β2-Microglobulin: A Multidimensional Perspective from Immunobiology to Clinical Medicine

β2-microglobulin (beta 2-microglobulin, abbreviated as β2-M or B2M), as the light chain component of the major histocompatibility complex (MHC) class I molecules, plays a pivotal role in maintaining immune system function and the pathogenesis of diseases. This article comprehensively explores the molecular characteristics, physiological functions, and pathological significance of β2-M in various diseases, with a particular focus on its clinical application value as a biomarker in kidney diseases, hematologic malignancies, and inflammatory diseases. By systematically reviewing the fundamental biological properties and clinical correlations of β2-M, we can gain deeper insights into how this multifunctional protein participates in immune surveillance, cell signaling, and pathological processes, while also envisioning its potential as a diagnostic indicator and therapeutic target.

Molecular Characteristics and Physiological Functions of β2-Microglobulin

The structural features of β2-M underpin its biological functions. As a small protein with a molecular weight of approximately 11.8 kDa, β2-M consists of 99 amino acids and exhibits a typical immunoglobulin-like fold structure, featuring a sandwich-like formation of two β-sheets stabilized by a conserved disulfide bond. This compact and stable structure allows β2-M to tolerate a wide range of pH and temperature variations, maintaining relative stability in bodily fluids. From an evolutionary perspective, β2-M is highly conserved among vertebrates, with a 70% amino acid sequence similarity between humans and mice, reflecting its central role in physiological processes. Notably, β2-M lacks a transmembrane domain and is anchored to the cell surface through non-covalent binding with the heavy chain of MHC class I molecules. This characteristic also determines its release into the extracellular environment during cell turnover or activation.

The synthesis and metabolism of β2-M reflect its dynamic equilibrium. β2-M is continuously produced by all nucleated cells as an essential component for the assembly and expression of MHC class I molecules. Intracellularly, β2-M synthesis begins in the rough endoplasmic reticulum, where it assembles with the MHC class I heavy chain and antigenic peptides to form a complete trimeric complex, which is then transported to the cell surface. Under normal physiological conditions, adult serum β2-M concentrations are maintained at 0.8–2.2 mg/L, with a relatively constant production rate of approximately 150–200 mg per day. β2-M is almost entirely excreted by the kidneys, with about 99.9% of filtered β2-M reabsorbed and degraded in the proximal tubules, leaving only trace amounts in the final urine (<0.3 mg/L). This highly efficient renal clearance mechanism makes serum β2-M levels extremely sensitive to changes in glomerular filtration function, establishing it as an important indicator for assessing kidney function.

The immunological functions of β2-M constitute the core of its physiological role. As an essential component of MHC class I molecules, β2-M is critical for the proper folding, stability, and cell surface expression of these molecules. The MHC class I–β2-M–antigen peptide trimeric complex is fundamental for cytotoxic T lymphocyte (CTL) recognition of virus-infected cells and tumor cells, playing a key role in adaptive immune responses. Recent studies have revealed that β2-M also possesses independent immunomodulatory functions: it can activate osteoclasts to promote bone resorption, bind to neuronal surfaces to influence central nervous system function, and participate in the maintenance and differentiation of hematopoietic stem cells. Particularly noteworthy is the finding that free-form β2-M can bind to various cell surface receptors (such as CD3 and HFE) to regulate cell signaling. These discoveries have significantly expanded our understanding of β2-M’s physiological functions.

The genetic and regulatory properties of β2-M reflect the fine-tuned control of its expression. The human β2-M gene is located on the long arm of chromosome 15 (15q21.1) and consists of three exons and two introns, with a coding region spanning 354 base pairs. The expression of the β2-M gene is regulated by various transcription factors, including the interferon regulatory factor (IRF) family and nuclear factor kappa B (NF-κB), enabling rapid upregulation in response to inflammation and immune activation. Epigenetic modifications such as DNA methylation and histone acetylation also contribute to the long-term regulation of β2-M expression. At the protein level, β2-M has a half-life of approximately 2–4 hours, a rapid turnover that allows its levels to sensitively reflect pathological changes. β2-M gene knockout mice exhibit defective MHC class I expression and abnormal CD8+ T cell development, confirming its indispensable role in the immune system.

Pathological forms of β2-M are closely associated with disease. Under certain pathological conditions, β2-M can undergo conformational changes or post-translational modifications (e.g., glycosylation, oxidation), resulting in variants with distinct biological properties. The most typical example is β2-M amyloid fibrils in dialysis-related amyloidosis (DRA), where misfolded β2-M deposits in joints and bones, causing severe complications. Additionally, acidic conditions in the tumor microenvironment can promote β2-M conformational changes, enhancing its immunosuppressive functions. These pathological forms of β2-M not only participate in disease progression but also provide specific targets for therapeutic intervention. Understanding the structural changes and functional alterations of β2-M in different pathological contexts is crucial for developing targeted intervention strategies.

Pathological Roles of β2-Microglobulin in Diseases

Changes in β2-M in kidney diseases reflect the overall status of renal function. Since β2-M is almost entirely excreted by the kidneys, its serum concentration is inversely correlated with the glomerular filtration rate (GFR), making it a sensitive indicator for assessing kidney function. In acute kidney injury (AKI), serum β2-M levels often rise earlier than serum creatinine, providing an earlier warning of renal impairment. In chronic kidney disease (CKD), serum β2-M gradually accumulates as renal function declines, and elevated levels (>30 mg/L) are closely associated with poor prognosis. Notably, the renal clearance mechanism of β2-M is unique: it is first freely filtered through the glomeruli and then almost completely reabsorbed and degraded in the proximal tubules. Therefore, increased urinary β2-M primarily reflects proximal tubule dysfunction, as seen in Fanconi syndrome, heavy metal poisoning, or drug-induced nephrotoxicity. Combined analysis of serum and urinary β2-M can differentiate between glomerular and tubular damage, providing valuable information for the localization of kidney disease.

In hematologic malignancies, β2-M has emerged as an important prognostic marker. Since lymphocytes are a major source of β2-M, lymphoproliferative disorders such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) often exhibit elevated serum β2-M levels. In MM, β2-M levels closely correlate with tumor burden, and the International Staging System (ISS) classifies β2-M >3.5 mg/L as a key criterion for stage III disease, where the median survival is only 29 months, significantly shorter than in patients with low β2-M. Similarly, in CLL, β2-M >3.5 mg/L is a high-risk indicator in the Rai and Binet staging systems, associated with disease progression and poor prognosis. Mechanistic studies suggest that malignant lymphocytes not only produce large amounts of β2-M but may also exploit it to suppress anti-tumor immune responses, creating a vicious cycle of immune evasion. These findings position β2-M not only as a marker of tumor burden but also as a potential target for immunotherapy.

Dialysis-related amyloidosis (DRA) is a classic complication of β2-M accumulation. In long-term hemodialysis patients (typically >5–10 years), serum β2-M levels can increase 10- to 50-fold due to inadequate renal clearance and limited dialysis membrane efficiency. This persistent elevation leads to β2-M deposition in joints, bones, and other tissues, forming amyloid fibrils that cause severe complications such as carpal tunnel syndrome, destructive arthropathy, and pathological fractures. The development of DRA is closely linked to β2-M conformational changes: under conditions of inflammation or oxidative stress, β2-M undergoes partial unfolding, exposing its hydrophobic core and aggregating into amyloid fibrils. Recent studies have found that certain metal ions (e.g., Cu2+) and glycosaminoglycans can promote this process, while serum amyloid P component (SAP) may inhibit fibril formation. Understanding these molecular mechanisms has opened new avenues for DRA prevention and treatment, such as using high-flux dialysis membranes to enhance β2-M clearance or developing small-molecule drugs to inhibit β2-M aggregation.

Changes in β2-M in inflammatory and autoimmune diseases reflect immune system activation. As an acute-phase reactant, β2-M levels rise in various inflammatory conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). In RA patients, serum and synovial fluid β2-M levels correlate positively with disease activity and may contribute to joint destruction. Mechanistically, inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) can strongly induce β2-M expression, creating a positive feedback loop. Interestingly, serum β2-M levels are reduced in certain autoimmune diseases like ankylosing spondylitis (AS), possibly due to abnormal MHC class I expression. These differences highlight the complex role of β2-M in various immune pathologies, and its dynamic monitoring may provide useful information for assessing disease activity and treatment response.

The role of β2-M in tumor immune evasion has garnered increasing attention. Recent studies have found that some tumor cells evade immune surveillance by deleting or silencing the β2-M gene, leading to MHC class I deficiency. Approximately 15–20% of metastatic melanomas and 30% of colorectal cancers harbor β2-M gene mutations, making them less responsive to immune checkpoint inhibitors. On the other hand, soluble β2-M can directly inhibit T cell and NK cell function by binding to immune cell surface receptors (e.g., CD3, KIR), creating an immunosuppressive microenvironment. Based on these findings, β2-M-targeted immunotherapy strategies are being explored, such as using anti-β2-M antibodies to block its immunosuppressive effects or restoring β2-M expression in tumor cells via gene editing to enhance immunogenicity. These advances offer new directions for overcoming resistance to cancer immunotherapy.

Research on β2-M in neurological diseases has opened new frontiers. Surprisingly, β2-M has been identified as a pro-aging factor, with its accumulation in the blood of aged mice impairing cognitive function and neurogenesis. Alzheimer’s disease (AD) patients exhibit elevated cerebrospinal fluid β2-M levels, correlating with cognitive impairment. Mechanistically, β2-M may contribute to neurodegeneration by inhibiting hippocampal neurogenesis and promoting tau protein phosphorylation. Conversely, β2-M gene knockout mice display enhanced learning, memory, and neuroplasticity, suggesting that targeting β2-M could be a strategy to improve cognitive function. These findings significantly expand our understanding of β2-M’s pathological roles, extending from peripheral immune regulation to central nervous system function.

Detection Methods and Clinical Applications of β2-Microglobulin

The evolution of β2-M detection technology has progressed from radioimmunoassays to automated platforms. Early β2-M testing primarily used radioimmunoassay (RIA), which, while sensitive, posed risks of radioactive contamination. Modern clinical laboratories widely employ immunoturbidimetry or enzyme-linked immunosorbent assays (ELISA), which are based on β2-M-specific antibodies and are simple to perform and suitable for batch testing. In recent years, automated immunoassay platforms such as chemiluminescence (CLIA) and electrochemiluminescence (ECLIA) have further improved sensitivity and precision, with detection limits as low as 0.1 mg/L. Notably, differences exist between methods, particularly for high-value samples, necessitating method-specific reference intervals. Sample handling must also be standardized: serum or plasma samples should be processed promptly (within 2 hours) to prevent β2-M degradation at room temperature, while urine samples require acidification (pH <6) to prevent β2-M breakdown. Standardizing these technical parameters is critical for ensuring result comparability.

Applications in kidney disease diagnosis represent the traditional domain of β2-M testing. Serum β2-M concentration is closely correlated with GFR, making it a sensitive indicator for assessing kidney function, particularly for early detection of renal impairment. Compared to traditional markers like creatinine, β2-M is unaffected by age, sex, or muscle mass, offering advantages for patients with muscle atrophy. Urinary β2-M testing is primarily used to evaluate tubular function: normal urinary β2-M is <0.3 mg/L, while levels >0.5 mg/L suggest proximal tubule dysfunction. In kidney transplantation, elevated urinary β2-M is an early marker of acute rejection, appearing 1–3 days before creatinine rises. Importantly, combined serum and urinary β2-M analysis can differentiate glomerular from tubular injury patterns: glomerular diseases primarily show elevated serum β2-M with normal urinary levels, while tubular diseases exhibit normal or mildly elevated serum β2-M with significantly increased urinary excretion. This diagnostic value makes β2-M an essential tool for kidney disease assessment.

Prognostic evaluation in hematologic malignancies has established β2-M’s clinical significance. In MM, β2-M is a core component of the International Staging System (ISS), with β2-M ≤3.5 mg/L (stage I), 3.5–5.5 mg/L (stage II), and >5.5 mg/L (stage III) corresponding to markedly different prognoses. Similarly, in CLL, β2-M levels correlate strongly with tumor burden and disease stage, serving as an independent prognostic factor. NHL patients with pretreatment β2-M >3 mg/L exhibit higher aggressiveness and poorer outcomes. In clinical practice, β2-M testing is routinely incorporated into the evaluation of these diseases for risk stratification and treatment decision-making. Notably, dynamic changes in β2-M are more prognostically valuable than single measurements: failure of β2-M to decrease or rising levels after treatment often indicate resistance or early relapse, whereas sustained low β2-M suggests a favorable treatment response. These applications make β2-M an indispensable marker in the management of hematologic malignancies.

Monitoring dialysis-related amyloidosis is a specialized application of β2-M. For long-term dialysis patients, regular serum β2-M testing (every 3–6 months) helps assess dialysis adequacy and predict DRA risk. High-flux dialysis membranes can reduce serum β2-M by 20–30%, lowering amyloid deposition risk. When serum β2-M consistently exceeds 25 mg/L, DRA should be suspected, warranting closer evaluation of bones and joints. Recently developed β2-M clearance assays directly measure the efficiency of different dialysis modalities in removing β2-M, guiding personalized dialysis regimens. For patients with established DRA, kidney transplantation is the most effective treatment, normalizing serum β2-M within 1–2 weeks and gradually resolving amyloid deposits. These applications have significantly improved long-term outcomes and quality of life for dialysis patients.

Assessing inflammatory disease activity expands β2-M’s utility. In RA patients, serum β2-M correlates positively with disease activity scores (DAS28), and its changes can reflect treatment response. Compared to traditional inflammatory markers like C-reactive protein (CRP), β2-M is less affected by liver synthetic function, offering advantages for patients with liver disease. In transplantation medicine, elevated β2-M is a sensitive marker for rejection and infection, aiding differential diagnosis. Certain viral infections, such as HIV and CMV, can also elevate β2-M, with dynamic changes reflecting viral replication activity. While these applications are not yet routine, they provide valuable supplementary information in specific contexts.

Emerging applications demonstrate β2-M’s broad potential. In neurodegenerative diseases, cerebrospinal fluid β2-M levels correlate with AD severity, possibly serving as a disease monitoring tool. In cancer immunotherapy, β2-M gene mutation testing can predict response to immune checkpoint inhibitors, guiding treatment selection. In regenerative medicine, β2-M has been identified as a key mediator of hematopoietic stem cell aging, and targeted inhibition may improve stem cell function. Though most of these applications are still in the research phase, they highlight β2-M’s potential value across multiple medical fields, warranting further exploration and validation.

Future Perspectives on β2-Microglobulin Research

Innovations in detection technology will enhance β2-M’s clinical utility. Current assays primarily measure total β2-M concentration without distinguishing between modified or conformational states. Developing specific detection methods, such as mass spectrometry, could quantify glycosylated, oxidized, or other modified forms, providing more precise pathological information. Advances in microfluidics and chip technology may enable point-of-care testing (POCT), facilitating real-time clinical monitoring. Additionally, molecular imaging techniques, such as β2-M-specific PET probes, could visualize in vivo β2-M distribution, particularly for early detection of amyloid deposits. These technological innovations will expand β2-M’s clinical applications, transforming it from a laboratory marker into a multifunctional diagnostic tool.

Deeper insights into pathogenesis will reveal new β2-M functions. Current research focuses mainly on β2-M’s roles as an MHC component and soluble molecule, with limited understanding of its intracellular functions and signaling mechanisms. Studies have shown that β2-M can internalize into cells and influence lysosomal function and autophagy, suggesting broader biological roles. Gene-editing tools like CRISPR/Cas9 can create cell-specific β2-M knockout models to precisely dissect its tissue-specific functions. Single-cell sequencing could uncover cellular heterogeneity in β2-M expression regulation, particularly in the dynamic tumor microenvironment. Breakthroughs in these basic research areas will provide a stronger scientific foundation for β2-M’s clinical applications.

Development of targeted therapies will expand β2-M’s translational potential. Antibody drugs targeting β2-M, such as anti-B2M monoclonal antibodies, could block its immunosuppressive effects and enhance anti-tumor immune responses. Small-molecule inhibitors, like peptide mimetics, might specifically disrupt β2-M’s interaction with MHC heavy chains, modulating immune recognition. RNA interference could reduce β2-M expression, mitigating amyloid deposition. For DRA treatment, compounds that promote β2-M degradation or inhibit its aggregation hold significant promise. Though most of these strategies are in preclinical stages, they represent new directions for personalized medicine and may offer more precise interventions for related diseases.

Integrative multi-omics studies will deepen understanding of β2-M. Combining β2-M data with genomic, transcriptomic, proteomic, and metabolomic information can construct more comprehensive disease network models. For example, analyzing interactions between β2-M and HLA genotypes may reveal genetic predispositions to immune diseases. Proteomic studies of β2-M interactions could uncover new signaling pathways and regulatory nodes. Artificial intelligence algorithms could analyze large-scale clinical data to build β2-M-based disease prediction models. These systems biology approaches will shift β2-M research from a single-marker focus to network medicine, providing new insights into complex disease mechanisms and precision medicine.

Establishing clinical guidelines will promote standardized implementation. As β2-M testing becomes more widespread, uniform clinical application standards and interpretation protocols are needed. For different diseases like MM, CKD, and DRA, clear indications for β2-M testing, optimal sampling timing, and result interpretation should be defined. Multicenter studies should establish method-specific reference intervals and cutoffs to reduce assay variability. Professional societies could develop guidelines to standardize β2-M’s use in diagnosis, prognosis, and treatment monitoring. Such standardization is critical for maximizing β2-M’s clinical value and represents a key step in translational research.

Challenges and opportunities coexist in β2-M research. Despite its promise, β2-M research faces several challenges: lack of assay standardization, limited specificity in certain diseases, and incomplete understanding of pathological mechanisms. Future studies should address these bottlenecks while exploring new applications. Particularly promising areas include β2-M’s emerging roles in aging, neurodegeneration, and tumor immunology, which may yield groundbreaking discoveries. Interdisciplinary collaboration and technological innovation will drive β2-M research forward, ultimately translating basic findings into clinical applications that benefit a broader patient population.

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