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Acta Neuropathol Commun. 2019 Sep 3;7(1):145. doi: 10.1186/s40478-019-0786-3.

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Author information

1
Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia.
2
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
3
Discipline of Applied Medical Science, The University of Sydney, Sydney, Australia.
4
School of Mathematics and Statistics, The University of Sydney, Sydney, Australia.
5
Department of Neurosciences, Central Clinical School, Monash University, Melbourne, Australia.
6
Department of Neurology, Royal Children's Hospital and Neurosciences Research, Murdoch Children's Research Institute, Melbourne, Australia.
7
Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
8
Department of Neurology, Westmead Hospital, Sydney, Australia.
9
Department of Neurology, Monash Health, Melbourne, Australia.
10
Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
11
Hunter Medical Research Institute, Newcastle, Australia.
12
Faculty of Medicine and Public Health, The University of Newcastle, Newcastle, Australia.
13
Department of Neurology, John Hunter Hospital, Newcastle, Australia.
14
Brain and Mind Centre, The University of Sydney, Sydney, Australia.
15
Department of Neurology, Concord Repatriation General Hospital, Sydney, Australia.
16
Department of Neurology, School of Medicine, Gold Coast University Hospital, Griffith University, Gold Coast, Australia.
17
New South Wales Health Pathology, Institute of Clinical Pathology and Medical Research, and Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia.
18
Department of Neurology, University of Münster, Münster, Germany.
19
Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia. fabienne.brilot@sydney.edu.au.
20
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. fabienne.brilot@sydney.edu.au.
21
Discipline of Applied Medical Science, The University of Sydney, Sydney, Australia. fabienne.brilot@sydney.edu.au.
22
Brain and Mind Centre, The University of Sydney, Sydney, Australia. fabienne.brilot@sydney.edu.au.

Abstract

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.

KEYWORDS:

Antibody; Diagnosis; Epitope, antigen conformation; Multiple sclerosis; Myelin oligodendrocyte glycoprotein; Optic neuritis

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