Abstract
Antibodies and oxidative stress are hallmarks of multiple sclerosis (MS) lesions. We aimed to clarify the relation between them, their role in MS patients and to investigate their specificity, comparing MS with classical neurodegenerative diseases (ND). Brain samples from 14 MS cases, 6 with ND and 9 controls (without neurological diseases). Immunohistochemistry assays were used to detect oxidized lipids (EO6), IgG and IgM, oligodendrocytes (Olig2), axons (NF, neurofilament) and cellular (TUNEL) and axonal damage (APP, amyloid precursor protein). We did not observe EO6 in controls. All samples from MS patients showed EO6 in oligodendrocytes and axons within lesions. We did not detect co-localization between EO6 and antibodies. Neither did we between EO6 and TUNEL or APP. 94.4% of TUNEL-positive cells in normal appearing white matter were also stained for IgG and 75.5% for IgM. IgM, but not IgG, co-localized with APP. EO6 was associated with axonal damage in amyotrophic lateral sclerosis (ALS). We did not observe association between antibodies and cellular or axonal damage in ND patients. MS patients showed a higher number of B cells and plasma cells in the lesions and meninges than controls. The number of B cells and plasma cells was associated with the presence of antibodies and with the activity of the lesions. We observed a main role of B lymphocytes in the development of MS lesions. Antibodies contribute to the oligodendrocyte and axonal damage in MS. Oxidative stress was associated with axonal damage in ALS.
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The corresponding authors will provide anonymized data of this study on reasonable request from any qualified investigator, following relevant data protection regulations.
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Acknowledgements
We acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK and the NIHR Oxford Biomedical Research; Banco de Tejidos CIEN, Instituto Carlos III and Departamento de Anatomía de la Facultad de Medicina de la Universidad San Pablo CEU for providing human tissue; Dr. José Paredes, Dr. Silvano Heras and Dr Francisco J. García for providing tissue samples and Angelica Acebedo and Susana Arahuetes for technical help.
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This work was supported by grants from the Instituto de Medicina Molecular Aplicada, Universidad San Pablo CEU (USP-BS-PPC16/2012 and MEMERG-1) and grant from the Universidad San Pablo CEU-Banco Santander (PI14/01620) to Dra. Úrsula Muñoz and by UK National Institute for Health Research (NIHR) through the Oxford Biomedical Research Centre (UK) to Professor Margaret Esiri. Cristina Sebal was supported by a fellowship grant from the Instituto de Medicina Molecular Aplicada, Universidad San Pablo CEU (Spain).
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UM, MCS and ES: conception and design of the study; CS, JT and CSl: acquisition and analysis of data and MCS, UM, ME, and ES: drafting a significant portion of the manuscript or figures.
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Muñoz, U., Sebal, C., Escudero, E. et al. Main Role of Antibodies in Demyelination and Axonal Damage in Multiple Sclerosis. Cell Mol Neurobiol 42, 1809–1827 (2022). https://doi.org/10.1007/s10571-021-01059-6
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DOI: https://doi.org/10.1007/s10571-021-01059-6