Beta-2 microglobulin explained

β₂ microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α₁, α₂, and α₃ proteins which are present on all nucleated cells (excluding red blood cells).^{[1] [2]} In humans, the β₂ microglobulin protein^[3] is encoded by the B2M gene.^{[2] [4]}

Structure and function

β₂ microglobulin lies beside the α₃ chain on the cell surface. Unlike α₃, β₂ has no transmembrane region. Directly above β₂ (that is, further away from the cell) lies the α₁ chain, which itself is next to the α₂.

β₂ microglobulin associates not only with the alpha chain of MHC class I molecules, but also with class I-like molecules such as CD1 (5 genes in humans), MR1, the neonatal Fc receptor (FcRn), and Qa-1 (a form of alloantigen). Nevertheless, the β₂ microglobulin gene is outside of the MHC (HLA) locus, on a different chromosome.

An additional function is association with the HFE protein, together regulating the expression of hepcidin in the liver which targets the iron transporter ferroportin on the basolateral membrane of enterocytes and cell membrane of macrophages for degradation resulting in decreased iron uptake from food and decreased iron release from recycled red blood cells in the MPS (mononuclear phagocyte system) respectively. Loss of this function causes iron excess and hemochromatosis.^[5]

In a cytomegalovirus infection, a viral protein binds to β₂ microglobulin, preventing assembly of MHC class I molecules and their transport to the plasma membrane.

Mice models deficient for the β₂ microglobulin gene have been engineered. These mice demonstrate that β₂ microglobulin is necessary for cell surface expression of MHC class I and stability of the peptide-binding groove. In fact, in the absence of β₂ microglobulin, very limited amounts of MHC class I (classical and non-classical) molecules can be detected on the surface (bare lymphocyte syndrome or BLS). In the absence of MHC class I, CD8⁺ T cells cannot develop. (CD8⁺ T cells are a subset of T cells involved in the development of acquired immunity.)

Clinical significance

In patients on long-term hemodialysis, it can aggregate into amyloid fibers that deposit in joint spaces, a disease, known as dialysis-related amyloidosis.

Low levels of β₂ microglobulin can indicate non-progression of HIV.^[6]

Levels of β₂ microglobulin can be elevated in multiple myeloma and lymphoma, though in these cases primary amyloidosis (amyloid light chain) and secondary amyloidosis (amyloid associated protein) are more common. The normal value of β₂ microglobulin is < 2 mg/L.^[7] However, with respect to multiple myeloma, the levels of β₂ microglobulin may also be at the other end of the spectrum.^[8] Diagnostic testing for multiple myeloma includes obtaining the β₂ microglobulin level, for this level is an important prognostic indicator., a patient with a level < 4 mg/L is expected to have a median survival of 43 months, while one with a level > 4 mg/L has a median survival of only 12 months.^[9] β₂ microglobulin levels cannot, however, distinguish between monoclonal gammopathy of undetermined significance (MGUS), which has a better prognosis, and smouldering (low grade) myeloma.^{[10] [11]}

Loss-of-function mutations in this gene have been reported in cancer patients unresponsive to immunotherapies.

Virus relevance

β₂ microglobulin has been shown to be of high relevance for viral entry of Coxsackievirus A9 and Vaccinia virus (a Poxvirus).^[12] For Coxsackievirus A9, it is likely that β₂ microglobulin is required for the transport to plasma membrane of the identified receptor, the Human Neonatal Fc Receptor (FcRn).^[13] However, the specific function for Vaccinia virus has not yet been elucidated.

Further reading

• Huang WC, Havel JJ, Zhau HE, Qian WP, Lue HW, Chu CY, Nomura T, Chung LW . Beta2-microglobulin signaling blockade inhibited androgen receptor axis and caused apoptosis in human prostate cancer cells . Clinical Cancer Research . 14 . 17 . 5341–7 . September 2008 . 18765525 . 3032570 . 10.1158/1078-0432.CCR-08-0793 .
• Huang WC, Wu D, Xie Z, Zhau HE, Nomura T, Zayzafoon M, Pohl J, Hsieh CL, Weitzmann MN, Farach-Carson MC, Chung LW . beta2-microglobulin is a signaling and growth-promoting factor for human prostate cancer bone metastasis . Cancer Research . 66 . 18 . 9108–16 . September 2006 . 16982753 . 10.1158/0008-5472.CAN-06-1996 . free .
• Winchester JF, Salsberg JA, Levin NW . Beta-2 microglobulin in ESRD: an in-depth review . Advances in Renal Replacement Therapy . 10 . 4 . 279–309 . October 2003 . 14681859 . 10.1053/j.arrt.2003.11.003 .
• Krangel MS, Orr HT, Strominger JL . Assembly and maturation of HLA-A and HLA-B antigens in vivo . Cell . 18 . 4 . 979–91 . December 1979 . 93026 . 10.1016/0092-8674(79)90210-1 . free .
• Okon M, Bray P, Vucelić D . 1H NMR assignments and secondary structure of human beta 2-microglobulin in solution . Biochemistry . 31 . 37 . 8906–15 . September 1992 . 1390678 . 10.1021/bi00152a030 .
• Guo HC, Jardetzky TS, Garrett TP, Lane WS, Strominger JL, Wiley DC . 4324984 . Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle . Nature . 360 . 6402 . 364–6 . November 1992 . 1448153 . 10.1038/360364a0 . 1992Natur.360..364G .
• Gattoni-Celli S, Kirsch K, Timpane R, Isselbacher KJ . Beta 2-microglobulin gene is mutated in a human colon cancer cell line (HCT) deficient in the expression of HLA class I antigens on the cell surface . Cancer Research . 52 . 5 . 1201–4 . March 1992 . 1737380 .
• Saper MA, Bjorkman PJ, Wiley DC . Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution . Journal of Molecular Biology . 219 . 2 . 277–319 . May 1991 . 2038058 . 10.1016/0022-2836(91)90567-P .
• Caruana RJ, Lobel SA, Leffell MS, Campbell H, Cheek PL . Tumor necrosis factor, interleukin-1 and beta 2-microglobulin levels in chronic hemodialysis patients . The International Journal of Artificial Organs . 13 . 12 . 794–8 . December 1990 . 2289831 . 10.1177/039139889001301205 . 24952854 .
• Connors LH, Shirahama T, Skinner M, Fenves A, Cohen AS . In vitro formation of amyloid fibrils from intact beta 2-microglobulin . Biochemical and Biophysical Research Communications . 131 . 3 . 1063–8 . September 1985 . 2413854 . 10.1016/0006-291X(85)90198-6 .
• Hochman JH, Shimizu Y, DeMars R, Edidin M . Specific associations of fluorescent beta-2-microglobulin with cell surfaces. The affinity of different H-2 and HLA antigens for beta-2-microglobulin . Journal of Immunology . 140 . 7 . 2322–9 . April 1988 . 10.4049/jimmunol.140.7.2322 . 2450918 . 34035543 . free .
• Homma N, Gejyo F, Isemura M, Arakawa M . Collagen-binding affinity of beta-2-microglobulin, a preprotein of hemodialysis-associated amyloidosis . Nephron . 53 . 1 . 37–40 . 1989 . 2674742 . 10.1159/000185699 .
• Bataille R, Grenier J, Commes T . In vitro production of beta 2 microglobulin by human myeloma cells . Cancer Investigation . 6 . 3 . 271–7 . 1988 . 3048575 . 10.3109/07357908809080649 .
• Hönig R, Marsen T, Schad S, Barth C, Pollok M, Baldamus CA . Correlation of beta-2-microglobulin concentration changes to changes of distribution volume . The International Journal of Artificial Organs . 11 . 6 . 459–64 . November 1988 . 3060434 .
• Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC . 4373217 . Structure of the human class I histocompatibility antigen, HLA-A2 . Nature . 329 . 6139 . 506–12 . 1987 . 3309677 . 10.1038/329506a0 . 1987Natur.329..506B .
• Güssow D, Rein R, Ginjaar I, Hochstenbach F, Seemann G, Kottman A, Ploegh HL . The human beta 2-microglobulin gene. Primary structure and definition of the transcriptional unit . Journal of Immunology . 139 . 9 . 3132–8 . November 1987 . 10.4049/jimmunol.139.9.3132 . 3312414 . 38290153 . free .
• Cunningham BA, Wang JL, Berggård I, Peterson PA . The complete amino acid sequence of beta 2-microglobulin . Biochemistry . 12 . 24 . 4811–22 . November 1973 . 4586824 . 10.1021/bi00748a001 .
• Suggs SV, Wallace RB, Hirose T, Kawashima EH, Itakura K . Use of synthetic oligonucleotides as hybridization probes: isolation of cloned cDNA sequences for human beta 2-microglobulin . Proceedings of the National Academy of Sciences of the United States of America . 78 . 11 . 6613–7 . November 1981 . 6171820 . 349099 . 10.1073/pnas.78.11.6613 . 1981PNAS...78.6613S . free .
• Momoi T, Suzuki M, Titani K, Hisanaga S, Ogawa H, Saito A . Amino acid sequence of a modified beta 2-microglobulin in renal failure patient urine and long-term dialysis patient blood . Clinica Chimica Acta; International Journal of Clinical Chemistry . 236 . 2 . 135–44 . May 1995 . 7554280 . 10.1016/0009-8981(95)06039-G .
• Collins EJ, Garboczi DN, Karpusas MN, Wiley DC . The three-dimensional structure of a class I major histocompatibility complex molecule missing the alpha 3 domain of the heavy chain . Proceedings of the National Academy of Sciences of the United States of America . 92 . 4 . 1218–21 . February 1995 . 7862664 . 42670 . 10.1073/pnas.92.4.1218 . 1995PNAS...92.1218C . free .
• Matoba R, Okubo K, Hori N, Fukushima A, Matsubara K . The addition of 5'-coding information to a 3'-directed cDNA library improves analysis of gene expression . Gene . 146 . 2 . 199–207 . September 1994 . 8076819 . 10.1016/0378-1119(94)90293-3 .
• Wang Z, Cao Y, Albino AP, Zeff RA, Houghton A, Ferrone S . Lack of HLA class I antigen expression by melanoma cells SK-MEL-33 caused by a reading frameshift in beta 2-microglobulin messenger RNA . The Journal of Clinical Investigation . 91 . 2 . 684–92 . February 1993 . 8432869 . 288010 . 10.1172/JCI116249 .

Notes and References

1. Web site: Entrez Gene: Beta-2-microglobulin.
2. Güssow D, Rein R, Ginjaar I, Hochstenbach F, Seemann G, Kottman A, Ploegh HL . The human beta 2-microglobulin gene. Primary structure and definition of the transcriptional unit . Journal of Immunology . 139 . 9 . 3132–8 . November 1987 . 10.4049/jimmunol.139.9.3132 . 3312414 . 38290153 . free .
3. Cunningham BA, Wang JL, Berggård I, Peterson PA . The complete amino acid sequence of beta 2-microglobulin . Biochemistry . 12 . 24 . 4811–22 . November 1973 . 4586824 . 10.1021/bi00748a001 .
4. Suggs SV, Wallace RB, Hirose T, Kawashima EH, Itakura K . Use of synthetic oligonucleotides as hybridization probes: isolation of cloned cDNA sequences for human beta 2-microglobulin . Proceedings of the National Academy of Sciences of the United States of America . 78 . 11 . 6613–7 . November 1981 . 6171820 . 349099 . 10.1073/pnas.78.11.6613 . 1981PNAS...78.6613S . free .
5. Book: Hundall SD . Hematology: A Pathophysiologic Approach . 1st . 2011 . Chapter 3: Iron, Heme, and Hemoglobin . 17–25 . Elsevier - Health Sciences Division . 978-0-323-04311-3 .
6. Rao M, Sayal SK, Uppal SS, Gupta RM, Ohri VC, Banerjee S . Beta-2-Microglobulin Levels in Human-Immunodeficiency Virus Infected Subjects . Medical Journal, Armed Forces India . 53 . 4 . 251–254 . October 1997 . 28769505 . 5531080 . 10.1016/S0377-1237(17)30746-3 .
7. Book: Pignone M, Nicoll D . McPhee SJ . Pocket guide to diagnostic tests . 4th . McGraw-Hill . New York . 2004 . 191 . 0-07-141184-4 .
8. Web site: Amyloidosis . The Lecturio Medical Concept Library . 28 June 2021.
9. Book: Loscalzo J, Longo DL, Fauci AS, Dennis LK, Hauser SL . Harrison's Principles of Internal Medicine . Munshi NC, Longo DL, Anderson KC . Chapter 111: Plasma Cell Disorders . 936–44. 18th . McGraw-Hill Professional . 2011 . 978-0-07-174889-6 .
10. Rajkumar SV . MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management . Hematology. American Society of Hematology. Education Program . 2005 . 340–5 . 2005 . 16304401 . 10.1182/asheducation-2005.1.340 . free .
11. Bataille R, Klein B . Serum levels of beta 2 microglobulin and interleukin-6 to differentiate monoclonal gammopathy of undetermined significance . Blood . 80 . 9 . 2433–4 . November 1992 . 1421418 . 10.1182/blood.V80.9.2433.2433 . free .
12. Matía . Alejandro . Lorenzo . Maria M. . Romero-Estremera . Yolimar C. . Sánchez-Puig . Juana M. . Zaballos . Angel . Blasco . Rafael . Identification of β2 microglobulin, the product of B2M gene, as a Host Factor for Vaccinia Virus Infection by Genome-Wide CRISPR genetic screens . PLOS Pathogens . 27 December 2022 . 18 . 12 . e1010800 . 10.1371/journal.ppat.1010800. 36574441 . 9829182 . free .
13. Zhao . Xin . Zhang . Guigen . Liu . Sheng . Chen . Xiangpeng . Peng . Ruchao . Dai . Lianpan . Qu . Xiao . Li . Shihua . Song . Hao . Gao . Zhengrong . Yuan . Pengfei . Liu . Zhiheng . Li . Changyao . Shang . Zifang . Li . Yan . Zhang . Meifan . Qi . Jianxun . Wang . Han . Du . Ning . Wu . Yan . Bi . Yuhai . Gao . Shan . Shi . Yi . Yan . Jinghua . Zhang . Yong . Xie . Zhengde . Wei . Wensheng . Gao . George F. . Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B . Cell . May 2019 . 177 . 6 . 1553–1565.e16 . 10.1016/j.cell.2019.04.035. 31104841 . 7111318 .