Pathogenic Antibodies Identified in Rare Autoimmune Brain Disease

Researchers have provided direct evidence that patient-derived antibodies can actively damage nervous system cells in myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), a rare and recently defined CNS demyelinating disease affecting the brain, optic nerves, and spinal cord. In this study, scientists isolated individual MOG-reactive B cells from people with MOGAD and used them to generate monoclonal anti-MOG antibodies in the laboratory.

This allowed the team to study the behavior of single antibodies rather than mixed antibody pools found in patient blood.

The researchers found that these patient-derived antibodies could trigger multiple immune attack mechanisms, including antibody-dependent phagocytosis, antibody-dependent cellular cytotoxicity, and complement-mediated cell death. In laboratory models, these immune responses led to damage and death of MOG-expressing cells, supporting a direct pathogenic role for anti-MOG antibodies in MOGAD.

Importantly, the antibodies varied in how strongly they bound to MOG and how effectively they activated immune damage.

Some antibodies showed evidence of affinity maturation, suggesting that ongoing immune activity may contribute to relapsing disease in some patients. Others appeared to originate from naïve B cells, pointing to a breakdown in immune tolerance.

The findings also reinforce that MOGAD is biologically distinct from multiple sclerosis, with different immune mechanisms involved. Researchers say this detailed antibody mapping may help improve diagnostic testing and guide the development of targeted therapies that focus on specific B-cell populations or antibody functions rather than broad immune suppression.

This study strengthens the evidence that autoantibodies are not just markers of disease but active drivers of tissue damage in MOGAD. Understanding how specific antibodies harm myelin may lead to more precise treatments and avoid therapies that are ineffective or inappropriate for this distinct autoimmune condition.

Citation

Wetzel, N. S., Kulsvehagen, L., Lecourt, A. C., Filipek, B., Lipps, P., Rieder, L., Berve, K., Krishnamoorthy, G., ‘t Hart, B. A., Schirmer, L., Yandamuri, S. S., O’Connor, K. C., & Pröbstel, A. K. (2026). Patient-Derived Monoclonal Myelin Oligodendrocyte Glycoprotein Autoantibodies Mediate Cytotoxicity. Neurology(R) neuroimmunology & neuroinflammation, 13(1), e200520. https://doi.org/10.1212/NXI.0000000000200520