β2-Microglobulin (B2M) is a small molecule globulin that plays multiple key roles in the body as the β chain (light chain) part of the human lymphocyte antigen (HLA) on the cell surface. B2M is produced by lymphocytes, platelets, and polymorphonuclear leukocytes. Its structure and function are highly conserved in vertebrates and it is a key component of MHC I and MHC I-like molecules.

1. B2M function and its role in the immune system

B2M plays a vital role in the immune system. It binds to MHC class I molecules to form a complex, thereby presenting peptides produced within the cell to the CD8+ T cells of the immune system . This process is essential for identifying and clearing virus-infected cells and tumor cells in the body. In addition, B2M not only stabilizes the tertiary structure of MHC I or similar molecules , but also participates in regulating the activity of cytokines, such as binding to tumor necrosis factor (TNF), enhancing its effects, and promoting inflammatory responses and immune cell activation.

2. Clinical significance of B2M

As an early and sensitive diagnostic indicator of kidney disease, B2M is increasingly valued in clinical medicine. Increased B2M in urine indicates renal filtration disorder, while abnormal levels of B2M in the blood are associated with a variety of diseases, such as impaired renal function, tumors, infections, autoimmune diseases, and central nervous system diseases.

Renal function assessment: B2M can be used to assess glomerular lesions, hypertension, diabetic renal function impairment, and renal transplantation.

Tumor marker: B2M is a marker for diseases such as multiple myeloma and chronic lymphocytic leukemia, and can be used to evaluate the prognosis and treatment effect of myeloma.

Viral infection: B2M levels will increase in cases of cytomegalovirus, Epstein-Barr virus, hepatitis B or C virus and HIV infection.

Autoimmune diseases: B2M can be used to assess the activity and efficacy of autoimmune diseases (such as systemic lupus erythematosus and rheumatism).

Central nervous system diseases: In cerebral infarction, meningitis, encephalitis and polyneuropathy, the B2M content in cerebrospinal fluid increases, and it is a diagnostic and therapeutic marker for central nervous system leukemia CNSL.

3. Research Progress of B2M

In recent years, research on B2M in cognitive impairment has made breakthrough progress. A research paper published in the journal Cell by Professor Wang Xin's research group at Xiamen University School of Medicine pointed out that B2M can act as an endogenous NMDAR antagonist, impairing synaptic function and thus causing cognitive impairment. This discovery reveals a new mechanism by which peripheral blood B2M enters the brain through the blood-brain barrier and causes cognitive impairment.

The research team found that in the blood of patients with Down syndrome, B2M expression is increased, and it can cross the blood-brain barrier and act on the NMDA receptors of nerve cells, causing cognitive impairment. Reducing the B2M content in Down syndrome mouse models through gene knockout or antibody injection can significantly improve the mice's learning and memory abilities. In addition, B2M also serves as a pro-aging factor, with levels in the blood of older people being significantly higher than those of young people. The research team found that this peptide drug can also improve aging-related cognitive impairment. Research shows that B2M may serve as a common target for a variety of cognitive impairment diseases, providing new treatment ideas and drug targets for cognitive impairment diseases.

4. Conclusion

As a multifunctional star marker, B2-Microglobulin/B2M plays an important role in biology, immunology and clinical medicine. The conservation of its structure and function, as well as its abnormal expression in different disease states, make it an important target for disease diagnosis, prognosis assessment and drug treatment. With the deepening of research, the discovery of new mechanisms and new targets of B2M in cognitive disorders has provided new directions and ideas for research and treatment in related fields.

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Reference：

1. McParland, VJ, Kalverda, AP, Homans, SW, & Radford, SE (2002). Structural properties of an amyloid precursor of β2-microglobulin. Nature Structural Biology, 9(5), 326–
2. Schumacher, F.-R., Delamarre, L., Jhunjhunwala, S., Modrusan, Z., Phung, QT, Elias, JE, & Lill, JR (2017). Building proteomic tool boxes to monitor MHC class I and class II peptides. PROTEOMICS, 17(1-2), 1600061.
3. Yue Gao; Yujuan Hong; Lihong Huang; Shuang Zheng; Haibin Zhang; Shihua Wang; Yi Yao; Yini Zhao, et al. (2023). β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function. Cell,0092-8674.