| Neuroscience/ Translational neurology | Rare Neurological Diseases  

Complement-dependent and -independent pathomechanisms of myelin oligodendrocyte glycoprotein (MOG)-Abs: implications for therapeutic strategies in MOG-antibody-associated disease (MOGAD)

Mader et al. dissect the MOG IgG effector mechanisms that characterize MOG-antibody-associated disease. FcR pathway mediates the MOG-Abs enhanced activation of cognate MOG-specific T cells in the CNS, whereas C1q-binding does not.

Although both MOGAD and NMOSD are antibody-mediated inflammatory and demyelinating diseases of the CNS, existing evidence underlines different mechanisms of pathology to be involved. In NMOSD the role of complement has been previously investigated and led to the approval of an inhibitor of complement activation as a treatment for NMOSD. However, complement-mediated cell toxicity may not be as a prominent mechanism of pathology for MOGAD.

In MOGAD, existing evidence underline the potential role of antibody-dependent cellular cytotoxicity as a more prominent pathway of CNS damage, compared to NMOSD. MOG-Abs mediate demyelination experimentally when co-transferred with MOG-specific T cells (1) and they also induce CNS inflammation via cognate MOG-specific T cells (2), a mechanism not thoroughly elucidated so far.

In this experimental study, Mader et al. (3) used a monoclonal antibody (mAb) to MOG with a human IgG1 Fc part (r8-18C5), exhibiting similar pathogenic activity to MOG antibodies (Abs) from MOGAD patients. By generating Fc-mutated variants of the MOG-specific mAb, Mader et al. differentially studied their binding capacity either to C1q, or to Fcγ receptors (FcγR), thus deciphering the relative capacity of MOG-Abs to recruit complement-dependent and complement-independent mechanisms of pathology, respectively. Moreover, by implementing two models of Experimental Autoimmune Encephalomyelitis (EAE) anti-MOG Abs were shown to mediate demyelination via Fc-receptor (FcR) engagement and independent of complement activation. The results of Mader et al. have important implications for the development of therapeutic strategies in MOGAD.

Key Points:

  • Although autoantibodies against AQP4, which define neuromyelitis optica spectrum disorders (NMOSDs), are potent complement activators, complement seems to be a less prominent mediator of brain lesions in MOGAD.
  • Mader et al. aim to dissect the MOG IgG effector mechanisms that characterize MOG-antibody-associated disease (MOGAD).
  • Both Fc-receptor (FcR)-mediated effects and complement contribute to MOGAD pathology to a similar extent.
  • FcR pathway mediates the MOG-Abs enhanced activation of cognate MOG-specific T cells in the central nervous system (CNS), whereas C1q-binding does not.
  • Deciphering the extent to which complement-dependent and complement-independent mechanisms relatively contribute to brain lesions is crucial in MOGAD, a disease with no approved therapy so far, as it may potentiate the development of appropriate treatment strategies.


  1. Spadaro M, Winklmeier S, Beltrán E, Macrini C, Höftberger R, Schuh E, Thaler FS, Gerdes LA, Laurent S, Gerhards R, Brändle S, Dornmair K, Breithaupt C, Krumbholz M, Moser M, Krishnamoorthy G, Kamp F, Jenne D, Hohlfeld R, Kümpfel T, Lassmann H, Kawakami N, Meinl E. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol. 2018 Aug;84(2):315-328. doi: 10.1002/ana.25291.
  2. Flach AC, Litke T, Strauss J, Haberl M, Gómez CC, Reindl M, Saiz A, Fehling HJ, Wienands J, Odoardi F, Lühder F, Flügel A. Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease. Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):3323-8. doi: 10.1073/pnas.1519608113.
  3. Mader S, Ho S, Wong HK, Baier S, Winklmeier S, Riemer C, Rübsamen H, Fernandez IM, Gerhards R, Du C, Chuquisana O, Lünemann JD, Lux A, Nimmerjahn F, Bradl M, Kawakami N, Meinl E. Dissection of complement and Fc-receptor-mediated pathomechanisms of autoantibodies to myelin oligodendrocyte glycoprotein. Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2300648120. doi: 10.1073/pnas.2300648120.


Radu Tanasescu, Department of Neurology, NottinghamCentre for MS and Neuroinflammation, Nottingham University Hospitals NHS Trust, Nottingham, UK
Magdalena Mroczek, Center for Cardiovascular Genetics & Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich 8952, Switzerland

Publish on behalf of the Scientific Panel on Neuroscience/Translational neurology