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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

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Item Type:Letter
Title: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
Creators Name:Jarius, S. and Ringelstein, M. and Schanda, K. and Ruprecht, K. and Korporal-Kuhnke, M. and Viehöver, A. and Hümmert, M.W. and Schindler, P. and Endmayr, V. and Gastaldi, M. and Trebst, C. and Franciotta, D. and Aktas, O. and Höftberger, R. and Haas, J. and Komorowski, L. and Paul, F. and Reindl, M. and Wildemann, B.
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:Myelin Oligodendrocyte Glycoprotein (MOG), MOG Antibody-Associated Encephalomyelitis (MOG-EM), MOG Antibody-Associated Disease (MOGAD), Multiple Sclerosis, Neuromyelitis Optica Spectrum Disorders (NMOSD), Optic Neuritis, Myelitis, Immunoglobulin G (IgG), IgG Subclasses, MOG-IgG1, MOG-IgG3, Seroreversion, Seroconversion, Seronegativity, Seronegative, Aquaporin-4 (AQP4), Tests, Assays, Serology, Autoantibody, Antibodies, Detection Antibodies, Sensitivity, Rozanolixizumab
Source:Journal of Neurology
Date:13 April 2024
Official Publication:https://doi.org/10.1007/s00415-024-12285-5
PubMed:View item in PubMed

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