Inflammatory demyelination of the central nervous system: Pathomechanisms of autoantibodies and towards novel therapies

• Applicant: Professor Dr. Edgar Meinl
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548686850

Autoantibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) define distinct diseases, neuromyelitis optica spectrum disorders (NMOSD) and MOG-antibody associated disease (MOGAD). This allows to differentiate patients with these Abs from those with classical multiple sclerosis (MS) with insights into the pathogenesis and therapeutic implications. Supported by the SFB-TR128, we a) identified immunodominant epitopes on the extracellular part of MOG and uncovered that the intracellular part of MOG is required for recognition of its extracellular domain by patient Abs. In transfer experiments, we found that MOG-Abs from patients are pathogenic by two mechanisms, demyelination, and enhancement of cognate T cell activation. We created Fc variants of a murine anti-MOG mAb and with this, we could dissect complement and Fc-mediated pathomechanisms. We identified circulating B cells specific for MOG and GAD-65 and cloned recombinant Abs from patients with antibodies to GAD-65. b) identified a novel layer of complexity within the BAFF-APRIL system that regulates the survival of B cells and plasma cells, namely shedding of the receptors BCMA and TACI; we identified the biochemical mechanisms mediating this shedding; important for further therapeutic strategies, BCMA is directly released by the gamma-secretase. We found that the soluble receptors sBCMA and sTACI function as decoys and constitute biomarkers in MS, SLE and B cell malignancies. Based on these findings, we now aim to a) establish recombinant mAbs recognizing MOG from MOGAD patients. As preparatory work for this we have just identified expanded B cell clonotypes in the CSF from a MOGAD patient; now we want to clone the paired H+L chains from these collotypes and produce the mAbs recombinantly. With these mAbs we want to study effector mechanisms of MOG-Abs, FcR-engagement, complement activation and Ab-dependent cellular phagocytosis. Further, we want to establish effector profiles of the circulating MOG-Abs from individual MOGAD patients and we will analyze, if these effector functions are linked to recognition of certain epitopes or clinical features. The effector functions of MOG-Abs and AQP4-Abs will be compared. These studies are of potential therapeutic relevance, since in MOGAD no therapy has yet been approved, while in NMOSD a mAb blocking the degradation of the complement factor C5 is successfully applied. b) use our new animal model with an Fc-mutated mAb to MOG, we will test how FcR-mediated demyelination can be targeted, at first by inhibiting BTK. c) test if therapies applied in multiple myeloma can also be used to target autoantibody producing plasma cells. To this end, we will differentiate in vitro B cells from MOGAD and NMOSD patients and test, if these plasma cells can be eliminated by a bispecific BCMAxCD3 Ab in combination with inhibition of the gamma-secretase.

• DFG Programme: Research Grants