Improving the sensitivity of myelin oligodendrocyte glycoprotein-antibody testing: exclusive or predominant MOG-IgG3 seropositivity-a potential diagnostic pitfall in patients with MOG-EM/MOGAD

S Jarius; M Ringelstein; K Schanda; K Ruprecht; M Korporal-Kuhnke; A Viehöver; M W Hümmert; P Schindler; V Endmayr; M Gastaldi; C Trebst; D Franciotta; O Aktas; R Höftberger; J Haas; L Komorowski; F Paul; M Reindl; B Wildemann

doi:10.1007/s00415-024-12285-5

Improving the sensitivity of myelin oligodendrocyte glycoprotein-antibody testing: exclusive or predominant MOG-IgG3 seropositivity-a potential diagnostic pitfall in patients with MOG-EM/MOGAD

J Neurol. 2024 Apr 13. doi: 10.1007/s00415-024-12285-5. Online ahead of print.

Authors

S Jarius¹, M Ringelstein², K Schanda³, K Ruprecht⁴, M Korporal-Kuhnke⁵, A Viehöver⁵, M W Hümmert⁶, P Schindler⁴, V Endmayr^{7

8}, M Gastaldi⁹, C Trebst⁶, D Franciotta⁹, O Aktas², R Höftberger^{7

8}, J Haas⁵, L Komorowski¹⁰, F Paul^{11

12}, M Reindl³, B Wildemann¹³

Affiliations

¹ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.
² Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.
³ Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁴ Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁵ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
⁶ Department of Neurology, Hannover Medical School, Hanover, Germany.
⁷ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.
⁸ Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
⁹ Neuroimmunology Laboratory and Neuroimmunology Research Unit, IRCCS Mondino Foundation National Neurological Institute, Pavia, Italy.
¹⁰ Institute of Experimental Neuroimmunology, affiliated to Euroimmun AG, Lübeck, Germany.
¹¹ Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹² Neuroscience Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
¹³ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. brigitte.wildemann@med.uni-heidelberg.de.

PMID: 38609667
DOI: 10.1007/s00415-024-12285-5

Abstract

Background: Myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD) is the most important differential diagnosis of both multiple sclerosis and neuromyelitis optica spectrum disorders. A recent proposal for new diagnostic criteria for MOG-EM/MOGAD explicitly recommends the use of immunoglobulin G subclass 1 (IgG1)- or IgG crystallizable fragment (Fc) region-specific assays and allows the use of heavy-and-light-chain-(H+L) specific assays for detecting MOG-IgG. By contrast, the utility of MOG-IgG3-specific testing has not been systematically evaluated.

Objective: To assess whether the use of MOG-IgG3-specific testing can improve the sensitivity of MOG-IgG testing.

Methods: Re-testing of 22 patients with a definite diagnosis of MOG-EM/MOGAD and clearly positive MOG-IgG status initially but negative or equivocal results in H+L- or Fc-specific routine assays later in the disease course (i.e. patients with spontaneous or treatment-driven seroreversion).

Results: In accordance with previous studies that had used MOG-IgG1-specific assays, IgG subclass-specific testing yielded a higher sensitivity than testing by non-subclass-specific assays. Using subclass-specific secondary antibodies, 26/27 supposedly seroreverted samples were still clearly positive for MOG-IgG, with MOG-IgG1 being the most frequently detected subclass (25/27 [93%] samples). However, also MOG-IgG3 was detected in 14/27 (52%) samples (from 12/22 [55%] patients). Most strikingly, MOG-IgG3 was the predominant subclass in 8/27 (30%) samples (from 7/22 [32%] patients), with no unequivocal MOG-IgG1 signal in 2 and only a very weak concomitant MOG-IgG1 signal in the other six samples. By contrast, no significant MOG-IgG3 reactivity was seen in 60 control samples (from 42 healthy individuals and 18 patients with MS). Of note, MOG-IgG3 was also detected in the only patient in our cohort previously diagnosed with MOG-IgA⁺/IgG^- MOG-EM/MOGAD, a recently described new disease subvariant. MOG-IgA and MOG-IgM were negative in all other patients tested.

Conclusions: In some patients with MOG-EM/MOGAD, MOG-IgG is either exclusively or predominantly MOG-IgG3. Thus, the use of IgG1-specific assays might only partly overcome the current limitations of MOG-IgG testing and-just like H+L- and Fcγ-specific testing-might overlook some genuinely seropositive patients. This would have potentially significant consequences for the management of patients with MOG-EM/MOGAD. Given that IgG3 chiefly detects proteins and is a strong activator of complement and other effector mechanisms, MOG-IgG3 may be involved in the immunopathogenesis of MOG-EM/MOGAD. Studies on the frequency and dynamics as well as the clinical and therapeutic significance of MOG-IgG3 seropositivity are warranted.

Keywords: Antibodies; Aquaporin-4 (AQP4); Assays; Autoantibody; Detection antibodies; IgG subclasses; Immunoglobulin G (IgG); MOG antibody-associated disease (MOGAD); MOG antibody-associated encephalomyelitis (MOG-EM); MOG-IgG1; MOG-IgG3; Multiple sclerosis; Myelin oligodendrocyte glycoprotein (MOG); Myelitis; Neuromyelitis optica spectrum disorders (NMOSD); Optic neuritis; Rozanolixizumab; Sensitivity; Seroconversion; Serology; Seronegative; Seronegativity; Seroreversion; Tests.

Publication types

Letter