Did you mean: beta microglobulin
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Immunity Aug 2021As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone...
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
Topics: Amyloid; Animals; Cells, Cultured; Humans; Inflammation; Interleukin-18; Interleukin-1beta; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Myeloma; NLR Family, Pyrin Domain-Containing 3 Protein; Phagocytosis; Signal Transduction; Tumor Microenvironment; Tumor-Associated Macrophages; beta 2-Microglobulin
PubMed: 34289378
DOI: 10.1016/j.immuni.2021.07.002 -
The New England Journal of Medicine Sep 2016Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have...
BACKGROUND
Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
METHODS
We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
RESULTS
Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
CONCLUSIONS
In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biopsy; Drug Resistance, Neoplasm; Exome; Gene Expression Regulation, Neoplastic; Genes, MHC Class I; Humans; Immunotherapy; Interferon-gamma; Janus Kinase 1; Janus Kinase 2; Melanoma; Mutation; Programmed Cell Death 1 Receptor; Recurrence; Sequence Analysis, DNA; Signal Transduction; beta 2-Microglobulin
PubMed: 27433843
DOI: 10.1056/NEJMoa1604958 -
Nature Jan 2023DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint...
DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB). Here, in contrast to other cancer types, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of β2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8 T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1 γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy.
Topics: Humans; Colonic Neoplasms; Histocompatibility Antigens Class I; Immune Checkpoint Inhibitors; Immunotherapy; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes; beta 2-Microglobulin; DNA Mismatch Repair; Receptors, KIR; Cell Line, Tumor; Organoids; Antigen Presentation; Genes, MHC Class I
PubMed: 36631610
DOI: 10.1038/s41586-022-05593-1 -
Kidney360 Dec 2020Almost half a century has elapsed since the first description of dialysis-related amyloidosis (DRA), a disorder caused by excessive accumulation of -2 microglobulin... (Review)
Review
Almost half a century has elapsed since the first description of dialysis-related amyloidosis (DRA), a disorder caused by excessive accumulation of -2 microglobulin (B2M). Within that period, substantial advances in RRT occurred. These improvements have led to a decrease in the incidence of DRA. In many countries, DRA is considered a "disappearing act" or complication. Although the prevalence of patients living with RRT increases, not all will have access to kidney transplantation. Consequently, the number of patients requiring interventions for treatment of DRA is postulated to increase. This postulate has been borne out in Japan, where the number of patients with ESKD requiring surgery for carpal tunnel continues to increase. Clinicians treating patients with ESKD have treatment options to improve B2M clearance; however, there is a need to identify ways to translate improved B2M clearance into improved quality of life for patients undergoing long-term dialysis.
Topics: Amyloidosis; Carpal Tunnel Syndrome; Humans; Kidney Transplantation; Quality of Life; Renal Dialysis
PubMed: 35372889
DOI: 10.34067/KID.0004922020 -
Nature Medicine Aug 2015Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments...
Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP-Binding Cassette Transporters; Adult; Aged; Aged, 80 and over; Aging; Animals; Cognition; Humans; Major Histocompatibility Complex; Mice; Mice, Inbred C57BL; Middle Aged; Neurogenesis; beta 2-Microglobulin
PubMed: 26147761
DOI: 10.1038/nm.3898 -
Advances in Clinical and Experimental... May 2020The effect of bowel inflammation and cancer on the expression of the most prevalent internal controls: ACTB, GAPDH and B2M in whole blood is unknown, although at least...
Whole blood ACTB, B2M and GAPDH expression reflects activity of inflammatory bowel disease, advancement of colorectal cancer, and correlates with circulating inflammatory and angiogenic factors: Relevance for real-time quantitative PCR.
BACKGROUND
The effect of bowel inflammation and cancer on the expression of the most prevalent internal controls: ACTB, GAPDH and B2M in whole blood is unknown, although at least GAPDH occurred to be tightly regulated and suspected of supporting cancer growth, challenging its suitability as a reference.
OBJECTIVES
To evaluate the effect of colorectal cancer (CRC) and active inflammatory bowel disease (IBD) on the stability of ACTB, B2M, GAPDH, HPRT1, SDHA, and TBP leukocyte expression.
MATERIAL AND METHODS
Gene expression in controls and CRC and IBD patients (n = 21/18/25) was evaluated in real-time quantitative polymerase chain reaction (RT-qPCR) using NormFinder, geNorm, BestKeeper, and comparative ΔCt method, and validated by comparison with absolute quantification of interleukin 1β (IL-1β) and CCL4.
RESULTS
HPRT1, SDHA and TBP were superior normalizers in CRC and IBD. The highest expression variability was noted in active IBD. B2M was significantly lower in CRC but higher in IBD. GAPDH was higher in CRC and IBD. ACTB and GAPDH corresponded with CRC advancement (ρ = 0.52 and ρ = 0.53) and with clinical activity in Crohn's disease (ρ = 0.44 and ρ = 0.57) and ulcerative colitis (GAPDH: ρ = 0.72). ACTB, B2M and GAPDH correlated with circulating inflammatory/angiogenic indices, differently in IBD and CRC.
CONCLUSIONS
Leukocyte GAPDH, ACTB, and B2M expression is affected by bowel inflammation and cancer, rendering them unsuitable as a reference in CRC and IBD.
Topics: Actins; Angiogenesis Inducing Agents; Biomarkers, Tumor; Chemokine CCL4; Colorectal Neoplasms; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Inflammatory Bowel Diseases; Interleukin-1beta; Peptide Fragments; Real-Time Polymerase Chain Reaction; Reference Standards; beta 2-Microglobulin
PubMed: 32424999
DOI: 10.17219/acem/118845 -
Current Opinion in Ophthalmology Nov 2017Tubulointerstitial nephritis and uveitis (TINU) is an important yet underrecognized ocular inflammatory syndrome. This review summarizes key historical publications that... (Review)
Review
PURPOSE OF REVIEW
Tubulointerstitial nephritis and uveitis (TINU) is an important yet underrecognized ocular inflammatory syndrome. This review summarizes key historical publications that identified and defined the syndrome, and more recent literature that reveal the importance of urinary β2-microglobulin testing and kidney biopsy in the diagnostic evaluation of patients with TINU. Additionally, research studies providing new insights into disease pathogenesis are highlighted.
RECENT FINDINGS
In contrast with initial reports of TINU manifesting exclusively as an anterior uveitis in pediatric patients, more recent reports have identified TINU in patients of all ages with a wide range of ocular manifestations. Urinary β2-microglobulin has emerged as a sensitive and specific laboratory screening test, and the role of kidney biopsy in differentiating TINU from sarcoidosis continues to evolve. Genetic studies have identified HLA-DQA101, HLA-DQB105, and HLA-DRB101 as high-risk alleles and the identification of antimonomeric C-reactive protein antibodies suggests a role for humoral immunity in disease pathogenesis. Management strategies have evolved to include systemic anti-inflammatory treatment as a result of important outcome studies in patients with significant renal and ocular disease.
SUMMARY
With greater recognition, understanding, and treatment of this syndrome, both ocular inflammation and renal disease can be better addressed.
Topics: Anti-Inflammatory Agents; Biopsy; Diagnosis, Differential; Humans; Kidney; Nephritis, Interstitial; Uveitis; Uveitis, Anterior; beta 2-Microglobulin
PubMed: 28806188
DOI: 10.1097/ICU.0000000000000421 -
Blood Mar 2019Follicular lymphoma (FL) is a low-grade B-cell malignancy that transforms into a highly aggressive and lethal disease at a rate of 2% per year. Perfect isolation of the...
Follicular lymphoma (FL) is a low-grade B-cell malignancy that transforms into a highly aggressive and lethal disease at a rate of 2% per year. Perfect isolation of the malignant B-cell population from a surgical biopsy is a significant challenge, masking important FL biology, such as immune checkpoint coexpression patterns. To resolve the underlying transcriptional networks of follicular B-cell lymphomas, we analyzed the transcriptomes of 34 188 cells derived from 6 primary FL tumors. For each tumor, we identified normal immune subpopulations and malignant B cells, based on gene expression. We used multicolor flow cytometry analysis of the same tumors to confirm our assignments of cellular lineages and validate our predictions of expressed proteins. Comparison of gene expression between matched malignant and normal B cells from the same patient revealed tumor-specific features. Malignant B cells exhibited restricted immunoglobulin (Ig) light chain expression (either Igκ or Igλ), as well the expected upregulation of the gene, but also downregulation of the , , and major histocompatibility complex class II genes. By analyzing thousands of individual cells per patient tumor, we identified the mosaic of malignant B-cell subclones that coexist within a FL and examined the characteristics of tumor-infiltrating T cells. We identified genes coexpressed with immune checkpoint molecules, such as and in regulatory T (Treg) cells, providing a better understanding of the gene networks involved in immune regulation. In summary, parallel measurement of single-cell expression in thousands of tumor cells and tumor-infiltrating lymphocytes can be used to obtain a systems-level view of the tumor microenvironment and identify new avenues for therapeutic development.
Topics: Biopsy; CCAAT-Enhancer-Binding Proteins; CD4-Positive T-Lymphocytes; CD52 Antigen; Cell Lineage; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cells; Histocompatibility Antigens Class II; Humans; Immune System; Immunoglobulin G; Lectins, C-Type; Leukocytes, Mononuclear; Lymphoma, B-Cell; Lymphoma, Follicular; Palatine Tonsil; Receptors, IgE; Sequence Analysis, RNA; T-Lymphocytes, Regulatory; Transcriptome; Tumor Microenvironment; beta 2-Microglobulin
PubMed: 30591526
DOI: 10.1182/blood-2018-08-862292 -
The Journal of Biological Chemistry Dec 2022Self-association of WT βmicroglobulin (WT-βm) into amyloid fibrils is associated with the disorder dialysis related amyloidosis. In the familial variant D76N-βm, the...
Self-association of WT βmicroglobulin (WT-βm) into amyloid fibrils is associated with the disorder dialysis related amyloidosis. In the familial variant D76N-βm, the single amino acid substitution enhances the aggregation propensity of the protein dramatically and gives rise to a disorder that is independent of renal dysfunction. Numerous biophysical and structural studies on WT- and D76N-βm have been performed in order to better understand the structure and dynamics of the native proteins and their different potentials to aggregate into amyloid. However, the structural properties of transient D76N-βm oligomers and their role(s) in assembly remained uncharted. Here, we have utilized NMR methods, combined with photo-induced crosslinking, to detect, trap, and structurally characterize transient dimers of D76N-βm. We show that the crosslinked D76N-βm dimers have different structures from those previously characterized for the on-pathway dimers of ΔN6-βm and are unable to assemble into amyloid. Instead, the crosslinked D76N-βm dimers are potent inhibitors of amyloid formation, preventing primary nucleation and elongation/secondary nucleation when added in substoichiometric amounts with D76N-βm monomers. The results highlight the specificity of early protein-protein interactions in amyloid formation and show how mapping these interfaces can inform new strategies to inhibit amyloid assembly.
Topics: Humans; beta 2-Microglobulin; Amyloid; Amyloidogenic Proteins; Amino Acid Substitution; Amyloidosis; Biophysical Phenomena; Polymers
PubMed: 36328246
DOI: 10.1016/j.jbc.2022.102659 -
Annals of Medicine Dec 2023Beta-2-microglobulin (B2M), cystatin C and lipocalin-2 (LCN-2) are established renal biomarkers, yet their roles in stroke have not been fully evaluated. We aimed to...
INTRODUCTION
Beta-2-microglobulin (B2M), cystatin C and lipocalin-2 (LCN-2) are established renal biomarkers, yet their roles in stroke have not been fully evaluated. We aimed to investigate the relationship of B2M, cystatin C, and LCN-2 with stroke risk in a general Chinese population.
METHODS
We used ordinal regression to study the relationship between serum B2M, cystatin C, and LCN-2 with stroke risk in 1060 participants (mean age 45.4 ± 10.8 years, 46% male) from the Shenzhen-Hong Kong United Network on Cardiovascular Disease (SHUN-CVD) study. Stroke risk was classified into low-risk, middle-risk and high-risk groups according to the China National Stroke Screening Survey criteria. Serum biomarker levels were measured using immunoturbidimetric assays. Participants with valid data on serum biomarker levels and stroke risk were included in the analysis.
RESULTS
The number of participants in the low-risk, middle-risk and high-risk stroke risk groups were 663, 143 and 254 respectively. Elevated serum B2M, cystatin C, and LCN-2 levels were associated with being male, overweight/obesity, hypertension, alcohol consumption and smoking. Serum B2M, cystatin C and LCN-2 levels were significantly associated with stroke risk in the overall population (B2M: = 0.595, < .001; cystatin C: = 3.718, < .001; LCN-2: = 0.564, < .001) after adjustment for age.
CONCLUSION
Elevated serum B2M, cystatin C and LCN-2 levels are associated with stroke risk. They may be novel biomarkers for clinicians to assess stroke risk.Key messagesSerum beta-2-microglobulin, cystatin C and lipocalin-2 levels are significantly associated with stroke risk.Beta-2-microglobulin, cystatin C and lipocalin-2 may serve as useful biomarkers for stroke risk stratification in the general population.
Topics: Humans; Male; Adult; Middle Aged; Female; Cystatin C; Lipocalin-2; East Asian People; Biomarkers; Stroke; Creatinine
PubMed: 37155257
DOI: 10.1080/07853890.2023.2203516