Role of Myelin-Associated Glycoprotein (MAG) in Multiple Sclerosis
Myelin-associated glycoprotein (MAG) plays a significant role in multiple sclerosis pathogenesis through its early selective loss in developing MS plaques compared to other myelin proteins, suggesting it may be a key factor in disease initiation and progression.
MAG Structure and Function
- MAG is a 100-kD integral membrane glycoprotein belonging to the immunoglobulin superfamily 1
- Located in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths 2
- Functions in interactions between myelin-forming cells (oligodendrocytes and Schwann cells) and the axolemma 1
- Contains highly immunogenic carbohydrate determinants that are also expressed on other neural glycoconjugates 1
MAG in MS Pathophysiology
Early Loss in MS Lesions
- MAG shows preferential loss at the periphery of MS plaques compared to other myelin proteins 3
- In outer periplaque regions, while myelin basic protein (MBP) and proteolipid protein (PLP) remain close to control levels, MAG is significantly reduced to approximately 57% of control levels 3
- This selective loss suggests MAG may play a critical role in the early stages of MS plaque formation 1
Mechanisms of MAG Loss
- Human MAG is highly susceptible to cleavage by Ca²⁺-activated neutral protease 1, 3
- A high proportion of MAG in MS samples is often found in the form of dMAG, a proteolytic derivative formed by myelin-associated Ca²⁺-activated neutral protease 3
- This proteolytic conversion to dMAG may initiate the preferential loss of MAG at MS plaque peripheries 3
Immune Responses to MAG in MS
Antibody Responses
- Elevated anti-MAG antibodies have been detected in cerebrospinal fluid (CSF) of MS patients compared to those with other neurological diseases and healthy controls 4
- These antibodies appear to be directed toward carbohydrate determinants in the glycoprotein 4
- The antibodies react with human MAG but not with rat MAG 4
- CSF samples from high IgG producers show significantly greater anti-MAG antibody levels than those from low IgG producers 4
T and B Cell Responses
- Both MS patients and patients with polyneuropathy show elevated levels of T and B cells recognizing MAG and its peptides 5
- Multiple MAG peptides can function as immunodominant T and/or B cell epitopes in individual subjects 5
- The enhanced T and B cell response to MAG may contribute to disease initiation and/or progression, though they could also represent secondary responses to myelin damage 5
Diagnostic and Monitoring Implications
- Advanced MRI techniques like magnetization transfer imaging can help assess myelin content and integrity, which correlates with the degree of myelin loss and axonal damage in MS patients 6
- Decreases in magnetization transfer ratio have been shown to correlate with myelin loss and axonal damage, potentially reflecting MAG-related pathology 6
- Quantitative MRI techniques might enable measurement of disease-related mechanisms that occur before atrophy development 6
Clinical Relevance and Future Directions
- The weak immune response to MAG detected in MS patients may be secondary to the demyelinating process but could play a role in disease progression 4
- Future research should focus on identifying new MRI markers of neuroinflammation and remyelination to better monitor MAG-related pathology 6
- Understanding MAG's role in MS may help develop targeted therapies aimed at preventing its loss or promoting remyelination
Important Distinctions
- It's crucial to differentiate MS from other demyelinating disorders like MOG antibody disease (MOGAD), as some MS therapies may be ineffective or potentially harmful in MOGAD patients 7
- Unlike in MOGAD, where MOG antibodies are diagnostic, MAG's role in MS is primarily pathophysiological rather than serving as a specific biomarker 7
The early and selective loss of MAG in MS lesions, combined with its susceptibility to proteolytic cleavage and the presence of anti-MAG immune responses, suggests that MAG plays an important role in MS pathogenesis, potentially serving as both an early marker of disease activity and a contributor to the demyelinating process.