β2-МИКРОГЛОБУЛИН И ПРОЦЕСС СТАРЕНИЯ

DOI: https://doi.org/10.29296/24999490-2020-04-04

Б.И. Кузник(1, 2), доктор медицинских наук, профессор, Н.И. Чалисова(3, 4), доктор биологических наук, профессор 1-ФГБОУ ВО «Читинская государственная медицинская академия», Российская Федерация, 672090, Чита, ул. Бабушкина, 46; 2-Иновационная клиника «Академия здоровья», Российская Федерация, 672000, Чита, ул. Коханского, 13; 3-ФГБУН «Институт физиологии им. И.П. Павлова» Российской академии наук, Российская Федерация, 199034, Санкт-Петербург, наб. Макарова 6; 4-АНО НИЦ «Санкт-Петербургский институт биорегуляции и геронтологии», Российская Федерация, 197110, Санкт-Петербург, пр. Динамо, 3 Е-mail: ni_chalisova@ mail.ru

Актуальными для современной геронтологии являются не только проблемы увеличения продолжительности жизни, но и значительного улучшения ее качества. Для этого необходимо решать задачи ранней диагностики и таргетной профилактики возраст-ассоциированных заболеваний. Рассматриваются данные об одном из наиболее часто встречающихся маркеров старения – β2-микроглобулине (β2М) плазмы крови. Представлены сведения о строении, свойствах и функциях β2М, содержание которого увеличивается при старении организма. В экспериментах показано, что концентрация β2M увеличивается в гиппокампе старых животных, а также молодых гетерохронных парабионтов. Обнаружена положительная корреляция между концентрацией β2М и степенью нарушения когнитивных функций, деменции. Большую роль β2М играет в развитии заболеваний сердечно-сосудистой системы. У больных с высоким уровнем β2М в сыворотке крови более тяжело протекала ИБС, сильнее поражались сонные артерии и периферические сосуды. Показана положительная корреляция тяжести и продолжительности сахарного диабета с высокой концентрацией β2М. Кроме того β2М стимулирует рост и метастазирование различных видов рака. Определение концентрации β2М в сыворотке крови имеет большое прогностическое значение для предиктивной медицины и профилактики патологии, ассоциированной с возрастом.
Ключевые слова: 
старение, заболевания сердечно-сосудистой системы
Для цитирования: 
Кузник Б.И., Чалисова Н.И. β2-МИКРОГЛОБУЛИН И ПРОЦЕСС СТАРЕНИЯ. Молекулярная медицина, 2020; (4): -https://doi.org/10.29296/24999490-2020-04-04

Список литературы: 
  1. Кузник Б.И., Давыдов С.О., Поправка Е.С., Линькова Н.С., Козина Л.С., Хавинсон В.Х. Эпигенетические механизмы пептидной регуляции и нейропротекторный белок FKBP1B. Молекулярная биология. 2019; 53 (2): 339–48. [Kuznir B.I., Davidov S.O., Popravka E.S., Kinkova N.S., Kozina L.S., Khavinson V.Kh. Epigenetic mechanisms of peptide regulation and neuroprotector protein FKBP1B. Molecular Biology. 2019; 53 (2): 339–48 (in Russian)]
  2. Хавинсон В.Х., Кузник Б.И., Рыжак Г.А. Пептидные биорегуляторы – новый класс геропротекторов. Успехи геронтологии. 2013; 26 (1): 20–37.
  3. [Khavinson V.Kh., Kuznir B.I., Rigak G.A. Peptide regulators – a new class of neuroprotectors. Uspekhi Gerontologii. 2013; 26 (1): 20–37 (in Russian)]
  4. Чалисова Н.И., Концевая Е.А., Войцеховская М.А., Рыжак Г.А. Влияние коротких пептидов на развитие органотипической культуры ткани кожи молодых и старых крыс. Профилактическая и клиническая медицина. 2011; 2 (2): 110–3. [Chalisova N.I., Kontsevaya E.A., Voitsekhovskaya M.A., Rigak G.A. Effect of short peptides on the development of skin organotypic tissue culture in young and old rats. Prophylactic and Clinical Medicine. 2011; 2 (2): 110–3 (in Russian)]
  5. Annweiler Cédric, Bataille Régis, Ferrière Nicolas, Douillet Bruno Delphine, Fantino Beauchet Olivier. Plasma Beta-2 Microglobulin as a Marker of Frailty in Older Adults: A Pilot Study. The J. of Gerontology. 2011; 66A (10): 1077–79. https://doi.org/10.1093/gerona/glr104.
  6. Brew B.J., Dunbar N., Pemberton L., Kaldor J. Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta 2-microglobulin and neopterin. The J. of infectious diseases. 1996; 174: 294–98.
  7. Carrette O. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer’s disease. Proteomics. 2003; 3: 1486–94.
  8. Villeda S.A., Luo J., Mosher K.I. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011; 477: 90–4.
  9. Hilt Z.T, Ture S.K., Mohan A., Arne A., Morrell C.N. Platelet-derived β2m regulates age related monocyte/macrophage functions. Aging (Albany NY). 2019; 11. https://doi.org/10.18632/aging.102520.
  10. Smith L.K., He Y., Park J.S., Bieri G., Snethlage C.E., Lin K., Gontier G., Wabl R., Plambeck K.E., Udeochu J., Wheatley E.G., Bouchard J., Eggel A., Narasimha R., Grant J.L., Luo J., Wyss-Coray T., Villeda S.A. β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med. 2015; 21 (8): 932–7. https://doi.org/10.1038/nm.3898.
  11. Villeda S. A., Plambeck, K. E., Middeldorp, J. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine. 2014; 20 (6): 659–63.
  12. Das M.M., Godoy M., Chen S., Moser V.A., Avalos P., Roxas K.M., Dang I., Yáñez A., Zhang W., Bresee C., Arditi M., Liu G.Y., Svendsen C.N., Goodridge H.S. Young bone marrow transplantation preserves learning and memory in old mice. Commun Biol. 2019; 20 (2): 73–9. https://doi.org/10.1038/s42003-019-0298-5.
  13. Shimbo A., Kosaki Y., Ito I., Watanabe S. Mice lacking hippocampal left-right asymmetry show non-spatial learning deficits. Behav Brain Res. 2018; 336: 156–65. https://doi.org/10.1016/j.bbr.2017.08.043. Epub 2017 Aug 31.
  14. Swanson E.C., Schleiss M.R. Congenital cytomegalovirus infection: new prospects for prevention and therapy.Pediatr Clin North Am. 2013; 60 (2): 335–49. https://doi.org/10.1016/j.pcl.2012.12.008.
  15. Alarcon A.., Martinez-Biarge M, Cabañas F., Hernanz A., Quero J., Garcia-Alix A. Clinical, biochemical, and neuroimaging findings predict long-term neurodeve-lopmental outcome in symptomatic congenital cytomegalovirus infection. J. Pediatr. 2013; 163 (3): 828–34. https://doi.org/10.1016/j.jpeds.2013.03.014.
  16. Murray A.M. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Advances in chronic kidney disease. 2008; 15: 123–32.
  17. Filiano A.J., Kipnis J. Breaking bad blood: β2-microglobulin as a pro-aging factor in blood Nat. Med. 2015; 21 (8): 844–5. https://doi.org/10.1038/nm.3926.
  18. Yang R., Fu S., Zhao L., Zhen B., Ye L., Niu X, Li X., Zhang P., Bai J. Quantitation of circulating GDF-11 and β2-MG in aged patients with age-related impairment in cognitive function. Clin Sci (Lond). 2017; 131 (15): 1895–904. https://doi.org/10.1042/CS20171028.
  19. Załęska-Kocięcka M., Jezierski P., Grabowski M., Kuśmierski K., Dąbrowski M., Piotrowska K., Banaszewski M., Imiela J., Stępińska J. Role of β2-microglobulin in postoperative cognitive decline. Biomark. Med. 2017; 11 (3): 245–53. https://doi.org/10.2217/bmm-2016-0274.
  20. Martinez M., Frank A., Hernanz A. Relationship of interleukin-1 beta and beta 2-microglobulin with neuropeptides in cerebrospinal fluid of patients with dementia of the Alzheimer type. J. Neuroimmunol. 1993; 48 (2): 235–40.
  21. Doecke J.D., Laws S.M., Faux N.G., Wilson W., Burnham S.C., Lam C.P., Mondal A., Bedo J., Bush A.I., Brown B., De Ruyck K., Ellis K.A., Fowler C., Gupta V.B., Head R., Macaulay S.L., Pertile K., Rowe C.C., Rembach A., Rodrigues M., Rumble R., Szoeke C., Taddei K., Taddei T., Trounson B., Ames D., Masters C.L., Martins R.N. Alzheimer’s Disease Neuroimaging Initiative; Australian Imaging Biomarker and Lifestyle Research Group. Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol. 2012; 69 (10): 1318–25.
  22. Rembach A., Stingo F.C., Peterson C., Vannucci M., Do K.A., Wilson W.J., Macaulay S.L., Ryan T.M., Martins R.N., Ames D., Masters C.L., Doecke J.D. AIBL Research Group. Bayesian graphical network analyses reveal complex biological interactions specific to Alzheimer’s disease. J. Alzheimers Dis. 2015; 44 (3): 917–25. https://doi.org/10.3233/JAD-141497.
  23. Dominici R., Finazzi D., Polito L., Oldoni E., Bugari G., Montanelli A., Scarpini E., Galimberti D., Guaita A. Comparison of β2-microglobulin serum level between Alzheimer’s patients, cognitive healthy and mild cognitive impaired individuals. Biomarkers. 2018; 23 (6): 603–8. https://doi.org/10.1080/1354750X.2018.1468825.
  24. Chen S.M., Yi Y.L., Zeng D., Tang Y.Y., Kang X., Zhang P., Zou W., Tang X.Q. Hydrogen Sulfide Attenuates β2-Microglobulin-Induced Cognitive Dysfunction: Involving Recovery of Hippocampal Autophagic Flux. ront Behav Neurosci. 2019; 25 (13): 244–9. https://doi.org/10.3389/fnbeh.2019.00244.
  25. Boccadoro M., Tarella C., Palumbo A., Argentino C., Triolo S., Dominietto A., Callea V., Lauta V.M., Molica S., Musto P., Marmont F., Gianni A.M., Pileri A. An analysis of which subgroups of multiple myeloma patients, divided according to b(2)-microglobulin and plasma cell labeling index, benefit from high dose vs conventional chemotherapy. Haematologica. 1999; 84 (10): 905–10.
  26. Wu Y., Shi L., Feng L.., Lv D.L., Zhongguo Shi, Yan Xue, Ye Xue, Za Zhi. Clinical Analysis of Autologous Cytokine-induced Killer Cells Combined with IL-2 for Treating of Elderly Patients with B-cell Malignant Lymphoma]. 2016; 24 (3): 738–43. https://doi.org/10.7534/j.issn.1009-2137.2016.03.019.
  27. Kim Y.D., Yim D.H., Eom S.Y., Moon S.I., Park C.H., Kim G.B., Yu S.D., Choi B.S., Park J.D., Kim H. Temporal changes in urinary levels of cadmium, N-acetyl-β-d-glucosaminidase and β2-microglobulin in individuals in a cadmium-contaminated area. Environ Toxicol Pharmacol. 2015; 39 (1): 35–41. https://doi.org/10.1016/j.etap.2014.10.016.
  28. Standl E., Balletshofer B., Dahl B., Weichenhain B., Stiegler H., Hörmann A., Holle R. Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioner Project. Diabetologia. 1996; 39 (12): 1540–5.
  29. Liu Y.S., Wang X., Jiang W.D., Luciani M., Troncone L., Monte F.D. Current and future circulating biomarkers for cardiac amyloidosis. Acta Pharmacol. Sin. 2018; 39 (7): 1133–41. https://doi.org/10.1038/aps.2018.38.
  30. Hoke M., Pernicka E., Niessner A., Goliasch G., Amighi J., Koppensteiner R., Minar E., Mlekusch W., Rumpold H., Wagner O., Schillinger M. Renal function and long-term mortality in patients with asymptomatic carotid atherosclerosis. Тhromb Haemost. 2012; 107 (1): 150–7. https://doi.org/10.1160/TH11-06-0383.
  31. Rönsholt F.F., Ullum H., Katzenstein T.L., Gerstoft J., Ostrowski S.R. Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy. PLoS One. 2013; 8 (6): e65182. https://doi.org/10.1371/journal.pone.0065182.
  32. Stanga Z., Nock S., Medina-Escobar P,. Nydegger U.E., Risch M., Risch L. Factors other than the glomerular filtration rate that determine the serum beta-2-microglobulinlevel. PLoS One. 2013; 8 (8): e72073. https://doi.org/10.1371/journal.pone.0072073.
  33. Juraschek S.P., Coresh J., Inker L.A., Levey A.S., Köttgen A., Foster M.C., Astor B.C., Eckfeldt J.H., Selvin E. Comparison of serum concentrations of β-trace protein, β2-microglobulin, cystatin C, and creatinine in the US population. Clin. J. Am. Soc. Nephrol. 2013; 8 (4): 584–92. https://doi.org/10.2215/CJN.08700812.
  34. Stakhova T.Iu., Shcherbak A.V., Kozlovskaia L.V., Taranova M.V., Balkarov I.M. Clinical value of the determination of markers for endothelial dysfunction (endothelin-1, microalbuminuria) and tubulointerstitial tissue lesion (β2-microglobulin, monocyte chemotactic protein-1) in hypertensive patients with uric acid metabolic disorders]. Ter Arkh. 2014; 86 (6): 45–51.
  35. Leffers H.C.B., Hermansen M.L., Sandholt B., Fuchs A., Sillesen H., Køber L., Kofoed K.F., Faurschou M., Jacobsen S. Plasma levels of β2-microglobulin are associated with atherosclerosis in patients with systemic lupus erythematosus: a cross-sectional cohort study. Lupus. 2018; 27 (9): 1517–23. https://doi.org/10.1177/0961203318784661.
  36. Dong X.M., Cai R.., Yang F, Zhang Y.Y., Wang X.G.., Fu S.L., Zhang J.R. Predictive value of plasma β2-microglobulin on human body function and senescence. Eur. Rev. Med. Pharmacol. Sci. 2016; 20 (11): 2350–6.
  37. Keefe J.A., Hwang S.J., Huan T., Mendelson M., Yao C., Courchesne P., Saleh M.A., Madhur M.S., Levy D. Evidence for a Causal Role of the SH2B3-β2M Axis in Blood Pressure. Regulation. Hypertension. 2019; 73 (2): 497–503.
  38. Li Y., Zhang X., Li L., Wang X., Chen Z., Wang X., Wang Y., Kang L., Ye Y., Jia J., Zhang G., Yang C., Yuan J., Zhou J., Ge J., Gong H., Zou Y. Mechanical stresses induce paracrine β-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor. Clin. Sci. (Lond). 2018; 132 (16): 1855–74. https://doi.org/10.1042/CS20180486.
  39. Zhang C., Li F., Long T., Li F., Peng L., Xia K., Jing R., Xie Q., Yang T. Beta 2-Microglobulin and the Severity of Coronary Stenosis in Patients With Acute Coronary Syndrome. Heart Lung Circ. 2019; 28 (4): 575–82. https://doi.org/10.1016/j.hlc.2018.02.016.
  40. Foster M.C., Weiner D.E., Bostom A.G., Carpenter M.A., Inker L.A., Jarolim P., Joseph A.A., Kusek J.W., Pesavento T., Pfeffer M.A., Rao M., Solomon S.D., Levey A.S. Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial. Am. J. Transplant. 2017; 17 (9): 2390–9. https://doi.org/10.1111/ajt.14258.
  41. Kay T.W., Parker J.L., Stephens L.A., Thomas H.E., Allison J. RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice. J. Immunol. 1996; 157 (8): 3688–93.
  42. Ekrikpo U.E., Effa E.E., Akpan E.E., Obot A.S., Kadiri S. Clinical Utility of Urinary β2-Microglobulin in Detection of Early Nephropathy in African Diabetes Mellitus Patients. Int. J. Nephrol. 2017; 40 (9): 3171–8. https://doi.org/10.1155/2017/4093171.
  43. Colombo M., Looker H.C., Farran B., Hess S., Groop L., Palmer C.N.A., Brosnan M.J., Dalton R.N., Wong M., Turner C., Ahlqvist E., Dunger D., Agakov F., Durrington P., Livingstone S., Betteridge J., McKeigue P.M., Colhoun H.M. Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes. SUMMIT Investigators. Diabetologia. 2019; 62 (1): 156–68. https://doi.org/10.1007/s00125-018-4741-9.
  44. Azenabor A., Ogbera A.O., Adejumo N.E., Adejare A.O. Acute phase reactant dynamics and incidence of microvascular dysfunctions in type 2 diabetes mellitus. J. Res. Med. Sci. 2011; 16 (10): 1298–305.
  45. Javadi S., Asri-Rezaei S., Allahverdizadeh M. Interrelationship of βeta-2 microglobulin, blood urea nitrogen and creatinine in streptozotocin-induced diabetes mellitus in rabbits Vet Res Forum. 2014; 5 (1): 7–11.
  46. Li L., Dong M., Wang X.G. The Implication and Significance of Beta 2 Microglobulin: A Conservative Multifunctional Regulator. Chin. Med. J. (Engl). 2016; 129 (4): 448–55. https://doi.org/10.4103/0366-6999.176084.
  47. Shi C.1., Zhu Y., Su Y., Chung L.W., Cheng T. Beta2-microglobulin: emerging as a promising cancer therapeutic target. Drug Discov. Today. 2009; 14 (1–2): 25–30. https://doi.org/10.1016/j.drudis.2008.11.001.
  48. Sliker B.H., Goetz B.T., Peters H.L., Poelaert B.J., Borgstahl G.E.O., Solheim J.C. Beta 2-microglobulin regulates amyloid precursor-like protein 2 expression and the migration of pancreatic cancer cells. Cancer Biol Ther. 2019; 20 (6): 931–40. https://doi.org/10.1080/15384047.2019.1580414.
  49. Chai D., Li K., Du H., Yang S., Yang R., Xu Y., Lian X. β2-microglobulin has a different regulatory molecular mechanism between ER+ and ER- breast cancer with HER2. BMC Cancer. 2019; 19 (1): 22331. https://doi.org/10.1186/s12885-019-5410-1.
  50. Sun W., Gui L., Zuo X., Zhang L., Zhou D., Duan X., Ren W., Xu G. Human epithelial-type ovarian tumour marker beta-2-microglobulin is regulated by the TGF-β signaling pathway. J. Transl. Med. 2016; 14: 75–83. https://doi.org/10.1186/s12967-016-0832-x
  51. Yusuke Kanemasa Tatsu, Shimoyama Yuki, Sasaki Miho, Tamura Takeshi, SawadaYasushi, Omuro Tsunekazu Hishima. Beta-2 microglobulin as a significant prognostic factor and a new risk model for patients with diffuse large B-cell lymphoma. Hematological Oncolog, 2017. https://doi.org/10.1002/hon.2312.
  52. Lucarelli G., Ditonno P., Bettocchi C., Vavallo A., Rutigliano M., Galleggiante V., Larocca A.M., Castellano G., Gesualdo L., Grandaliano G., Selvaggi F.P., Battaglia M. Diagnostic and prognostic role of preoperative circulating CA 15-3, CA 125, and beta-2 microglobulin in renal cell carcinoma. Dis. Markers. 2014; 68: 9795–8. https://doi.org/10.1155/2014/689795. Epub 2014 Feb 17
  53. Hinterleitner C., Pecher A.C., Kreißelmeier K.P., Budde U., Kanz L., Kopp H.G., Jaschonek K. Disease progression and defects in primary hemostasis as major cause of bleeding in multiple myeloma. Eur. J. Haematol. 2020; 104 (1): 26–35. https://doi.org/10.1111/ejh.13331.
  54. Prizment A.E., Linabery A.M., Lutsey P.L., Selvin E., Nelson H.H., Folsom A.R., Church T.R., Drake C.G., Platz E.A., Joshu C. Circulating Beta-2 Microglobulin and Risk of Cancer: The Atherosclerosis Risk in Communities Study (ARIC).Cancer Epidemiol. Biomarkers Prev. 2016; 25 (4): 657–64. https://doi.org/10.1158/1055-9965.EPI-15-0849.