ミエリンオリゴデンドロサイト糖タンパク質に対する自己抗体の補体およびFcレセプターを介した病態メカニズムの解明に迫る Dissection of complement and Fc-receptor-mediated pathomechanisms of autoantibodies to myelin oligodendrocyte glycoprotein
Simone Mader,Samantha Ho,Hoi Kiu Wong,Selia Baier,Stephan Winklmeier,Carolina Riemer,Heike Rübsamen,Iris Marti Fernandez,Ramona Gerhards ,Cuilian Du,Omar Chuquisana,Jan D. Lünemann,Anja Lux,Falk Nimmerjahn ,Monika Bradl,Naoto Kawakami,Edgar Meinl
Proceedings of the National Academy of Sciences Published:March 21, 2023
Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) define a new disease, MOG-antibody-associated disease (MOGAD). MOG-Abs from patients are pathogenic, but precise effector mechanisms are unclear and there is no approved therapy. Starting from a pathogenic MOG-specific mAb with a human IgG1 Fc part, we generated mutants with differential FcR and complement binding and studied their pathogenic activity in two animal models. First, MOG-Abs induced demyelination, about equally by FcR activation and complement activation. Second, MOG-Abs enhanced infiltration and activation of cognate T cells via FcRs. Thus a complement-directed therapy, which is effective in neuromyelitis optica spectrum disorders (NMOSD), a related disease with Abs to astrocytes, might not be sufficient in MOGAD. Instead, an FcR-targeted therapy might be more promising in MOGAD.
Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have recently been established to define a new disease entity, MOG-antibody-associated disease (MOGAD), which is clinically overlapping with multiple sclerosis. MOG-specific antibodies (Abs) from patients are pathogenic, but the precise effector mechanisms are currently still unknown and no therapy is approved for MOGAD. Here, we determined the contributions of complement and Fc-receptor (FcR)-mediated effects in the pathogenicity of MOG-Abs. Starting from a recombinant anti-MOG (mAb) with human IgG1 Fc, we established MOG-specific mutant mAbs with differential FcR and C1q binding. We then applied selected mutants of this MOG-mAb in two animal models of experimental autoimmune encephalomyelitis. First, we found MOG-mAb-induced demyelination was mediated by both complement and FcRs about equally. Second, we found that MOG-Abs enhanced activation of cognate MOG-specific T cells in the central nervous system (CNS), which was dependent on FcR-, but not C1q-binding. The identification of complement-dependent and -independent pathomechanisms of MOG-Abs has implications for therapeutic strategies in MOGAD.