Humoral signatures of MOG-antibody-associated disease track with age and disease activity

Marianna Spatola; Omar Chuquisana; Wonyeong Jung; Joseph A Lopez; Eva-Maria Wendel; Sudarshini Ramanathan; Christian W Keller; Tim Hahn; Edgar Meinl; Markus Reindl; Russell C Dale; Heinz Wiendl; Douglas A Lauffenburger; Kevin Rostásy; Fabienne Brilot; Galit Alter; Jan D Lünemann

doi:10.1016/j.xcrm.2022.100913

Humoral signatures of MOG-antibody-associated disease track with age and disease activity

Cell Rep Med. 2023 Feb 21;4(2):100913. doi: 10.1016/j.xcrm.2022.100913. Epub 2023 Jan 19.

Authors

Marianna Spatola¹, Omar Chuquisana², Wonyeong Jung³, Joseph A Lopez⁴, Eva-Maria Wendel⁵, Sudarshini Ramanathan⁶, Christian W Keller², Tim Hahn⁷, Edgar Meinl⁸, Markus Reindl⁹, Russell C Dale¹⁰, Heinz Wiendl¹¹, Douglas A Lauffenburger¹², Kevin Rostásy¹³, Fabienne Brilot⁴, Galit Alter¹⁴, Jan D Lünemann¹⁵

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard Medical School, Cambridge, MA 02139, USA. Electronic address: marianna.spatola@gmail.com.
² Department of Neurology with Institute of Translational Neurology, University Hospital Münster, WWU, Münster 48149, Germany.
³ Ragon Institute of MGH, MIT and Harvard Medical School, Cambridge, MA 02139, USA; Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Specialty of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia.
⁵ Department of Pediatric Neurology, Olgahospital/Klinikum Stuttgart, 70174 Stuttgart, Germany.
⁶ Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia; Department of Neurology, Concord Hospital, Sydney, NSW 2139, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
⁷ Institute for Translational Psychiatry, University of Münster, 48149 Münster, Germany.
⁸ Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig-Maximilians-Universität München, 82152 Munich, Germany.
⁹ Clinical Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
¹⁰ Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Specialty of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia.
¹¹ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, WWU, Münster 48149, Germany; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia.
¹² Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹³ Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, 45711 Datteln, Germany.
¹⁴ Ragon Institute of MGH, MIT and Harvard Medical School, Cambridge, MA 02139, USA.
¹⁵ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, WWU, Münster 48149, Germany. Electronic address: jan.luenemann@ukmuenster.de.

Abstract

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral immune responses in 123 patients with MOGAD. We show that age is a major determinant for MOG-antibody-related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (IgG) glycovariants is associated with clinically active disease. Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.

Keywords: Fc gamma receptors; MOGAD; antibody; demyelination; humoral signatures; myelin oligodendrocyte glycoprotein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Immunoglobulin G*
Mammals / metabolism
Myelin-Oligodendrocyte Glycoprotein / metabolism
Receptors, IgG*

Substances

Receptors, IgG
Myelin-Oligodendrocyte Glycoprotein
Immunoglobulin G