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1
Chen, Zhaosan, Nianzhi Zhang, Shuangshuang Lu, Mansoor Tariq, Junya Wang, and Chun Xia. "Crystallization and preliminary X-ray diffraction analysis of the two distinct types of zebrafish β2-microglobulin." Acta Crystallographica Section F Structural Biology Communications 71, no. 6 (May 22, 2015): 794–98. http://dx.doi.org/10.1107/s2053230x15005737.
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β2-Microglobulin (β2m) noncovalently associates with the heavy chain of major histocompatibility complex class I (MHC I) molecules, which bind foreign antigen peptides to control the cytotoxic T lymphocyte (CTL) immune response. In contrast to mammals, there are distinct types of β2ms derived from two loci in a number of teleost species. In order to clarify the structures of the β2ms, the zebrafish (Danio rerio) β2msDare-β2m-I andDare-β2m-II were expressed inEscherichia coli, purified and crystallized, and diffraction data were collected to 1.6 and 1.9 Å resolution, respectively. Both crystals belonged to space groupP212121. The unit-cell parameters were determined to bea= 38.2,b= 50.4,c= 50.9 Å forDare-β2m-I anda= 38.9,b= 52.7,c= 65.8 Å forDare-β2m-II. Each asymmetric unit was constituted of one molecule, with Matthews coefficients of 2.22 and 3.01 Å3 Da−1and solvent contents of 45 and 59% forDare-β2m-I andDare-β2m-II, respectively. These two β2m structures will provide relevant information for further studies of the structures of the MHC I complex.
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Lonnemann, Gerhard, and Karl M. Koch. "β2-Microglobulin Amyloidosis: Effects of Ultrapure Dialysate and Type of Dialyzer Membrane." Journal of the American Society of Nephrology 13, suppl 1 (January 2002): S72—S77. http://dx.doi.org/10.1681/asn.v13suppl_1s72.
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ABSTRACT. The available data on the pathophysiology of β2-microglobulin amyloidosis (β2mA) suggest that this progressive disease associated with end-stage renal failure develops in several consecutive phases. First, declining kidney function leads to retention of β2 microglobulin (β2m) and its deposition preferentially in the synovial tissue of bigger joints such as wrists, shoulders, and hips. Second, at the site of deposition, formation of unique amyloid fibrils, whose major component is β2m, takes place. Deposition and fibril formation occur in the absence of modification of β2mA by advanced glycoxidation end products and also in the absence of a local inflammatory response. It is later, in the third phase, that advanced glycoxidation end product modification of β2m induces a local inflammatory response by attracting macrophages chemotactically and by stimulating these cells to produce and release proinflammatory cytokines. In addition, unmodified β2m itself induces inflammatory activities such as upregulation of cyclooxygenase-2 and metalloproteinase-1. The severity of the local inflammation seems to determine the degree of the destructive processes in tissue and bone accompanying β2mA.
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Shields, Michael J., Nassim Assefi, Wesley Hodgson, Ellen J. Kim, and Randall K. Ribaudo. "Characterization of the Interactions Between MHC Class I Subunits: A Systematic Approach for the Engineering of Higher Affinity Variants of β2-Microglobulin." Journal of Immunology 160, no. 5 (March 1, 1998): 2297–307. http://dx.doi.org/10.4049/jimmunol.160.5.2297.
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Abstract Human β2m (hβ2m) binds to murine MHC I molecules with higher affinity than does murine β2m and therefore can be used as a model system to define and dissect the interactions between β2m and MHC I heavy chains that promote the stability of the complex. In the present study we compare three-dimensional crystal structures of human and murine MHC I molecules and use functional studies of chimeric human:murine β2m variants to define a region of β2m that is involved in the higher affinity of hβ2m for murine MHC I heavy chains. Further examination of the three-dimensional structure in this region revealed conformational differences between human and murine β2m that affect the ability of an aspartic acid residue at position 53 (D53) conserved in both β2ms to form an ionic bond with arginine residues at positions 35 and 48 of the heavy chain. Mutation of residue D53 to either asparagine (D53N) or valine (D53V) largely abrogated the stabilizing effects of hβ2m on murine MHC I expression in a predictable manner. Based on this observation a variant of hβ2m was engineered to create an ionic bond between the heavy chain and β2m. This variant stabilizes cell surface H-2Dd heavy chains to a greater extent than wild-type hβ2m. Studying these interactions in light of the growing database of MHC I crystal structures should allow the rational design of higher affinity hβ2m variants for use in novel peptide-based vaccines capable of inducing cell-mediated immune responses to viruses and tumors.
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Stefanovic', Vladisav, Svetislav Kostic', Vidojko Djordjevic', Marina Mitic', and Momcilo Bogicevic'. "β2-Microglobulin Elimination in End-Stage Renal Disease Patients on Renal Replacement Therapy." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 13, no. 2_suppl (January 1993): 520–22. http://dx.doi.org/10.1177/089686089301302s127.
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β2-microglobulin (β2M) is a small molecular mass protein associated with dialysis amyloidosis. We have studied β2M elimination in end-stage renal disease (EsRD) patients treated by peritoneal dialysis. In 12 patients on continuous ambulatory peritoneal dialysis (CAPD) and 7 patients on intermittent peritoneal dialysis (IPD) 30.4±4.2 mg/day and 21.3± 1.8 mg/12 hour of β2M, respectively, were removed by dialysis fluid. Approximately the same amount of β2M was removed by each of four 2-L exchanges in CAPD; however, the most efficient removal of β2M was in the first IPD exchange. Serum β2M levels in these patients were 25.7 ±4.4 and 31.4±5.2 mg/L, respectively. In 24 patients on hemodialysis using cuprophan membrane the serum level of β2M was 55.1±4.1 mg/L. After a 3-month dialysis on polyacrylonitrile (PAN) membrane, the serum β2M level decreased to 45.0±2.3 mg/L. A substantial amount of β2M was removed by urine, 14.6.:1:2.3 mg/L, and saliva, 2.3±0.4 mg/L. This study has shown markedly increased β2M levels in patients on conventional hemodialysis treatment, predisposing to β2M-related amyloidosis. A significant amount of β2M was removed during both CAPD and IPD treatment.
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Zhang, Fan, Yu-Ming Chu, and Wei-Mao Qian. "Bounds for the Arithmetic Mean in Terms of the Neuman-Sándor and Other Bivariate Means." Journal of Applied Mathematics 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/582504.
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We present the largest valuesα1,α2, andα3and the smallest valuesβ1,β2, andβ3such that the double inequalitiesα1M(a,b)+(1-α1)H(a,b)<A(a,b)<β1M(a,b)+ (1-β1)H(a,b),α2M(a,b)+(1-α2) H-(a,b) < A(a,b)<β2M(a,b)+(1-β2)H-(a,b), andα3M(a,b)+(1-α3)He(a,b)< A(a,b)<β3M (a,b)+(1-β3)He(a,b)hold for alla,b>0witha≠b, whereM(a,b),A(a,b),He(a,b),H(a,b)andH-(a,b)denote the Neuman-Sándor, arithmetic, Heronian, harmonic, and harmonic root-square means ofaandb, respectively.
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Corlin, Dorthe B., Jette W. Sen, Søren Ladefoged, Grethe Bjerregaard Lund, Mogens H. Nissen, and Niels HH Heegaard. "Quantification of Cleaved β2-Microglobulin in Serum from Patients Undergoing Chronic Hemodialysis." Clinical Chemistry 51, no. 7 (July 1, 2005): 1177–84. http://dx.doi.org/10.1373/clinchem.2005.049544.
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Abstract Background: Patients on chronic hemodialysis are prone to develop amyloid deposits of misfolded β2-microglobulin (β2M) in osteoarticular tissues. β2M with various deletions/truncations and chemical modifications has been found together with structurally intact β2M in extracts of β2M amyloid fibrils. The state of the circulating population of β2M molecules has not been characterized previously with high-resolution methods. Methods: We used immunoaffinity–liquid chromatography–mass spectrometry analysis of serum samples to examine whether structurally modified β2M is generated in the circulation. In addition, we developed an immunoassay for the quantification of a cleaved β2M variant in biological fluids based on novel monoclonal antibodies and applied this assay to patient and control sera. Results: A specific alteration compatible with the generation of lysine-58–cleaved and truncated β2M (ΔK58-β2M) was found in the sera of many (20%–40%) dialysis patients but not in control sera or sera from patients with cerebral amyloidosis (Alzheimer disease). Applied to patient sera, specific immunoassays revealed that dialysis, as expected, significantly lowered the total β2M concentration, but the concentrations of ΔK58-β2M remained unchanged after dialysis. The results also show that patients dialyzed with less biocompatible membranes have higher serum concentrations of cleaved β2M (mean, 8.5, 1.8, and 0.7 mg/L in cuprophane membrane-dialyzed, polysulfone membrane-dialyzed, and control sera, respectively). Conclusions: This study for the first time demonstrates and assigns the structure of a specific β2M variant in sera from dialysis patients. Because this variant is conformationally unstable in vitro, it may be involved in in vivo amyloidogenesis.
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ZHU, Xiaoping, Junmin PENG, Raktima RAYCHOWDHURY, Atsushi NAKAJIMA, Wayne I. LENCER, and Richard S. BLUMBERG. "The heavy chain of neonatal Fc receptor for IgG is sequestered in endoplasmic reticulum by forming oligomers in the absence of β2-microglobulin association." Biochemical Journal 367, no. 3 (November 1, 2002): 703–14. http://dx.doi.org/10.1042/bj20020200.
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The heavy chain (HC) of the neonatal Fc receptor (FcRn) for IgG is non-convalently associated with β2-microglobulin (β2m). In β2m-/- mice, FcRn functions are greatly impaired. We sought to determine how FcRn HC, particularly its structure and biogenesis, is affected by the absence of β2m. Human FcRn HC, expressed from the β2m-null cell line FO-1FcRn, was present as a monomeric 45-kDa protein under reducing conditions but primarily as a 92-kDa oligomeric protein under non-reducing conditions. Two-dimensional electrophoresis and MS analysis showed that the 92-kDa protein was a dimer of the 45-kDa HC. Immunostaining showed that FcRn HC in FO-1FcRn was co-localized with the endoplasmic reticulum (ER) protein Bip/GRP78 but not with an endosome protein, EEA1. In contrast, FcRn HC in FO-1FcRn+β2m was detected in both the ER and endosome. The dimeric HC in FcRn oligomers was free of β2m association in FO-1FcRn+β2m. Mutation of non-paired cysteine residues at positions 48 and 251 within the human FcRn cDNA failed to eliminate the oligomers. The FcRn HC oligomers could be reduced by reconstitution of FO-1FcRn with β2m or by balanced expression of FcRn HC with β2m, or β2m fused with a KDEL retention sequence. Similarly, the majority of FcRn HC isolated from neonatal β2m-/- mice was in a dimeric form under non-reducing conditions. The amount of FcRn HC was significantly decreased in β2m-/- mice and FO-1FcRn. Furthermore, β2m-free FcRn HC was sensitive to endoglycosidase digestion. These results indicate that FcRn HC alone can form disulphide-bonded oligomers in the ER, which may represent a misfolded protein. The β2m association with FcRn HC is critical for correct folding of FcRn and exiting the ER for routing to endosomes and the cell surface.
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Good, Sarah C., Katherine M. Dewison, Sheena E. Radford, and Patricija van Oosten-Hawle. "Global Proteotoxicity Caused by Human β2 Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans." International Journal of Molecular Sciences 22, no. 19 (October 4, 2021): 10752. http://dx.doi.org/10.3390/ijms221910752.
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Aggregation of β2 microglobulin (β2m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 β2m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the β2m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β2 microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human β2m, or the two highly amyloidogenic naturally occurring variants, D76N β2m and ΔN6 β2m, in the C. elegans bodywall muscle. Nematodes expressing the D76N β2m and ΔN6 β2m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both β2m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of β2m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all β2m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal β2m toxicity and a disrupted ER secretory metabolism.
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Yuichiro Higashimoto and Yoshihiro Motomiya. "Heparin and β2-microglobulin amyloidogenesis." GSC Biological and Pharmaceutical Sciences 22, no. 2 (February 28, 2023): 070–78. http://dx.doi.org/10.30574/gscbps.2023.22.2.0061.
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β2-Microglobulin (β2M) occurs as a precursor protein in dialysis-related amyloidosis (DRA), which is a major complication in lives of patients undergoing dialysis. However, the underlying mechanism by which a native β2M transform into an amyloid β2M remain unclear. This disease has developed exclusively in interstitial tissues, which suggest possible implication of extracellular matrix substances in amyloidogenesis of this precursor protein. By using our monoclonal antibody specific for amyloid β2M, we investigated the function of heparin, that is, one of the glycosaminoglycans, as associated with amyloidogenic conversion of the β2M molecule. We confirmed that heparin induced a dose-dependent and time-dependent unfolding at the C-terminal region of the β2M molecule, which led to amyloidogenic transformation of the β2M molecule and brought about intermolecular interactions between β2M and substances in the interstitial matrix such as GAGs and collagen.
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Morales, Pedro J., Judith L. Pace, Jeralyn S. Platt, and Joan S. Hunt. "Placental cytotrophoblast HLA-G5 is synthesized as a β2m-free heavy chain homodimer (42.13)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S35—S36. http://dx.doi.org/10.4049/jimmunol.178.supp.42.13.
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Abstract Placental villous cytotrophoblast cells (vCTB) contain an unusual member of the HLA class I gene family, HLA-G5. Recently we showed that HEK293-derived recombinant HLA-G5 protein is predominantly composed of H:H homodimers. Here, we examined the HLA-G5 produced in primary vCTB. Determining the structure is critical because recombinant ectodomains of the inhibitory leukocyte Ig-like LILRB1 (ILT2) and LILRB2 (ILT4) receptors bind HLA-G dimers with higher affinity than monomers. Analysis of vCTB cell extracts by immunoblotting demonstrated that vCTB cell HLA-G5 H chain proteins are primarily disulfide bonded dimers. The H chains were not associated with β2m L chains; although β2m mRNA was identified by RT-PCR, immunoblots failed to detect β2m protein even when additional β2m mRNA was introduced. Furthermore, sequencing failed to reveal any abnormalities in the translational start codon of either endogenous β2m mRNA or introduced β2m mRNA, and EGF-induced syncytialization did not promote β2m in vCTB cells. The inability of vCTB cells to translate β2m messages in vitro was reflected in failure to detect β2m in vCTB cells in situ. Thus, vCTB cells may synthesize a disulfide-bonded, β2m-free homodimeric form of HLA-G5 due to an inability to synthesize β2m protein. This molecule could comprise a particularly effective tolerogenic molecule at the maternal-fetal interface.
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Li, Yang, Xiaoyi Zhang, Lu Li, Xiang Wang, Zhidan Chen, Xingxu Wang, Ying Wang, et al. "Mechanical stresses induce paracrine β-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor." Clinical Science 132, no. 16 (August 30, 2018): 1855–74. http://dx.doi.org/10.1042/cs20180486.
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By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of β-2 microglobulin (β2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum β2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum β2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), β2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous β2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of β2M significantly reduced cardiac β2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of β2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from β2M-knockdown cardiomyocytes. In vivo, knockdown of β2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the β2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that β2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.
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Pascolo, Steve, Nathalie Bervas, Jan M. Ure, Austin G. Smith, François A. Lemonnier, and Béatrice Pérarnau. "HLA-A2.1–restricted Education and Cytolytic Activity of CD8+ T Lymphocytes from β2 Microglobulin (β2m) HLA-A2.1 Monochain Transgenic H-2Db β2m Double Knockout Mice." Journal of Experimental Medicine 185, no. 12 (June 16, 1997): 2043–51. http://dx.doi.org/10.1084/jem.185.12.2043.
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Three different HLA-A2.1 monochains were engineered in which either the human or mouse β2-microglobulin (β2m) is covalently linked to the NH2 terminus of the heavy chain by a 15– amino acid long peptide: HHH, entirely human, HHD, with the mouse H-2Db α3, transmembrane, and cytoplasmic domains, and MHD, homologous to HHD but linked to the mouse β2mb. The cell surface expression and immunological capacities of the three monochains were compared with transfected cells, and the selected HHD construct was introduced by transgenesis in H-2Db−/− β2m−/− double knockout mice. Expression of this monochain restores a sizable peripheral CD8+ T cell repertoire essentially educated on the transgenic human molecule. Consequently, infected HHD, H-2Db−/− β2m−/− mice generate only HLA-A2.1–restricted CD8+ CTL responses against influenza A and vaccinia viruses. Interestingly, the CTL response to influenza A virus is mostly, if not exclusively, directed to the 58-66 matrix peptide which is the HLA-A2.1–restricted immunodominant epitope in humans. Such mice might constitute a versatile animal model for the study of HLA-A2.1–restricted CTL responses of vaccine interest.
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Praetor, Asja, and Walter Hunziker. "β2-microglobulin is important for cell surface expression and pH-dependent IgG binding of human FcRn." Journal of Cell Science 115, no. 11 (June 1, 2002): 2389–97. http://dx.doi.org/10.1242/jcs.115.11.2389.
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FcRn is a heterodimer of an α-chain andβ 2-microglobulin (β2m) and differs from other IgG Fc receptors in that it is structurally related to MHC class I molecules. Several functions attributed to FcRn are affected inβ 2-microglobulin (β2m)-deficient mice,suggesting that the α-chain needs to assemble with β2m to form a functional receptor. However, the precise role ofβ 2m in FcRn function is not known. Here we expressed the human FcRn α-chain alone or in combination with β2m in human melanoma FO-1 cells. We show that β2m is important for cell surface expression of FcRn and that, in the absence of β2m,the receptor is retained in the endoplasmic reticulum. Furthermore, in the absence of β2m, IgG binding is decreased compared with that of native FcRn. Thus, assembly of the FcRn α-chain with β2m is important for both transport of FcRn from the ER to the cell surface and efficient pH-dependent IgG binding.
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Gao, Na, Ying Wang, Chun-Ming Zheng, Yan-Li Gao, Hui Li, Yan Li, Ting-Ting Fu, et al. "β2-Microglobulin participates in development of lung emphysema by inducing lung epithelial cell senescence." American Journal of Physiology-Lung Cellular and Molecular Physiology 312, no. 5 (May 1, 2017): L669—L677. http://dx.doi.org/10.1152/ajplung.00516.2016.
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β2-Microglobulin (β2M), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of β2M in the development of lung emphysema. Here, we found that concentrations of β2M in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 vs. 1.42 ± 0.06 mg/l, P < 0.01). Moreover, the expression of β2M was significantly higher in lung tissue of emphysema (39.90 ± 1.97 vs. 23.94 ± 2.11%, P < 0.01). Immunofluorescence showed that β2M was mainly expressed in prosurfactant protein C-positive (pro-SPC+) alveolar epithelial cells and CD14+ macrophages. Exposure to recombinant human β2M and cigarette smoke extract (CSE) in vitro enhanced cellular senescence and inhibited proliferation of A549 cells, which was partially reversed by the presence of anti-β2M antibody. However, anti-β2M antibody did not attenuate the elevated production of IL-1β, IL-6, and TNF-α in A549 cells that were exposed to CSE. Immunofluorescence showed that colocalization of β2M, and the hemochromatosis gene (HFE) protein was observed on A549 cells. These data suggest β2M might participate in the development of lung emphysema through induction of lung epithelial cell senescence and inhibition.
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Yamamoto, Suguru, Akio Kasai, and Hisaki Shimada. "High Peritoneal Clearance of Small Molecules Did Not Provide Low Serum β2–Microglobulin Concentrations in Peritoneal Dialysis Patients." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 23, no. 2_suppl (December 2003): 34–36. http://dx.doi.org/10.1177/089686080302302s07.
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Objective Although early reports demonstrated that serum β2-microglobulin (s-β2m) concentrations in patients on peritoneal dialysis (PD) were lower than those in patients on hemodialysis (HD), more recent studies demonstrated lower s-β2m concentrations in HD patients treated mainly with high-flux synthetic membranes. We therefore compared s-β2m concentrations between patients on PD and on HD, and also analyzed the relationship between s-β2m concentrations and other parameters in patients on PD. Patients and Methods We investigated 24 patients who had been undergoing PD [11 on continuous ambulatory peritoneal dialysis, 13 on continuous cycling peritoneal dialysis] for 4.3 ± 2.7 years, and 24 patients who had been undergoing HD with high-flux synthetic membranes for 6.1 ± 3.2 years. Concentrations of s-β2m in the PD patients were compared to concentrations in the HD patients. In patients on PD, we also analyzed the relationship between s-β2m concentration and other parameters, including residual renal function, total weekly Kt/V urea, total weekly creatinine clearance (CCr), and dialysis schedules. Results We found no significant difference in s-β2m concentrations between the PD and HD patients (33.6 ± 10.4 mg/L vs 30.3 ± 10.5 mg/L respectively). Concentrations of s-β2m in PD patients rose with PD duration and were significantly inversely correlated with residual renal function ( r = –0.71, p < 0.0001). Unexpectedly, concentrations of s-β2m in anuric PD patients rose as peritoneal CCr increased. And most of the patients with high s-β2m levels fell into the high or high-average transport categories according to a peritoneal equilibration test. Conclusions Concentrations of s-β2m in patients on PD did not differ significantly from concentrations in HD patients who were using high-flux synthetic membranes. The contribution of residual renal function to removal of β2m was more important than the contribution of peritoneal clearance. High peritoneal clearance of small molecules did not result in low s-β2m concentrations, especially in anuric patients with accelerated peritoneal permeability.
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Gobin, Sam J. P., Paula Biesta, and Peter J. Van den Elsen. "Regulation of human β2-microglobulin transactivation in hematopoietic cells." Blood 101, no. 8 (April 15, 2003): 3058–64. http://dx.doi.org/10.1182/blood-2002-09-2924.
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Abstract β2-Microglobulin (β2m) is a chaperone of major histocompatibility complex (MHC) class I (–like) molecules that play a central role in antigen presentation, immunoglobulin transport, and iron metabolism. It is therefore of importance that β2m is adequately expressed in cells that perform these functions, such as hematopoietic cells. In this study, we investigated the transcriptional regulation of β2m in lymphoid and myeloid cell lines through a promoter containing a putative E box, Ets/interferon-stimulated response element (ISRE), and κB site. Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate β2m transactivation. The nuclear factor κB (NF-κB) subunits p50 and p65 bind to the κB box and p65 transactivates β2m. Interferon regulatory factor 1 (IRF1), IRF2, IRF4, and IRF8, but not PU.1, bind to the Ets/ISRE, and IRF1 and IRF3 are strong transactivators of β2m. Together, all 3 boxes are important for the constitutive and cytokine-induced levels of β2m expression in lymphoid and myeloid cell types. As such, β2m transactivation is under the control of important transcriptional pathways, which are activated during injury, infection, and inflammation.
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Hilt, Zachary T., Preeti Maurya, Laura Tesoro, Daphne N. Pariser, Sara K. Ture, Simon J. Cleary, Mark R. Looney, Kathleen E. McGrath, and Craig N. Morrell. "β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction." Circulation Research 128, no. 5 (March 5, 2021): 655–69. http://dx.doi.org/10.1161/circresaha.120.317119.
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Rationale: Circulating monocytes can have proinflammatory or proreparative phenotypes. The endogenous signaling molecules and pathways that regulate monocyte polarization in vivo are poorly understood. We have shown that platelet-derived β2M (β-2 microglobulin) and TGF-β (transforming growth factor β) have opposing effects on monocytes by inducing inflammatory and reparative phenotypes, respectively, but each bind and signal through the same receptor. We now define the signaling pathways involved. Objective: To determine the molecular mechanisms and signal transduction pathways by which β2M and TGF-β regulate monocyte responses both in vitro and in vivo. Methods and Results: Wild-type– (WT) and platelet-specific β2M knockout mice were treated intravenously with either β2M or TGF-β to increase plasma concentrations to those in cardiovascular diseases. Elevated plasma β2M increased proinflammatory monocytes, while increased plasma TGFβ increased proreparative monocytes. TGF-βR (TGF-β receptor) inhibition blunted monocyte responses to both β2M and TGF-β in vivo. Using imaging flow cytometry, we found that β2M decreased monocyte SMAD2/3 nuclear localization, while TGF-β promoted SMAD nuclear translocation but decreased noncanonical/inflammatory (JNK [jun kinase] and NF-κB [nuclear factor-κB] nuclear localization). This was confirmed in vitro using both imaging flow cytometry and immunoblots. β2M, but not TGF-β, promoted ubiquitination of SMAD3 and SMAD4, that inhibited their nuclear trafficking. Inhibition of ubiquitin ligase activity blocked noncanonical SMAD-independent monocyte signaling and skewed monocytes towards a proreparative monocyte response. Conclusions: Our findings indicate that elevated plasma β2M and TGF-β dichotomously polarize monocytes. Furthermore, these immune molecules share a common receptor but induce SMAD-dependent canonical signaling (TGF-β) versus noncanonical SMAD-independent signaling (β2M) in a ubiquitin ligase dependent manner. This work has broad implications as β2M is increased in several inflammatory conditions, while TGF-β is increased in fibrotic diseases. Graphic Abstract: A graphic abstract is available for this article.
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Latoch, Eryk, Katarzyna Konończuk, Katarzyna Taranta-Janusz, Katarzyna Muszyńska-Rosłan, Magdalena Sawicka, Anna Wasilewska, and Maryna Krawczuk-Rybak. "Urinary Beta-2-Microglobulin and Late Nephrotoxicity in Childhood Cancer Survivors." Journal of Clinical Medicine 10, no. 22 (November 13, 2021): 5279. http://dx.doi.org/10.3390/jcm10225279.
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The objectives of this study were to evaluate urinary beta-2-microglobulin (β2M) levels in long-term childhood cancer survivors and to establish its association with anticancer drug-induced nephrotoxicity. The study consisted of 165 childhood cancer survivors (CCS) who were in continuous complete remission. We reported that CCS had a significantly higher level of β2M (p < 0.001) and β2M/Cr. ratio (p < 0.05) than healthy peers. Among all participants, 24 (14.5%) had decreased eGFR (<90 mL/min/1.73 m2). A significant positive correlation between β2M/Cr. ratio and body mass index (coef. 14.48, p = 0.046) was found. Furthermore, higher levels of urinary β2M were detected among CCS with a longer follow-up time (over 5 years) after treatment. Subjects with decreased eGFR showed statistically higher urinary β2M levels (20.06 ± 21.56 ng/mL vs. 8.55 ± 3.65 ng/mL, p = 0.007) compared with the healthy peers. Twelve survivors (7.2%) presented hyperfiltration and they had higher urinary β2M levels than CCS with normal glomerular filtration (46.33 ± 93.11 vs. 8.55 ± 3.65 ng/mL, p = 0.029). This study did not reveal an association between potential treatment-related risk factors such as chemotherapy, surgery, radiotherapy, and the urinary β2M level. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). We demonstrated that urinary beta-2-microglobulin may play a role in the subtle kidney injury in childhood cancer survivors; however, the treatment-related factors affecting the β2M level remain unknown. Further prospective studies with a longer follow-up time are needed to confirm the utility of urinary β2M and its role as a non-invasive biomarker of renal dysfunction.
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Smith, Hugh I., Nicolas Guthertz, Emma E. Cawood, Roberto Maya-Martinez, Alexander L. Breeze, and Sheena E. Radford. "The role of the IT-state in D76N β2-microglobulin amyloid assembly: A crucial intermediate or an innocuous bystander?" Journal of Biological Chemistry 295, no. 35 (July 13, 2020): 12474–84. http://dx.doi.org/10.1074/jbc.ra120.014901.
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The D76N variant of human β2-microglobulin (β2m) is the causative agent of a hereditary amyloid disease. Interestingly, D76N-associated amyloidosis has a distinctive pathology compared with aggregation of WT-β2m, which occurs in dialysis-related amyloidosis. A folding intermediate of WT-β2m, known as the IT-state, which contains a nonnative trans Pro-32, has been shown to be a key precursor of WT-β2m aggregation in vitro. However, how a single amino acid substitution enhances the rate of aggregation of D76N-β2m and gives rise to a different amyloid disease remained unclear. Using real-time refolding experiments monitored by CD and NMR, we show that the folding mechanisms of WT- and D76N-β2m are conserved in that both proteins fold slowly via an IT-state that has similar structural properties. Surprisingly, however, direct measurement of the equilibrium population of IT using NMR showed no evidence for an increased population of the IT-state for D76N-β2m, ruling out previous models suggesting that this could explain its enhanced aggregation propensity. Producing a kinetically trapped analog of IT by deleting the N-terminal six amino acids increases the aggregation rate of WT-β2m but slows aggregation of D76N-β2m, supporting the view that although the folding mechanisms of the two proteins are conserved, their aggregation mechanisms differ. The results exclude the IT-state as the origin of the rapid aggregation of D76N-β2m, suggesting that other nonnative states must cause its high aggregation rate. The results highlight how a single substitution at a solvent-exposed site can affect the mechanism of aggregation and the resulting disease.
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Yun, Jae-Pil, Cheolwon Suh, Eunkyoung Lee, Jai Won Chang, Won Seok Yang, Jung Sik Park, and Su-Kil Park. "Creatinine Clearance Is More Important Prognostic Factor Than ß2 Microglobulin in Multiple Myeloma." Blood 104, no. 11 (November 16, 2004): 4864. http://dx.doi.org/10.1182/blood.v104.11.4864.4864.
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Abstract In the new staging system of multiple myeloma (MM) by South West Oncology Group (SWOG), the concentration of serum β2 microglobulin (β2m) and serum albumin were focused as the most important prognostic factors for survival. However, serum concentration of β2m has been known as an indicator of glomerular filtration rate. The aim of this study was to compare the prognostic value of the level of β2m with that of creatinine clearance (Ccr) in patients with multiple myeloma. Retrospectively, from January 1, 1996 to November 30, 2003, we reviewed 176 MM patients (M: F 110:66 mean age: 58.5±11.0) whose 24-hour urinary creatinine clearance was available at the time of diagnosis. We collected clinical data such as hemoglobin, serum creatinine, calcium, albumin, β2m, creatinine clearance before chemotherapies, and patients’ survival time. Pretreatment β2m was inversely related to Ccr (Spearman’s correlation coefficient = −0.781, P <0.01). In univariate analysis, relative risk (RR) of death was 1.047 (p< 0.001) for β2m and 0.985 (p< 0.001) for Ccr. But multivariate analysis using Cox’s proportional hazard model showed β2m was not significant prognostic factor in patients’ survival after adjustment for Ccr (RR 1.025, p=0.054) but Ccr was an independent risk factor of death after adjustment for β2m (RR 0.990, p=0.013). And univariate analysis identified that RR for β2m is not significant in 88 MM patients (66 patients with β2m ≥ 2.5mg/l) with relatively normal renal function (Ccr ≥ 50 ml/min) (RR = 1.110, p=0.306) We could propose another new staging system with β2m replaced by Ccr in SWOG staging system. The stages were defined as: stage 1, Ccr ≥ 80ml/min; stage 2, 50< Ccr <80; stage 3, Ccr < 50 and albumin ≥ 3.0g/dl; and stage 4 Ccr < 50 ml/min and albumin< 3.0 g/dl. According to this proposed staging system, median survival time of each stage from 1 to 4 is 1475, 887, 513, and 196 days, respectively. (Log Rank test < 0.0001) In conclusion, Ccr could be more important prognostic factor than the level of β2m in patients of MM and we propose that Ccr should be reassessed as the component of staging system of MM.
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Sulatskaya, Anna, Natalia Rodina, Dmitry Polyakov, Maksim Sulatsky, Tatyana Artamonova, Mikhail Khodorkovskii, Mikhail Shavlovsky, Irina Kuznetsova, and Konstantin Turoverov. "Structural Features of Amyloid Fibrils Formed from the Full-Length and Truncated Forms of Beta-2-Microglobulin Probed by Fluorescent Dye Thioflavin T." International Journal of Molecular Sciences 19, no. 9 (September 14, 2018): 2762. http://dx.doi.org/10.3390/ijms19092762.
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The persistence of high concentrations of beta-2-microglobulin (β2M) in the blood of patients with acute renal failure leads to the development of the dialysis-related amyloidosis. This disease manifests in the deposition of amyloid fibrils formed from the various forms of β2M in the tissues and biological fluids of patients. In this paper, the amyloid fibrils formed from the full-length β2M (β2m) and its variants that lack the 6 and 10 N-terminal amino acids of the protein polypeptide chain (ΔN6β2m and ΔN10β2m, respectively) were probed by using the fluorescent dye thioflavin T (ThT). For this aim, the tested solutions were prepared via the equilibrium microdialysis approach. Spectroscopic analysis of the obtained samples allowed us to detect one binding mode (type) of ThT interaction with all the studied variants of β2M amyloid fibrils with affinity ~104 M−1. This interaction can be explained by the dye molecules incorporation into the grooves that were formed by the amino acids side chains of amyloid protofibrils along the long axis of the fibrils. The decrease in the affinity and stoichiometry of the dye interaction with β2M fibrils, as well as in the fluorescence quantum yield and lifetime of the bound dye upon the shortening of the protein amino acid sequence were shown. The observed differences in the ThT-β2M fibrils binding parameters and characteristics of the bound dye allowed to prove not only the difference of the ΔN10β2m fibrils from other β2M fibrils (that can be detected visually, for example, by transmission electron microscopy (TEM), but also the differences between β2m and ΔN6β2m fibrils (that can not be unequivocally confirmed by other approaches). These results prove an essential role of N-terminal amino acids of the protein in the formation of the β2M amyloid fibrils. Information about amyloidogenic protein sequences can be claimed in the development of ways to inhibit β2M fibrillogenesis for the treatment of dialysis-related amyloidosis.
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Noble, Alistair, Zi-Shan Zhao, and Harvey Cantor. "Suppression of Immune Responses by CD8 Cells. II. Qa-1 on Activated B Cells Stimulates CD8 Cell Suppression of T Helper 2 Responses." Journal of Immunology 160, no. 2 (January 15, 1998): 566–71. http://dx.doi.org/10.4049/jimmunol.160.2.566.
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Abstract We have investigated the role of MHC class I products and CD8 T cells in regulating Ab responses using β2-microglobulin deficient (β2m−/−) mice. β2m−/− mice produced stronger IgM and IgG responses than did control β2m+/+ mice to both cellular and viral Ags. These Ab responses could be suppressed by infusion of activated B cells from β2m+/+ mice. Further investigation showed that the β2m-associated molecule on activated B cells that induced CD8 suppression was Qa-1 and that the Th2 component of CD4 cells was most affected by CD8-suppressive activity. Our findings suggest a novel pathway of Th inhibition in which B cell presentation of Qa-1-associated peptides stimulates CD8 suppressive activity.
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Aghdashi, Miramir, Simak Salami, and Ahmad Nezhadisalami. "Evaluation of the serum β2 Microglobulin level in patients with systemic lupus erythematosus and its correlation with disease activity." BioMedicine 9, no. 3 (August 27, 2019): 16. http://dx.doi.org/10.1051/bmdcn/2019090316.
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Background: Designation of disease activity is serious for the management of systemic lupus erythematosus (SLE). Serum level of β2 microglobulin (β2M) may be associated with illness activity in SLE disease. Since the role of β2M for assessing of illness activity in SLE is not completely clear, the current study aimed to discern evaluation of β2M in patients with SLE and its correlation with sickness activity. Materials and Methods: In this case-control study, 50 patients with SLE disease and 25 healthy individuals were selected in Imam Khomeini Hospital in central of Urmia. Blood samples were collected safely from patients, serum was removed, and β2M measured using an ELISA method. The results for other parameters including C reactive protein, C3, C4, anti dsDNA and erythrocyte sedimentation rate were obtained from patients’ medical record. Data analyzed using appropriate statistical tests including Mann-Whitney U test, Independent f-test, Kruskal-Wallis, and Spearman used for analysis of data. Results: In the current study, a significant difference was seen between two groups in terms of β2M (p < 0.001). Remarkable correlation was seen between the level of β2M with disease activity (p < 0.001). Furthermore, there are significant relevancy between the level of β2M with 24-hour urine protein, ESR, disease activity score, and CRP (p < 0.05). Conclusion: The results revealed that serum amount of β2M in SLE patients is higher compared to healthy ones, which is significantly correlated to score of illness activity, CRP, and ESR in patients with SLE disease. Hence β2M might be an excellent serological marker helping the prediction of sickness activity and inflammation in SLE patients.
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Volkova, Maya, Alvina A. Molodyk, Tatiana E. Bialik, and Marina A. Frenkel. "Prognostic Value of β2-Microglobulin (β2M) Expression on Lymphocyte Surface in Chronic B-Lymphocytic Leukemia (B-CLL)." Blood 112, no. 11 (November 16, 2008): 4192. http://dx.doi.org/10.1182/blood.v112.11.4192.4192.
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Abstract Background: Modern therapy diminished prognostic significance of serum β2M level. Aims: This study was designed to investigate the correlation between the number of lymphocytes expressing β2M, serum β2M level, and the results of treatment. Methods: 45 patients (pts) were included (Binet stage B, 36 and C, 9). β2M expression on the lymphocyte surface was detected with immunocytochemical method by means of Dako-Cytomation LSAB2 System HRP, β2M serum level by ELISA. Results: In 29 pts β2M was expressed on 80–100% of lymphocytes (group I), in 16 pts on 35–79% (group II). Number of lymphocytes expressing β2M did not correlate with lumphocyte dimension, form of nucleus, and presence of prolymphocytes in peripheral blood (PB). β2M serum level ranged from 3,0 to 10,5 mg/L. Number of leukocytes and lymphocytes in PB and bone marrow in both groups had no difference. Number of pts with normal β2M serum level (3,5 mg/L or less) was practically the same (group I, 13,8%; group II, 18,8%). Among pts with high β2M serum level (> 6 mg/L) there were 28% in group I and 69,0% in group II. Increased level of LDG (>450 MU/L) was detected in 10% of pts of group I and in 50% in group II. Treatment in both groups was similar: regimens with fludarabine–gr.I, 23 of 29 pts and gr.II, 12 of 16; R-COP–gr.I, 3 pts and gr.II, 2 pts. Two pts in gr.II received leukeran; 3 pts in gr.I didn’t need any treatment. Of 42 pts treated 20 pts achieved complete remission; 13, partial remission, and 9 pts failed. In gr.I complete remission was achieved in 17 of 26 treated pts (65,4%), in gr.II, in 3 of 16 (18,8%), p=0,0038. Partial remission was received in 6 pts of gr.I (23,1%) and in 7 pts (43,8%) of gr.II, p=0,14. Three pts of gr.I (11,5%) and 6 pts of gr.II (37,2%) failed (p=0,05). Conclusion: Comparison of the therapy results showed that β2M expression on large number (80–100%) of lymphocytes in B-CLL can be considered as the favourable prognostic sign. It was associated with lower level (<6 mg/L) of serum β2M (in 71,2% vs. 31% of pts, p=0,009) and LDG (90% vs. 50% of pts, p=0,0051). Disclosure: No relevant conflicts of interest to declare.
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Yi, Qing, Jing Yang, Jianfei Qian, Siqing Wang, Michele Wezeman, and Larry W. Kwak. "Targeting β2-Microglobulin for Induction of Tumor Apoptosis in Human Hematological Malignancies." Blood 106, no. 11 (November 16, 2005): 618. http://dx.doi.org/10.1182/blood.v106.11.618.618.
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Abstract We discovered that monoclonal antibodies (mAbs) specific to human β2-microglobulin (β2M) induce programmed death of myeloma and other hematological tumor cells. The mAbs exhibited potent in vitro tumoricidal activity on all 14 β2M/HLA-ABC-bearing myeloma, lymphoma, and leukemia cell lines and primary myeloma cells isolated from eight patients. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. Although the expression of β2M on normal hematopoietic cells is a potential safety concern, the mAbs seem to be selective to tumor-transformed cells and did not induce apoptosis of normal cells, including T and B lymphocytes and CD34+ bone marrow stem cells. Furthermore, the mAbs were able to selectively kill myeloma cells without damaging normal stromal cells in their cocultures. After binding to cell surface, the mAbs mediated internalization and down-modulation of surface β2M and HLA-ABC molecules. The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, upregulating Bad and Bax protein expression, inducing phosphorylation of Bcl-2, and decreasing phosphorylation of Bad, all of which compromised mitochondrial integrity, leading to cytochrome c release into cytosol and activation of the caspase-9-dependent cascade. Inhibitors to pan-caspases or caspase-9, but not to caspase-8, or to JNK, and knockdown of surface β2M and HLA-ABC expression by β2M-specific siRNA, but not control siRNA, abrogated apoptosis of tumor cells induced by the mAbs. Furthermore, anti-β2M mAbs were also active and therapeutic in vivo; After administration subcutaneous or intraperitoneal, the mAbs substantially reduced tumor burdens and retarded tumor growth in SCID mice subcutaneously implanted with human myeloma cell lines ARP-1 or MM.1S. Therefore, such mAbs offer the potential for a novel therapeutic approach to hematological malignancies and possibly to other cancers that express surface β2M. This study also suggests that differential expression of β2M/MHC class I molecules by normal and cancer cells might be a crucial point in the sensitivity and selectivity of anti-β2M mAb-induced apoptosis.
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Hussein, Zainab, Sura Abdulsattar, and Issam Salman. "The usefulness of serum beta-2 microglobulin as a biomarker for evaluating renal function decline in type II diabetes mellitus." Baghdad Journal of Biochemistry and Applied Biological Sciences 3, no. 01 (March 15, 2022): 51–59. http://dx.doi.org/10.47419/bjbabs.v3i01.40.
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Background and objective: Serum beta-2 microglobulin (β2M) has been used as a useful clinical marker of chronic kidney dysfunction. The current study aims to evaluate the diagnostic accuracy of β2M for the early detection of diabetic nephropathy among Iraqi patients with type II diabetes mellitus. Methods: The study included 84 participants divided into four groups, three of them were type II diabetics and the fourth is the healthy individuals’ (control) group. The diabetic’ subgroups were named according to the Micral test as: normoalbuminuria (21 patients), microalbuminuria (21 patients), and macroalbuminuria group (21 patients). The control group included 21, age- and sex-matched, healthy participants. Biochemical markers for diabetes mellitus as well as β2M were determined for each participant and then were analyzed statistically. Results: The serum β2M of normoalbuminuria group was (2.86±0.95 µg/mL), microalbuminuria group was (5.06±1.97 µg/mL) and macroalbuminuria group (3.6±1.59 µg/mL). The results showed significant increase (p˂0.05) in the β2M level of microalbuminuria group when compared with that of normoalbuminuria and macroalbuminuria groups. In addition, a highly significant increase (p˂0.01) in β2M concentration was observed in microalbuminuria group when compared with that of the control group. Conclusions: β2M can be used as a useful biomarker for the early detection of diabetic nephropathy.
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Sliker, Bailee H., Mohammad Awaji, Thanh Nguyen, Poomy Pandey, and Joyce C. Solheim. "HLA Class I Components Increase Pancreatic Cancer Proliferation and Migration." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 142.6. http://dx.doi.org/10.4049/jimmunol.196.supp.142.6.
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Abstract Recent studies in transplantation models have implicated HLA class I molecules as important factors in activating downstream pathways that lead to cell proliferation and migration. In a few cancers, β2m alone has been proposed to be high in expression and to increase proliferation and migration. No research to date has reported if β2m and/or the HLA class I heavy chain promote the migration and proliferation of pancreatic cancer cells and, if so, whether β2m and the HLA class I heavy chain work together or as separate entities within the signaling pathways to promote these processes. Using pancreatic cancer cells, we demonstrate that siRNA knockdown of β2m causes a decrease in cell migration and proliferation without altering viability. This decrease of β2m also leads to a reduction in the expression of the HLA class I heavy chain as well as downstream signaling molecules, pCREB and pFAK. Downregulation of HLA-A leads to decreased pCREB while HLA-B knockdown does not and neither heavy chain isotype has an effect on pFAK expression. Overall, this study demonstrates the importance of β2m in cancer cell migration and proliferation through signaling pathways involving pCREB and pFAK. We show that HLA class I heavy chains are expressed by pancreatic cancer cells and that HLA-A heavy chains may be more influential in cell migration and proliferation than HLA-B heavy chains. Loss of β2m expression causes a decrease in HLA class I heavy chains, suggesting that β2m may exert some of its effects on growth and migration via the heavy chain. However, the fact that some downstream molecules are altered in cells with β2m reduction, yet no change is observed with the downregulation of either HLA heavy chain isoform, indicates that each may also work in divergent pathways.
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Lins, R. L., P. Zachée, R. Daelemans, E. Vanden Broecke, M. A. Boogaerts, and M. E. De Broe. "Red Blood Cell Function and β2 Microglobulin Kinetics during Cuprophan Hemodialysis: A Hypothesis." International Journal of Artificial Organs 12, no. 10 (October 1989): 638–41. http://dx.doi.org/10.1177/039139888901201007.
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The exact role of β2microglobulin (β2m) in dialysis amyloidosis is yet not known. Local release of β2m from the endothelial cells of the lung and other tissues as a consequence of acute-phase activation due to the contact of blood with membranes has still to be considered a possible pathogenetic factor in this syndrome. β2m kinetics and decrease of glutathione content in RBC were studied in 41 chronic hemodialysis patients during cuprophan dialysis. The latter test reflects the RBC scavenger function for free oxygen radicals. Only 30% of patients showed a clinically significant increase in β2m. The change in β2m in this group between the start and 180 minutes, corrected for plasma volume, was 23.1±3.6% and the change in gluthathione content between the start and 15 minutes was 4.5±3.4%. In these patients there was a significant correlation between β2m production and decrease of gluthathione (R= -0.61, p= 0.0299). It is possible that the production of free oxygen radicals during bioincompatible dialysis leads to cellular toxicity with release ofβ2m which may be prevented to some extent by the scavenger role of RBC.
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Zhang, Chun-ming, Keiichi Yamaguchi, Masatomo So, Kenji Sasahara, Toru Ito, Suguru Yamamoto, Ichiei Narita, József Kardos, Hironobu Naiki, and Yuji Goto. "Possible mechanisms of polyphosphate-induced amyloid fibril formation of β2-microglobulin." Proceedings of the National Academy of Sciences 116, no. 26 (June 10, 2019): 12833–38. http://dx.doi.org/10.1073/pnas.1819813116.
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Polyphosphate (polyP), which is found in various microorganisms and human cells, is an anionic biopolymer consisting of inorganic phosphates linked by high-energy phosphate bonds. Previous studies revealed that polyPs strongly promoted the amyloid formation of several amyloidogenic proteins; however, the mechanism of polyP-induced amyloid formation remains unclear. In the present study using β2-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, we investigated amyloid formation in the presence of various chain lengths of polyPs at different concentrations under both acidic (pH 2.0 to 2.5) and neutral pH (pH 7.0 to 7.5) conditions. We found that the amyloid formation of β2m at acidic pH was significantly accelerated by the addition of polyPs at an optimal polyP concentration, which decreased with an increase in chain length. The results obtained indicated that electrostatic interactions between positively charged β2m and negatively charged polyPs play a major role in amyloid formation. Under neutral pH conditions, long polyP with 60 to 70 phosphates induced the amyloid formation of β2m at several micromoles per liter, a similar concentration range to that in vivo. Since β2m with an isoelectric point of 6.4 has a slightly negative net charge at pH 7, polyPs were unlikely to interact with β2m electrostatically. PolyPs appear to dehydrate water molecules around β2m under the unfolded conformation, leading to the preferential stabilization of less water-exposed amyloid fibrils. These results not only revealed the pH-dependent mechanism of the amyloid formation of β2m but also suggested that polyPs play an important role in the development of dialysis-related amyloidosis.
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Lin, Gloria, Parameswaran Hari, Saurabh Chhabra, Mehdi Hamadani, Anita D'Souza, Aniko Szabo, and Binod Dhakal. "The significance of beta-II microglobulin (β2M) and International Staging System (ISS) in multiple myeloma (MM) patients (pts.) with renal impairment (RI)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 8544. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.8544.
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8544 Background: ISS stage which underlies prognostic models used in MM, is derived from albumin and β2M at diagnosis. β2M, a low molecular polypeptide, is present on all nucleated cells and is elevated in pts. with RI. In MM, although the association between β2M and prognosis has been interpreted to reflect a higher tumor burden, RI by itself may explain at least in part the higher levels of β2M seen with this disease. Historically, those presenting with MM and severe RI had a poor prognosis and quite likely the β2M elevation irrespective of kinetics predicted poor prognosis. In this study, we investigated the significance of β2M and ISS staging in MM patients in the setting of RI in the modern era when renal recovery is more common after induction. Methods: MM pts. treated at our institution from 2012-2014 were included and divided into two groups by creatinine (Cr) level at diagnosis: < 2 and ≥2 mg/dl. Demographic and disease characteristics were compared between the two groups using ANOVA and chi-square tests as appropriate. COX regression was used for the multi-variate analysis for survival and the effect of β2M levels, adjusting for albumin levels, on survival was allowed to vary by Cr level to evaluate potential interaction. Results: Of 201 total pts., 163 (81.6%) had Cr < 2 mg/dL and 38 (18.4%) ≥ 2mg/dL at diagnosis with higher β2M and ISS stage in Cr≥2 group. On adjusted analysis, albumin was significantly associated with overall survival (OS) (hazard ratio, HR 0.60; 95% CI 0.36-1; p = 0.04); however, β2M was associated with OS only when Cr < 2 mg/dl (HR 1.13, 95% CI 1.06-1.19; p < 0.0001) but not when Cr≥2 mg/dl (HR 0.98, 95% CI 0.91-1.06; p = 0.65) with significant interaction (p = 0.004). Likewise, the effect of β2M on progression-free survival was significant when Cr < 2 (HR 1.1, 95% CI 1.05-1.19; p = 0.0002), but not Cr≥2 (HR 1.02; 95% CI 0.97-1.08; p = 0.42) with significant interaction (p = 0.03). Conclusions: Our results show that in the era of modern induction therapy and rapid improvement in kidney function, a high β2M may not impact prognosis as adversely, at least in those with RI, since an elevated β2M may be disproportionate to true tumor burden. Thus, ISS staging in these patients should be reevaluated after induction and potential renal recovery. Novel biomarkers may refine MM staging independent of the level of kidney function.
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Afrough, Aimaz, Samer A. Srour, Qaiser Bashir, Neeraj Saini, Chitra Hosing, Uday R. Popat, Partow Kebriaei, et al. "Prognostic Impact of Beta 2 Microglobulin in Patients with Immunoglobulin Light-Chain Amyloidosis Undergoing Autologous Hematopoietic Stem Cell Transplantation." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-141360.
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Background: Risk stratification for Immunoglobulin light chain amyloidosis (AL) has been refined with advances in the understanding of disease biology. Although nonspecific, beta 2 microglobulin (β2M) levels correlate with disease burden and are considered a prognostic marker in several hematologic malignancies. Recently, we and others have shown the association of β2M levels with survival in AL. In this study, we evaluated the role of β2M as a predictor of outcome for high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) in patients with AL. Methods: We identified 175 consecutive patients with AL who received auto-HCT between 2009 and 2019 at our institution. A β2M≥3.5 mg/L, regardless of renal function status was used as a cutoff value. Hematologic and organ responses were evaluated according to the Consensus Guidelines for AL. Revised Mayo staging system was utilized for Cardiac staging. Results: The median age at auto-HCT was 60 years (range, 27 to 77). Of 175 patients, 153 (87%) had a β2M value available, of whom 57 (37%) had a β2M ≥ 3.5 mg/L. There were no significant differences in baseline characteristics between the 2 groups, except for the higher level of LDH, worse renal function, and more patients with renal involvement in the β2M ≥ 3.5 group, and more patients with lambda light chain type in the β2M <3.5 group (Table 1). The median follow-up from auto-HCT was 38 months (range; 1 to 124). One-year non-relapse mortality (NRM) was 2%. The 1-year NRM was 5% (n=3) and 1% (n=1) in patients with β2M≥3.5, and β2M<3.5, respectively (p=0.115). Hematologic CR after auto-HCT was seen in 21 (37%), and 38 (40%) patients with β2M≥3.5 and β2M<3.5, respectively (p=0.864). Organ response (OR) after auto-HCT was seen in 36 (73%), and 65 (71%) patients with β2M≥3.5 and β2M<3.5, respectively (p=1.00). The 3-year progression-free survival (PFS) was 66%, and 74% in patients with β2M≥3.5, and β2M<3.5 (p=0.17) (Figure 1A).The 3-year overall survival (OS) was 73%, ad 89% in patients with β2M≥3.5, and β2M<3.5 (p=0.009) (Figure 1B). On Cox-regression multivariate analysis, cardiac involvement with AL (p=0.043), and β2M≥3.5 (p=0.029) were associated with a shorter OS. Conclusion: In this single-center retrospective analysis, we showed that high serum β2M is associated with shorter OS. β2M may be incorporated as a prognostic marker for AL if these findings are confirmed in larger studies. Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; Takeda: Other: Advisory Board, Research Funding; KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Novartis: Other: Served on advisory board; Jazz: Consultancy; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support. Shpall:Takeda: Other: Licensing Agreement; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Manasanch:Sanofi: Research Funding; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding. Lee:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy. Kaufman:Janssen: Research Funding; Karyopharm: Honoraria; Bristol Myers Squibb: Research Funding. Patel:Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding. Thomas:BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Champlin:Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy; Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Janssen: Research Funding.
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Santos, Manuela, Hans Clevers, Maria de Sousa, and J. J. M. Marx. "Adaptive Response of Iron Absorption to Anemia, Increased Erythropoiesis, Iron Deficiency, and Iron Loading in β2-Microglobulin Knockout Mice." Blood 91, no. 8 (April 15, 1998): 3059–65. http://dx.doi.org/10.1182/blood.v91.8.3059.3059_3059_3065.
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Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that β2-microglobulin knockout (β2m−/−) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of β2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and β2m−/−mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the β2m−/−mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and β2m−/− mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the β2m−/− mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the β2m−/− mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the β2m−/− mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.
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Cordeiro, Isis S. F., Lilian Cordeiro, Carolina S. Wagner, Luiza Karla R. P. Araújo, Benedito J. Pereira, Hugo Abensur, Rosilene M. Elias, and Bruno C. Silva. "High-Flux versus High-Retention-Onset Membranes: In vivo Small and Middle Molecules Kinetics in Convective Dialysis Modalities." Blood Purification 49, no. 1-2 (July 30, 2019): 8–15. http://dx.doi.org/10.1159/000502082.
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Background: Patients undergoing maintenance hemodialysis (HD) exhibit increased levels of uremic toxins, which are associated with poor outcomes. Recently, new dialysis membranes have allowed clearance of solutes with higher molecular weight, without significant albumin losses high-retention-onset-HD (HRO-HD). Methods: Prospective crossover trial, in which 16 prevalent patients switched from high-flux HD (HF-HD) to online hemodiafiltration (olHDF) and HRO-HD for 4 weeks. The following variables were evaluated: pre- and post-dialysis serum concentrations of albumin, urea, phosphate (P), beta-2 microglobulin (β2M), and total mass (TM) extraction and dialyzer clearance of urea, P, and β2M. Results: Comparing HF-HD, olHDF, and HRO-HD, respectively, there were no differences regarding pre-dialysis serum concentrations of albumin (3.94 ± 0.36, 4.06 ± 0.22, and 3.93 ± 0.41 g/dL, p = 0.495), urea (166 ± 29, 167 ± 30, and 164 ± 27 mg/dL, p = 0.971), P (4.9 ± 2.1, 5.2 ± 1.6, and 4.9 ± 2.1 mg/dL, p = 0.879), and β2M (31.3 ± 7.1, 32.6 ± 8.6, and 33.7 ± 5.9 µg/mL, p = 0.646). β2M clearance was significantly lower in HF-HD in comparison to both olHDF and HRO-HD: 43 (37–53) versus 64 (48–85) mL/min, p = 0.013, and 69 (58–86) mL/min, p = 0.015, respectively. Post-dialysis β2M serum concentration was higher in HF-HD in comparison to olHDF and HRO-HD: 11.6 (9.6–12.4) vs. 5.7 (4.5–7.0) µg/mL, p = 0.001, and 5.6 (5.3–7.6) µg/mL, p = 0.001, respectively. TM extraction of urea, P, and β2M were similar across the 3 dialysis modalities. Conclusions: olHDF and HRO-HD were superior to HF-HD regarding β2M clearance, leading to lower post-dialysis β2M levels.
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Robinson, Peter J., Paul J. Travers, Arthur Stackpoole, Lorraine Flaherty, and Hakim Djaballah. "Maturation of Qa-1b Class I Molecules Requires β2-Microglobulin But Is TAP Independent." Journal of Immunology 160, no. 7 (April 1, 1998): 3217–24. http://dx.doi.org/10.4049/jimmunol.160.7.3217.
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Abstract Two conformationally distinct and stable forms of Qa-1b, one strongly associated with β2-microglobulin (β2m) and the other associated with a novel molecule, gp44, were observed during immunochemical studies on the expression of Qa-1b molecules in mouse spleen cells. Both forms are efficiently processed and expressed at the cell surface. However, a large proportion of Qa-1b was found to be disulfide linked to gp44 without any detectable β2m. In TAP1-deficient mice, both forms undergo carbohydrate processing and are expressed on the cell surface, suggesting that they may traffic using a pathway not requiring a TAP association step. Consistent with this, size exclusion chromatography of newly synthesized class I molecules shows that high molecular mass complexes containing H-2Kk do not contain Qa-1b. Although Qa-1b can be stably expressed without β2m, there was no maturation of either form in cells from β2m-deficient mice where heavy chains were rapidly degraded. These results suggest that Qa-1b, like most other class I molecules, requires β2m for an initial folding step. However, β2m is not essential for subsequent processing of Qa-1b molecules.
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Rytova, Valeria, Fumio Takei, and Boxiang Jiang. "The licensing of natural killer cells (113.3)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 113.3. http://dx.doi.org/10.4049/jimmunol.186.supp.113.3.
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Abstract The interaction between inhibitory Ly49 receptors and MHCI is important for the functional maturation of NK cells, known as “NK cell licensing.” NK cells from MHCI-deficient β2microglobulin (β2m)-KO mice are not cytotoxic and cannot efficiently kill their targets, as they are not licensed. Our goal is to determine the mechanism through which β2m-KO NK cells are kept hyporesponsive to otherwise NK-sensitive targets. Comparison through cytotoxicity assays confirmed that ex-vivo NK cells from poly-IC-injected wild type (WT) mice kill the prototypic YAC1 target, whereas NK cells from β2m-KO mice do not. Interestingly, both express similar levels of granzyme B and adhere to immobilized ICAM-1, the ligand for LFA-1. Further, confocal analysis of NK cells interacting with YAC1 showed that WT NK cells aggregate and polarize lytic granules toward their targets, while β2m-KO NK cells are deficient in granule polarization. Once stimulated by plastic beads coated with ICAM-1, both WT and β2m-KO NK cells reorganize their actin cytoskeleton. Stimulation by beads coated with ICAM-1, H60 and CD48 (ligands for stimulatory NKG2D and 2B4 receptors), induces aggregation and polarization of lytic granules in WT but not in β2m-KO NK cells. This suggests that critical components of the cytotoxicity pathway generated by stimulatory receptor interactions are impaired in β2m-KO NK cells, preventing aggregation and polarization of cytotoxic granules, and the release of their contents towards targets.
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Tsimberidou, Apostolia-Maria, Hagop M. Kantarjian, Michael J. Keating, Susan O’Brien, Sijin Wen, Jorge Cortes, Francis Giles, et al. "Prognostic Significance of β-2 Microglobulin Levels in Acute Myeloid Leukemia: Analysis of 1293 Patients." Blood 108, no. 11 (November 16, 2006): 802. http://dx.doi.org/10.1182/blood.v108.11.802.802.
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Abstract Introduction: β-2 Microglobulin (β2M) is a single polypeptide chain that is linked non-covalently to the major histocompatibility complex class I cell surface antigen. Its specific function is unknown, but serum β2M levels reflect membrane turnover (tumor mass and growth rate) and renal function. Elevated serum β2M levels are associated with poor survival in several hematologic malignancies, but its prognostic significance in acute myeloid leukemia (AML) is unknown. The purpose of this study was to determine the association between β2M levels and pretreatment characteristics and clinical outcomes in newly diagnosed AML. Patients and Methods: From 1990 to 2005, β2M levels were prospectively measured in 1293 patients with AML. Serum β2M was quantified by radioimmunoassay (normal range, 0.7–2.0 mg/L). Results: The median patient age was 61 yrs (range, 16–89 yrs); 54% were >60 yrs. Cytogenetics were favorable in 7% of patients, intermediate in 60%, poor-risk in 29%, and 4% of patients had insufficient metaphases. Zubrod performance status (PS) was 0–1 in 73% of patients, 2 in 20%, and 3–4 in 7%. Eighty-five percent had de novo AML, and 91% received Ara-C-based therapy. High β2M levels were more common in patients who were older (cor=0.22); had high early risk of mortality (ERM) score (cor =0.33); high levels of creatinine (cor=0.63), and uric acid (cor=0.29), high white blood cell counts (cor=0.26), or circulating monocytes (cor = 0.23); prolonged prothrombin time (PT) (cor=0.26); worse PS (cor=0.27); and low albumin levels (cor=−0.22)(p<0.001 for all variables). High β2M levels were correlated with worse-risk cytogenetics (p=0.03), RAS mutation (p=0.003), baseline infection (p=0.04), and secondary AML (p=0.01). The median follow-up of surviving patients was 3.8 yrs. In multivariate analysis, independent factors predicting response were younger age (p<0.0001), better-risk cytogenetics (p<0.0001), Ara-C-based therapy (p<0.0001), lower levels of β2M (p=0.0001), shorter PT (p=0.006), de novo AML (p=0.007), lower LDH levels (p=0.02), and lower bilirubin levels (p=0.03). Factors independently prognostic of longer survival were younger age (p<0.0001), better-risk cytogenetics (p<0.0001), better PS (p<0.0001), de novo AML (p<0.0001), lower serum uric acid levels (p=0.0001), lower LDH levels (p=0.0007), shorter PT (p=0.0009), lower β2M levels (p=0.003), higher hemoglobin levels (p=0.005), Ara-C-based therapy (p=0.007), and lower bilirubin levels (p=0.02). Factors independently prognostic of longer event-free survival (EFS) were younger age (p<0.0001), better-risk cytogenetics (p<0.0001), Ara-C-based therapy (p<0.0001), de novo AML (p=0.0001), better PS (p=0.0003), lower uric acid levels (p=0.0004), lower LDH levels (p=0.001), lower β2M levels (p=0.002), higher hemoglobin levels (p=0.003), shorter PT (p=0.02), and lower bilirubin levels (p=0.045). Conclusions: Elevated serum β2M levels are an independent adverse prognostic factor for response, survival, and EFS in the context of established prognostic factors for AML. Outcomes by β2M levels β2M (mg/L) <2.0 2.0–2.9 3.0–3.9 ≥4.0 p-value No. pts. 251 448 260 334 CR, % 67 66 54 39 <0.0001 Median EFS (yrs) 0.69 0.58 0.31 0.15 <0.0001 Median Survival (yrs) 1.33 1.19 0.63 0.42 <0.0001
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Wierda, William G., X. Wang, S. OBrien, S. Faderl, A. Ferrajoli, D. Thomas, F. Ravandi, et al. "Serum Beta-2 Microglobulin: The Universal Independent Prognostic Factor for Patients with CLL." Blood 106, no. 11 (November 16, 2005): 5018. http://dx.doi.org/10.1182/blood.v106.11.5018.5018.
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Abstract Prognostic factors are tools to address heterogeneity in clinical behavior and survival in patients with disease. They are particularly relevant for patients with malignancy, including chronic lymphocytic leukemia (CLL). There is striking heterogeneity in overall survival (OS) of patients with CLL as well as in response to treatment, time to treatment failure (TTF), and time to progression (TTP) following response. Serum β2 microglobulin (β2M) has previously been reported to correlate with OS and TTP in patients with CLL. We performed a retrospective analysis of 659 Rx-naïve and 1062 previously treated patients with CLL enrolled on clinical trials from 5/74 to 7/05 at MD Anderson Cancer Center evaluating for predictors for response to treatment, amount of treatment given, incidence of myelosuppression, TTF, TTP in responders, and OS. Univariate analysis was performed, then significant factors were used to develop multivariate models for these endpoints. Groups were analyzed separately. The clinical factors evaluated included: age, Rai stage, # nodal sites, liver and spleen size, β2M, WBC, ALC, HGB, PLT, serum LDH, Cr, ALB, CD38 expression, and serum Ig levels, and refractoriness to alkylating agents and fludarabine and # prior treatments for previously treated patients. In the Rx-naïve group, characteristics (median and range) were as follows: age=57 yrs(17–86); β2M=3.3 mg/L(1.1–16.4); WBC=74.7k/μL(2.1–552); ALC= 63k/μL(1–512); HGB=12.7 g/dL(5.7–18.7); PLT=156 k/μL(8–450); LDH=545 IU/L(103–3600); and IgG=754 mg/dL(45–5000). Patients with Rai stage 0=28; Rai I-II=402; and Rai III-IV=196. In the previously treated group, characteristics (median and range) were as follows: age=61 yrs(25–83); β2M= 4.4 mg/L(1.4–59.4); WBC= 43 k/μL(.6–953); ALC=36 k/μL(0–829); HGB=11.4 g/dL(3.8–17.6); PLT= 121 k/μL(2–703); LDH=597 IU/L(21–4739); and IgG=586 mg/dL(14–5000). Patients with Rai stage 0=37; Rai I-II=392; and Rai III-IV=563. Multivariate models identified the following predictors (p<.05) for response to treatment for Rx-naive patients: β2M, PLT, ALC, age, and treatment regimen; for previously treated patients they were β2M, PLT, HGB, age, # prior Rx, and treatment regimen. TTF was correlated in multivariate analysis (p<.05) with β2M, age, extent of bone marrow (BM) involvement, and treatment regimen for Rx-naïve patients and with β2M, HGB, IgM, # prior Rx, and treatment regimen for previously treated patients. TTP for responders correlated (p<.05) in multivariate analysis with treatment regimen and BM involvement for Rx-naïve and with # prior Rx and treatment regimen for previously treated patients. Finally, Cox proportinal hazards model for OS identified the following predictors in Rx-naïve patients: β2M, age, treatment regimen; and for previously treated patients they included β2M, # prior Rx, age, treatment regimen, IgM, HGB, and PLT. Therefore, β2M and treatment regimen were consistent and significant independent predictors of outcome. In Rx-naïve patients, β2M level rose prior to initiating treatment, decreased with response to treatment for responders, and rose again with relapse in those patients with serial β2M determinations. β2M is a powerful prognostic factor for patients with CLL predicting for multiple clinical endpoints. We are currently incorporating it into our risk-stratification for clinical trials and it should be incorporated into the routine evaluation of patients with CLL.
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Tsimberidou, A. M., C. Tam, W. Wierda, S. O' Brien, S. Lerner, and M. J. Keating. "Beta-2 microglobulin (B2M) is an independent prognostic factor for clinical outcomes in patients with CLL treated with frontline fludarabine, cyclophosphamide, and rituximab (FCR) regardless of age, creatinine clearance (CrCl)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7034. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7034.
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7034 Introduction: High β2M levels are a risk factor in CLL. PCR therapy has been reported to be better tolerated than FCR in older or with decrease renal function pts (Shanafelt, Blood 108:15a). We assessed the association between age, CrCl, PS, β2M and outcomes in pts treated with FCR. Methods: From 7/99 to 1/04, 300 pts received rituximab 375 mg/m2 D1; fludarabine 25 mg/m2/d D2–3; and cyclophosphamide 250 mg/m2/d D2–3. Serum β2M levels were measured by radioimmunoassay. CrCl was calculated (Cockcroft-Gault equation). Results: The median age was 57 yrs (≥70, 14%). Age ≥70 was associated with fewer FCR courses (p<.0001); lower rates of CR (p=.001), overall response (OR; p=.04), survival (OS; p<.0001), and FFS (p=.008); and higher rates of G3–4 thrombopenia (p<.0001) or anemia (p=.002) compared with age<70. The median CrCl was 90 mL/min (CrCl <70, 27%). Pts with CrCl <70 had higher rates of G3–4 thrombopenia (p=.006) or anemia (p=.01) than others. There were no differences between the 2 groups in the other outcomes. PS was 0 in 40%, 1 in 57%, and 2 in 3% of pts. Better PS was associated with higher rates of CR (p=.007) and FFS (p=.02) but did not affect OR or OS. The median β2M level was 3.7 mg/L (β2M ≥ 4, 43%). The rates of CR, survival, and FFS were lower in pts with β2M ≥ 4 compared with others (p<.0001 each). High β2M levels were associated with older age, lower CrCl levels, poorer PS (p<.0001 each), higher rates of G3–4 neutropenia (p=.005), thrombocytopenia (p=.01), and infections (p=.03), and fewer FCR courses (p=.004). The median follow-up was 5 yrs. The rates of CR, 3-yr OS and 3-yr FFS were 72%, 87% and 76%, respectively. Independent factors predicting response were lower β2M (p=.0004) and lower WBC counts (p=.02). Independent factors predicting longer OS were younger age (p=.001), lower β2M (p=.003) and lower WBC (p=.03). Independent factors predicting longer FFS were lower β2M levels (p=.0006), and lower WBC counts (p=.005). Conclusion: Age ≥70 yrs and poor PS, but not CrCl level were associated with poor clinical outcomes. High β2M levels are an independent adverse prognostic factor for CR, OS, and FFS in the context of other prognostic factors. No significant financial relationships to disclose.
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Banda, Justor, Raquel Duarte, Therese Dix-Peek, Caroline Dickens, Pravin Manga, and Saraladevi Naicker. "Biomarkers for Diagnosis and Prediction of Outcomes in Contrast-Induced Nephropathy." International Journal of Nephrology 2020 (January 24, 2020): 1–11. http://dx.doi.org/10.1155/2020/8568139.
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Background. Serum creatinine is suboptimal as a biomarker in the early diagnosis of contrast-induced nephropathy (CIN). In this study, we investigated a panel of novel biomarkers in the early diagnosis of CIN and in assessing patient outcomes. Methods. This single-centre, nested, prospective case-controlled study included 30 patients with CIN and 60 matched controls. Serum and urine samples were collected before contrast administration and at 24 hours, 48 hours, and ≥5 days after contrast administration. Concentrations of NGAL, cystatin C, β2M, IL18, IL10, KIM1, and TNFα were determined using Luminex and ELISA assays. Outcomes were biomarker diagnostic discrimination performance for CIN and mortality after generation of area under receiver operating characteristic curves (AUROCs). Results. Median serum levels for 24 h cystatin C (p<0.01) and 48 h β2M levels (p<0.001) and baseline urine NGAL (p=0.02) were higher in CIN patients compared to controls with AUROCs of 0.75, 0.78, and 0.74, respectively, for the early diagnosis of CIN. Serum β2M levels were higher in CIN patients at all time points. Elevated baseline serum concentrations of IL18 (p<0.001), β2M (p=0.04), TNFα (p<0.001), and baseline urine KIM (p=0.01) and 24 h urine NGAL (p=0.02) were significantly associated with mortality. Baseline serum concentrations of IL18, β2M, and TNFα showed the best discrimination performance for mortality with AUROCs, all >0.80. Baseline NGAL was superior for excluding patients at risk for CIN, with positive and negative predictive ranges of 0.50–0.55 and 0.81–0.88, respectively. Cystatin C (p=0.003) and β2M (p=0.03) at 24 h independently predicted CIN risk. β2M predicted increased mortality of 40% at baseline and 50% at 24 hours. Conclusion. Serum cystatin C at 24 h was the best biomarker for CIN diagnosis, while baseline levels of serum IL18, β2M, and TNFα were best for predicting prognosis.
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Xie, Jin, Ying Wang, Muta E. Freeman, Bart Barlogie, and Qing Yi. "β2-Microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells." Blood 101, no. 10 (May 15, 2003): 4005–12. http://dx.doi.org/10.1182/blood-2002-11-3368.
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Abstract Two common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of β2-microglobulin (β2M) and activation or inhibition of the immune system. We hypothesized that β2M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of β2M on monocyte-derived dendritic cells (MoDCs). The addition of β2M (more than 10 μg/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)–ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, β2M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. β2M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factor-α and IL-1β. During cell culture, β2M down-regulated the expression of phosphorylated mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factor-κB (NF-κB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that β2M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NF-κB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms.
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Miranda, Carlos J., Hortence Makui, Nancy C. Andrews, and Manuela M. Santos. "Contributions of β2-microglobulin–dependent molecules and lymphocytes to iron regulation: insights from HfeRag1-/- and β2mRag1-/- double knock-out mice." Blood 103, no. 7 (April 1, 2004): 2847–49. http://dx.doi.org/10.1182/blood-2003-09-3300.
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Abstract Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a β2-microglobulin (β2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of β2mRag1-/- double-deficient mice, lacking all β2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with β2m single knock-out mice. To evaluate whether the observed phenotype in β2mRag1-/- mice was due solely to the absence of Hfe or to other β2m-dependent molecules, we generated HfeRag1-/- double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with β2mRag1-/- mice. These results suggest that other β2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity. (Blood. 2004;103: 2847-2849)
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Cartarozzi, Luciana Politti, Matheus Perez, Frank Kirchhoff, and Alexandre Leite Rodrigues de Oliveira. "Role of MHC-I Expression on Spinal Motoneuron Survival and Glial Reactions Following Ventral Root Crush in Mice." Cells 8, no. 5 (May 21, 2019): 483. http://dx.doi.org/10.3390/cells8050483.
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Lesions to the CNS/PNS interface are especially severe, leading to elevated neuronal degeneration. In the present work, we establish the ventral root crush model for mice, and demonstrate the potential of such an approach, by analyzing injury evoked motoneuron loss, changes of synaptic coverage and concomitant glial responses in β2-microglobulin knockout mice (β2m KO). Young adult (8–12 weeks old) C57BL/6J (WT) and β2m KO mice were submitted to a L4–L6 ventral roots crush. Neuronal survival revealed a time-dependent motoneuron-like cell loss, both in WT and β2m KO mice. Along with neuronal loss, astrogliosis increased in WT mice, which was not observed in β2m KO mice. Microglial responses were more pronounced during the acute phase after lesion and decreased over time, in WT and KO mice. At 7 days after lesion β2m KO mice showed stronger Iba-1+ cell reaction. The synaptic inputs were reduced over time, but in β2m KO, the synaptic loss was more prominent between 7 and 28 days after lesion. Taken together, the results herein demonstrate that ventral root crushing in mice provides robust data regarding neuronal loss and glial reaction. The retrograde reactions after injury were altered in the absence of functional MHC-I surface expression.
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Bulyáki, Éva, Judit Kun, Tamás Molnár, Alexandra Papp, András Micsonai, Henrietta Vadászi, Borbála Márialigeti, et al. "Pathogenic D76N Variant of β2-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States." Biology 10, no. 11 (November 17, 2021): 1197. http://dx.doi.org/10.3390/biology10111197.
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β2-microglobulin (β2m), the light chain of the MHC-I complex, is associated with dialysis-related amyloidosis (DRA). Recently, a hereditary systemic amyloidosis was discovered, caused by a naturally occurring D76N β2m variant, which showed a structure remarkably similar to the wild-type (WT) protein, albeit with decreased thermodynamic stability and increased amyloidogenicity. Here, we investigated the role of the D76N mutation in the amyloid formation of β2m by point mutations affecting the Asp76-Lys41 ion-pair of WT β2m and the charge cluster on Asp38. Using a variety of biophysical techniques, we investigated the conformational stability and partial unfolding of the native state of the variants, as well as their amyloidogenic propensity and the stability of amyloid fibrils under various conditions. Furthermore, we studied the intermolecular interactions of WT and mutant proteins with various binding partners that might have in vivo relevance. We found that, relative to WT β2m, the exceptional amyloidogenicity of the pathogenic D76N β2m variant is realized by the deleterious synergy of diverse effects of destabilized native structure, higher sensitivity to negatively charged amphiphilic molecules (e.g., lipids) and polyphosphate, more effective fibril nucleation, higher conformational stability of fibrils, and elevated affinity for extracellular components, including extracellular matrix proteins.
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Schaible, Ulrich E., Helen L. Collins, Friedrich Priem, and Stefan H. E. Kaufmann. "Correction of the Iron Overload Defect in β-2-Microglobulin Knockout Mice by Lactoferrin Abolishes Their Increased Susceptibility to Tuberculosis." Journal of Experimental Medicine 196, no. 11 (November 25, 2002): 1507–13. http://dx.doi.org/10.1084/jem.20020897.
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As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. β-2-microglobulin (β2m) knockout (KO) mice are more susceptible to tuberculosis than wild-type mice, which is generally taken as a proof for the role of major histocompatibility complex class I (MHC-I)–restricted CD8 T cells in protection against M. tuberculosis. However, β2m associates with a number of MHC-I–like proteins, including HFE. This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis). Accordingly, β2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in β2m–KO mice by lactoferrin treatment significantly reduces the burden of M. tuberculosis to numbers comparable to those observed in MHC class I–KO mice. In parallel, the generation of nitric oxide impaired in β2m–KO mice was rescued. Conversely, iron overload in the immunocompetent host exacerbated disease. Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria. Our data establish: (a) defective iron metabolism explains the increased susceptibility of β2m-KO mice over MHC-I–KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.
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Visconti, Lorenzo, Francesca Malagrinò, Luca Broggini, Chiara De Luca, Fabio Moda, Stefano Gianni, Stefano Ricagno, and Angelo Toto. "Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State." International Journal of Molecular Sciences 20, no. 2 (January 18, 2019): 396. http://dx.doi.org/10.3390/ijms20020396.
Full textAbstract:
Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since the three-dimensional structure of the protein is essentially unaffected by the mutation, the increased aggregation propensity of D76N has been generally ascribed to its lower thermodynamic stability and increased dynamics. In this study we compare the equilibrium unfolding and the aggregation propensity of wild type β2m and D76N variant at different experimental conditions. Our data revealed a surprising effect of the D76N mutation in the residual structure of the denatured state, which appears less compact than that of the wild type protein. A careful investigation of the structural malleability of the denatured state of wild type β2m and D76N pinpoint a clear role of the denatured state in triggering the amyloidogenic propensity of the protein. The experimental results are discussed in the light of the previous work on β2m and its role in disease.
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Skare, Thelma Larocca, Kellen Ferri, and Marcela Aimone Santos. "Systemic lupus erythematosus activity and beta two microglobulin levels." Sao Paulo Medical Journal 132, no. 4 (May 28, 2014): 239–42. http://dx.doi.org/10.1590/1516-3180.2014.1324703.
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CONTEXT AND OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease with a cyclical clinical course. Evaluation of the clinical activity of this disease is important for choosing the correct treatment. The objective of this study was to analyze the value of beta-2 microglobulin (β2M) serum levels in determining SLE clinical activity.DESIGN AND SETTING: Cross-sectional analytical study conducted at the rheumatology outpatient clinic of a private university hospital.METHODS: 129 SLE patients were studied regarding disease activity using SLEDAI (SLE Disease Activity Index) and cumulative damage using SLICC ACR (SLE International Collaborating Clinics/American College of Rheumatology Damage Index for SLE). At the same time, the β2M serum level, ESR (erythrocyte sedimentation rate), anti-dsDNA (anti-double-stranded DNA) and C3 and C4 complement fractions were determined.RESULTS: β2M levels correlated positively with SLEDAI (P = 0.02) and ESR (P = 0.0009) and negatively with C3 (P = 0.007). Patients who were positive for anti-dsDNA had higher β2M serum levels (P = 0.009).CONCLUSION: β2M levels are elevated in SLE patients with active disease.
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Foucras, Gilles, Christiane Coureau, Leo Beijleveld, Philippe Druet, Abdelhadi Saoudi, and Jean-Charles Guéry. "β2-Microglobulin-Dependent T Cells Are Not Necessary for Alloantigen-Induced Th2 Responses After Neonatal Induction of Lymphoid Chimerism in Mice." Journal of Immunology 161, no. 4 (August 15, 1998): 1751–57. http://dx.doi.org/10.4049/jimmunol.161.4.1751.
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Abstract We have analyzed the requirement for β2-microglobulin (β2m)-dependent T cells in the generation of allogeneic Th2 responses in vivo. A neonatal injection of semiallogeneic cells in BALB/c mice induces a state of chimerism that promotes the differentiation of donor-specific CD4+ T cells toward the Th2 phenotype. Polyclonal T-B cell interactions occur in this model between host Th2 and donor B cells, resulting in the production of IgE Abs. IgE production and Th2-priming are critically dependent upon the early production of IL-4. Our data in the present paper demonstrate that: 1) IgE synthesis and the up-regulation of MHC class II and CD23 molecules on B cells are independent of β2m expression in the host, 2) no difference in the induction of CD4 alloreactive Th2 cells could be observed between β2m−/− and their wild-type control littermates when Th2-priming was measured in adult mice, and 3) the Th2 response and IgE production is induced in the complete absence of β2m-dependent T cells both in the host and in the inoculum. Therefore, using a variety of assays, we could not demonstrate diminished responses in mice with a disrupted β2m gene in this model of Th2-mediated allogeneic interaction, indicating that β2m-dependent NK1.1+ and CD8+ T cells are not required for the generation of alloreactive Th2 responses in vivo.
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Bonomini, V., L. Colì, G. Feliciangeli, A. Nanni Costa, and M. P. Scolari. "Long-Term Comparative Evaluation of Synthetic and Cellulosic Membranes in Dialysis." International Journal of Artificial Organs 17, no. 7 (July 1994): 392–98. http://dx.doi.org/10.1177/039139889401700705.
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A long-term retrospective evaluation (5 years) compares two groups of RDT patients (group 1 on continuous treatment with cellulosic membranes and group 2 with synthetic membranes) regarding survival, general clinical morbidity, and β2M-related morbidity. The results showed no significant long-term differences between the groups either for survival or general morbidity despite some differences in biocompatibility. The higher intradialytic removal of β2M by synthetic membranes did not lead to a reduction in either pre-dialysis β2M values or β2M related morbidity. The higher cost of synthetic over cellulosic membranes and the disappointing of many clinical expectations suggest that the use of such membranes, in association with alternative techniques, should take place only according to certain “elective” indications such as old age, diabetes, vascular instability or intradialytic disequilibrium syndrome.
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Bossard, Celine, Juliette Eugene, Nicolas Jouand, Delphine Dansette, Edouard Leveque, Juliette Podevin, Tamara Matysiak, et al. "Intraepithelial CD94+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression as a new immune checkpoint to predict prognosis in colorectal carcinomas." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14592-e14592. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14592.
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e14592 Background: A better understanding of the immune-modulating interactions between tumor cells and immune cells underlying the balance between immune control and immune resistance in colorectal cancer (CRC) is crucial for the design of immunotherapies. We have previously demonstrated that overexpression of the human MHC class Ib molecule - HLA-E/β2 microglobulin - by tumor cells in CRC was associated with an unfavorable prognosis, suggesting its involvement in immune escape. However, the specific receptor of HLA-E/β2m - CD94/NKG2A, inhibitory or CD94/NKG2C, activating - expressed by tumor-infiltrating lymphocytes (TIL), as well as the influence of the microsatellite status in HLA-E/β2m overexpression, remain unknown. Methods: We investigated in the primary tumor of 245 CRC patients 1) the association of HLA-E/β2m overexpression and the density of CD94+ intraepithelial TIL (IEL-TIL) with the microsatellite status, 2) the nature of CD94+ TIL and the receptor expressed - CD94/NKG2A or CD94/NKG2C - and 3) the prognostic influence of CD94+ IEL-TIL. Results: HLA-E/β2m was preferentially overexpressed in MSI compared with MSS CRC (44,6 % vs 18,4 % respectively, p = 0.0001), and significantly associated with a high density of CD94+ IEL-TIL in MSI (0,9% in HLA-E/β2m+ vs 0,2% in HLA-E/β2m– CRC, p = 0,001), and in MSS CRC (0,38% vs 0,15%, p < 0,0001). These CD94+ TIL mostly corresponded to CD8+ αβ T cells preferentially expressing the inhibitory NKG2A chain. Finally, a high density of CD94+ IEL-TIL was independently associated with a worse OS (p = 0.03). Conclusions: These results strongly suggest that HLA-E/β2m - CD94/NKG2A interactions, preferentially up-regulated in MSI CRC, represent a promising inhibitory immune checkpoint. From a clinical point of view, this inhibitory immune checkpoint could be blocked by the new anti-NKG2A monoclonal antibody.
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Cole, J. W., R. J. Portman, Y. Lim, J. M. Perlman, and A. M. Robson. "Urinary β2-Microglobulin in Full-Term Newborns: Evidence for Proximal Tubular Dysfunction in Infants With Meconium-Stained Amniotic Fluid." Pediatrics 76, no. 6 (December 1, 1985): 958–64. http://dx.doi.org/10.1542/peds.76.6.958.
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Urinary concentrations of β2-microglobulin (β2M) and creatinine were measured in normal term infants and in those born with meconium-stained amniotic fluid. None of the infants or their mothers had conditions known to modify β2M excretion. Measurements of β2M were made on urines collected by bagging; urines obtained from diapers were not satisfactory. Urinary β2M concentrations increased significantly (P < .02) in the normal infants from the first day (0.36 ± 0.29 mg/L: n = 29) to the third day (0.60 ± 0.43 mg/L: n = 21) postpartum. Compared with the normal infants, values for the infants with meconium-stained amniotic fluid were increased significantly on days 1 (1.64 ± 2.16 mg/L: n = 25: P < .005) and 3 (2.12 ± 2.04 mg/L: n = 23: P < .005). Levels exceeded two standard deviations above the normal mean in 12 of the 26 infants with meconium-stained amniotic fluid on postpartum day 1, and 12 of the 23 infants with meconium-stained amniotic fluid on day 3. Urinary creatinine levels were similar in both the normal infants and those with meconium-stained amniotic fluid. All infants with meconium-stained amniotic fluid with a one-minute Apgar score of 6 or less had an elevated urinary β2M concentration. The elevated levels of urinary β2M in infants with meconium-stained amniotic fluid indicate the existence of tubular dysfunction, probably mild acute tubular necrosis secondary to hypoxia.