Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-Associated Disease (MOGAD) is a distinct neuroinflammatory disorder of the central nervous system (CNS). This condition involves an inflammatory attack on the myelin sheath, the protective covering of nerve fibers in the brain, spinal cord, and optic nerves. MOGAD is now recognized as separate from other demyelinating diseases, such as Multiple Sclerosis (MS), due to its unique underlying biological mechanisms and clinical presentation.
The Role of Myelin Oligodendrocyte Glycoprotein
The target of the immune system’s attack in MOGAD is the Myelin Oligodendrocyte Glycoprotein (MOG), a protein found exclusively in the CNS. MOG is a minor constituent of the myelin sheath but is situated strategically on the outermost surface of the oligodendrocyte cell membrane. This prominent external location makes it readily accessible to circulating autoantibodies and immune cells, which is central to the disease process.
MOG is believed to play a part in maintaining the structural integrity and stability of the myelin sheath. It is also thought to function as a cell adhesion molecule or a surface receptor. Its late appearance during development serves as a marker for the maturation of oligodendrocytes.
Autoimmunity and the MOG Antibody
MOGAD is classified as an autoimmune disease, meaning the body’s immune system mistakenly attacks its own healthy tissues. The defining characteristic and primary cause of the disease is the production of an antibody, specifically the MOG-Immunoglobulin G (MOG-IgG). The presence of this antibody in the blood serum is the definitive diagnostic marker for MOGAD.
The MOG-IgG antibody is T-cell-dependent, meaning its production by B cells requires the help of specialized T-cells. This links both the humoral and cellular arms of the immune system to the disease.
Upon production, these antibodies circulate and are able to cross the blood-brain barrier to enter the CNS. Once inside the CNS, MOG-IgG binds to the MOG protein on the surface of the oligodendrocytes and myelin. This antibody-mediated process is mechanistically different from the T-cell-driven process often associated with MS. The persistence of MOG-IgG antibodies in the serum after an initial attack is associated with a higher likelihood of future disease relapses.
Triggers for Immune System Misdirection
The initial misdirection of the immune system that leads to the production of MOG-IgG is thought to involve a combination of predisposing factors and environmental triggers. MOGAD is not a strictly inherited disease, but genetic susceptibility does play a role in increasing vulnerability. Certain genetic markers, particularly specific Human Leukocyte Antigen (HLA) types, are currently being investigated for their potential to increase a person’s risk of developing the disorder.
A major theory for the initiation of autoimmunity is molecular mimicry, which often occurs following an infection. In this scenario, the immune system generates an immune response, including T-cells, to fight a pathogen, such as a virus or bacterium. However, a component of the pathogen may share a structural similarity with a segment of the MOG protein. This similarity causes the pathogen-fighting T-cells to mistakenly cross-react with the self-antigen MOG.
Infectious prodromes, such as preceding respiratory or gastrointestinal illnesses, are reported in a significant proportion of MOGAD cases, ranging from 37% to 70%. This observation supports the theory that an infection acts as the environmental trigger, priming the immune system for the subsequent autoimmune attack. Another related theory is bystander activation, where the generalized inflammation from an infection damages the CNS, exposing MOG and activating MOG-specific immune cells.
The Mechanism of CNS Damage
The binding of the MOG-IgG antibody to the MOG protein on the oligodendrocyte surface initiates a cascade that results in the physical destruction of the myelin sheath and the oligodendrocyte cells. This process involves the recruitment of other components of the immune system to the site of the antibody binding. The MOG antibody, once bound, is capable of activating the complement system, a part of the immune response that helps clear pathogens.
Activation of the complement system leads to the formation of a membrane attack complex, which punctures the cell membranes of oligodendrocytes, causing cell lysis and demyelination. MOG-IgG also triggers antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In ADCC, immune cells like macrophages and granulocytes are attracted to the antibody-coated cells and release toxic substances to destroy them.
The resulting tissue damage is characterized by demyelination and inflammation. The lesions in MOGAD are often described as having a perivenous and confluent pattern, which contributes to the swelling and edema seen on imaging. This physical destruction of the myelin and the underlying oligodendrocytes disrupts nerve signal transmission, causing the neurological symptoms of MOGAD.