction.
Background And Objectives:
The role of the complement system in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not completely understood, and studies exploring its potential utility for diagnosis and prognosis are lacking. We aimed to investigate the value of complement factors (CFs) as diagnostic and prognostic biomarkers in patients with MOGAD.
Methods:
Multicentric retrospective cohort study including patients with MOGAD, multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD) with available paired serum and CSF samples. A panel of CFs were measured by multiplex ELISA, and the levels were compared between the 3 conditions. Univariable and multivariable analyses were performed to evaluate the association between levels of CFs and relapse and disability outcomes in MOGAD patients.
Results:
Ninety-four patients (MOGAD, n = 60; MS, n = 18; AQP4-NMOSD, n = 16) were included. Mean (SD) age at sampling was 39.4 (16.7), 40.7 (7.0), and 43.3 (21.0), respectively. Female were predominant, especially in AQP4-NMOSD (88%). Combination of the serum levels of C3a, C4a, and C3a/C3 ratio showed excellent potential to discriminate MOGAD from patients with MS (area under the curve [AUC] [95% CI] 0.95 [0.90-0.99]) and from AQP4-NMOSD (AUC 0.88 [0.76-1.00]). In patients with MOGAD, CSF levels of CFs of the classical/lectin pathway influenced relapse-related outcomes, and lower C4 levels were associated with higher number of relapses during follow-up (incidence rate ratio [95% CI] 0.88 [0.78-0.99]; p = 0.04 in multivariable analysis), and a high C4a/C4 ratio was associated with increased risk of second relapse during the first year (hazard ratio [95% CI] 3.68 [1.26-10.78]; p = 0.02 in multivariable analysis). Time to second relapse was shorter in patients with MOGAD with a high CSF C4a/C4 ratio (log-rank p = 0.01). CSF levels of the membrane attack complex SC5b9 influenced disability-related outcomes, and baseline CSF SC5b9 levels were higher in patients who reached the final Expanded Disability Status Scale (EDSS) ≥ 3.0 (p = 0.002), and elevated SC5b9 levels were associated with increased risk of reaching EDSS ≥ 3.0 (odds ratio [95% CI] 1.79 [1.16-3.67]; p = 0.04 in multivariable analyses).
Discussion:
Our results suggest that serum and CSF levels of CFs have diagnostic and prognostic value respectively in patients with MOGAD. These findings support the use of complement inhibitors as a therapeutic approach in these patients.
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