RT Journal Article
SR Electronic
T1 More Efficient Complement Activation by Anti–Aquaporin-4 Compared With Anti–Myelin Oligodendrocyte Glycoprotein Antibodies
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200059
DO 10.1212/NXI.0000000000200059
VO 10
IS 1
A1 Lerch, Magdalena
A1 Schanda, Kathrin
A1 Lafon, Eliott
A1 Würzner, Reinhard
A1 Mariotto, Sara
A1 Dinoto, Alessandro
A1 Wendel, Eva Maria
A1 Lechner, Christian
A1 Hegen, Harald
A1 Rostásy, Kevin
A1 Berger, Thomas
A1 Wilflingseder, Doris
A1 Höftberger, Romana
A1 Reindl, Markus
YR 2023
UL http://nn.neurology.org/content/10/1/e200059.abstract
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