Details of target-recognition by autoantibodies to the myelin protein MOG uncovered

The human immune system generates an enormous variety of different antibodies that are essential to protect us against infectious agents. However, this powerful system can go wrong giving rise to autoantibodies that target structures in the own body and thereby cause severe diseases like rheumatic diseases and different inflammatory disorders in the central nervous system (CNS).

The identification and characterization of such autoantibodies is essential for diagnosis and optimal therapy. Some patients with inflammation in the CNS have autoantibodies against a protein called myelin oligodendrocyte glycoprotein (MOG), which is localized on the outside of myelin, the insulating sheath of axons of neurons. These patients suffer from disturbed vision or paralysis just like patients with multiple sclerosis. The presence of autoantibodies to MOG, however, distinguishes these patients from those suffering from multiple sclerosis and defines a distinct disease, called MOGAD.

In their latest work, the lab of Prof. Edgar Meinl at the Biomedical Center has uncovered details on how antibodies against MOG (MOG-Abs) from patients with MOGAD recognize their target. In the past years, the Meinl lab and others have determined that the extracellular N-terminal part of the MOG protein (aa1-124) contains the epitopes detected by patients’ antibodies. Surprisingly, in laboratory diagnostics this N-terminal part of MOG alone is not sufficient to identify MOG-Abs in samples from MOGAD patients. The Meinl lab now uncovered the underlying reasons. Working with different truncated variants of MOG, they found that the second hydrophobic domain of MOG is required for the autoantibodies to bind strongly to the extracellular part. Furthermore, they showed that the MOG-Abs from patients require bivalent binding to target MOG. These findings led to a new model for the interaction of the autoantibodies and MOG: the intracellular part with the second hydrophobic domain holds MOG molecules apart at a distance that allows bivalent binding of the autoantibodies.

These new insights have clinical implications for diagnosis as well as the development of therapies. Firstly, it explains why in laboratory diagnostics a cell-based assay using full-length MOG is required to identify MOG-Abs. Secondly, the described bivalent binding mode suggests that complement activation may not be the major pathogenic effect of human MOG-Abs as bivalently bound antibodies are known to only poorly bind the complement component C1q. This finding is of direct clinical relevance as it suggests that complement inhibition, which is successful in treatment of the related disease neuromyelitis optica, may not be very effective in patients with MOGAD. Thus, the detailed understanding of interactions between autoantibodies and their targets has direct implications for therapeutic strategies.

Publication: Macrini et al.: Features of MOG required for recognition by patients with MOG antibody-associated disorders, Brain 2021