Can immune reactivity to MOG and PLP reflect loss of tolerance to myelin targets and promote demyelinating neuroinflammation?

The central nervous system (CNS) myelin proteins, myelin oligodendrocyte glycoprotein (MOG) and myelin proteolipid protein (PLP), are primary targets in autoimmune demyelinating disorders. Under physiological conditions, central and peripheral tolerance checkpoints delete or silence self-reactive B and T cells. A breakdown in these checkpoints allows autoreactive clones to escape and persist, initiating a targeted pathogenic cascade.

Mechanisms of neuroinflammation and demyelination

• Oligodendrocyte apoptosis: Patient-derived anti-MOG and anti-PLP antibodies directly trigger oligodendrocyte death. This occurs through complement-dependent pathways, Fc-receptor-mediated microglial activation, and complement-independent membrane signaling disruption.
• Impaired remyelination: Autoantibodies targeting the second extracellular loop of PLP impair the growth and differentiation of oligodendrocyte progenitor cells, directly inhibiting remyelination and tissue repair in vivo.
• Epitope spreading: The inflammatory tissue damage and subsequent release of sequestered myelin antigens during an active attack drive both intra- and intermolecular epitope spreading to secondary targets (including MOG, PLP, and myelin basic protein), which broadens the autoimmune response and accelerates disease progression.

Clinical implications

• Biomarker utility: The detection of high-affinity, class-switched anti-PLP and serum MOG-IgG antibodies serves as a critical diagnostic indicator for MOG-antibody-associated disease (MOGAD) and inflammatory demyelinating conditions.
• Therapeutic target: The direct pathogenicity of these circulating antibodies is clinically demonstrated by the therapeutic efficacy of rapid antibody removal, such as plasmapheresis or immunoadsorption, which successfully mitigates severe inflammatory attacks.

Bottom line

• Bottom line: Immune reactivity to MOG and PLP represents a fundamental loss of immunological tolerance, actively promoting demyelinating neuroinflammation by driving oligodendrocyte apoptosis, blocking remyelination pathways, and expanding the autoimmune response through epitope spreading.