PT  - JOURNAL ARTICLE
AU  - Lerch, Magdalena
AU  - Schanda, Kathrin
AU  - Lafon, Eliott
AU  - Würzner, Reinhard
AU  - Mariotto, Sara
AU  - Dinoto, Alessandro
AU  - Wendel, Eva Maria
AU  - Lechner, Christian
AU  - Hegen, Harald
AU  - Rostásy, Kevin
AU  - Berger, Thomas
AU  - Wilflingseder, Doris
AU  - Höftberger, Romana
AU  - Reindl, Markus
TI  - More Efficient Complement Activation by Anti–Aquaporin-4 Compared With Anti–Myelin Oligodendrocyte Glycoprotein Antibodies
AID  - 10.1212/NXI.0000000000200059
DP  - 2023 Jan 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e200059
VI  - 10
IP  - 1
4099  - http://nn.neurology.org/content/10/1/e200059.short
4100  - http://nn.neurology.org/content/10/1/e200059.full
SO  - Neurol Neuroimmunol Neuroinflamm2023 Jan 01; 10
AB  - Background and Objectives The objective was to study complement-mediated cytotoxicity induced by immunoglobulin G (IgG) anti–aquaporin-4 antibodies (AQP4-IgG) and anti–myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in human serum samples from patients suffering from the rare demyelinating diseases of the CNS neuromyelitis optica spectrum disorder (NMOSD) and MOG-IgG–associated disease (MOGAD).Methods A cell-based assay with HEK293A cells expressing different MOG isoforms (MOGα1-3β1-3) or AQP4-M23 was used. Cells were incubated with human MOG-IgG or AQP4-IgG–positive serum samples together with active or heat-inactivated human complement, and complement-dependent cytotoxicity (CDC) was measured with a lactate dehydrogenase assay. To further quantify antibody-mediated cell damage, formation of the terminal complement complex (TCC) was analyzed by flow cytometry. In addition, immunocytochemistry of the TCC and complement component 3 (C3) was performed.Results AQP4-IgG–positive serum samples induced higher CDC and TCC levels than MOG-IgG–positive sera. Notably, both showed a correlation between antibody titers and CDC and also between titers and TCC levels. In addition, all 6 MOG isoforms tested (MOGα1-3β1-3) could induce at least some CDC; however, the strongest MOG-IgG–induced CDC levels were found on MOGα1, MOGα3, and MOGβ1. Different MOG-IgG binding patterns regarding recognition of different MOG isoforms were investigated, and it was found that MOG-IgG recognizing all 6 isoforms again induced highest CDC levels on MOGα1 and MOGβ1. Furthermore, surface staining of TCC and C3 revealed positive staining on all 6 MOG isoforms tested, as well as on AQP4-M23.Discussion Both MOG-IgG and AQP4-IgG are able to induce CDC in a titer-dependent manner. However, AQP4-IgG showed markedly higher levels of CDC compared with MOG in vitro on target cells. This further highlights the role of complement in AQP4-IgG–mediated disease and diminishes the importance of complement activation in MOG-IgG–mediated autoimmune disease.ADCC=antibody-dependent cellular cytotoxicity; AP=alternative complement pathway; AQP4=aquaporin-4; C1, C3, C5=complement component 1, 3, 5; CDC=complement-dependent cytotoxicity; CP=classical complement pathway; IgG=Immunoglobulin G; LDH=lactate dehydrogenase; MOG=myelin oligodendrocyte glycoprotein; MOGAD=MOG-IgG–associated disease; MS=multiple sclerosis; NMOSD=neuromyelitis optica spectrum disorder; TCC=terminal complement complex