Autoimmune disease MOGAD: new insights into pathomechanisms

Enlarge

MOG antibody-associated disease is an inflammatory autoimmune disease of the central nervous system, sharing some symptoms with multiple sclerosis (MS). In this rare condition, the body’s defenses attack the myelin sheath, the outer layer of nerve fibers. Specific antibodies are directed against the so-called myelin oligodendrocyte glycoprotein (MOG), a protein on the outside of the insulating layer of nerve fibers.

The autoimmune disease chiefly affects the optic nerve and spinal cord. If the optic nerve is affected, it leads to vision defects, while inflammations of the spinal cord can cause paralysis. The disease progresses in bursts and there are no approved therapies. Through idenfication of autoantibodies to MOG, neurologists are able to differentiate MOGAD and multiple sclerosis amongst others.

“However, the MOG antibodies are not just diagnostic biomarkers, but play a decisive role in the disease process,” says Professor Edgar Meinl from LMU’s Institute of Clinical Neuroimmunology (Biomedical Center Munich) and University of Munich Hospital. Together with PD Dr. Simone Mader and PD Dr. Naoto Kawakami from University of Munich Hospital and further colleagues, including Professor Monika Bradl from the Medical University of Vienna, Meinl was able to demonstrate which effector mechanisms – that is to say, immunological responses – take place: Both the complement system and the binding of MOG antibodies to so-called Fc receptors on immune cells are involved in tissue destruction in patients with MOGAD, as the researchers report in the journal PNAS.

Humanized antibodies from mouse models

In a first step, the team led by Meinl and Mader humanized a monoclonal MOG antibody from established mouse models, equipping it with a human Fc fragment. Antibodies consist of an antigen-binding fragment (Fab) and an Fc fragment. With their Fab fragment, antibodies recognize their specific target antigen. The Fc fragment determines the biological effector functions, through binding to Fc receptors on immune system cells and through activation of the complement system. While the complement system plays an important role in the elimination of certain bacteria, it can also target the body’s own structures when things go wrong.

The researchers manufactured multiple variants of the humanized MOG antibody by means of mutagenesis. In vitro, these antibodies still recognized their target structure but differed in their ability to activate the complement system or bind Fc receptors. Next, the researchers tested selected antibody variants in an animal model. ´”We found that the destruction of the myelin sheath – that is, the insulating layer around nerves – is mediated by the complement system and by Fc receptor binding in roughly equal parts,” says Meinl. “The second pathomechanism of MOG antibodies, the enhanced activation of MOG-specific T cells, operates entirely via Fc receptors.”

Where does it go from here? “The big goal would be to establish a treatment,” explains Mader. There are currently no approved therapies for MOGAD. For a related condition (NMOSD with aquaporin-4 antibodies) a therapeutic antibody targeting a specific complement factor has been approved, which could potentially have some effect on MOGAD as well. “But on its own, this antibody would probably not be sufficient in the case of MOGAD according to our research findings, because any therapy likely to succeed would also have to address the Fc receptors as a target structure,” says Mader.

Simone Mader, Samantha Ho, Hoi Kiu Wong, Selia Baier, Stephan Winklmeier, Carolina Riemer, Heike Rübsamen, Iris Marti Fernandez, Ramona Gerhards, Cuilian Du, Omar Chuquisan, Jan D. Lünemann, Anja Lux, Falk Nimmerjahn, Monika Bradl, Naoto Kawakami, Edgar Meinl: Dissection of complement and Fc-receptor-mediated pathomechanisms of autoantibodies to myelin oligodendrocyte glycoprotein. PNAS 2023