Abstract
This study aimed to investigate the changes in B cell functional decline and antigen sensitization with aging using two Epstein Barr virus (EBV)-immortalized human B cell lines, one from a 22-year-old man (EBV-B young) and the other from a 65-year-old man (EBV-B old). The activity of senescence-associated β-galactosidase, a marker of cellular senescence, was enhanced in the EBV-B old cells compared with EBV-B young cells. Moreover, the levels of p16, p21, IL-6, TNF-α, and TGF-β1, which are senescence-associated secretary phenotypes, were also increased in EBV-B old cells. In vitro immunization of EBV-B cells with β-lactoglobulin further showed that EBV-B old cells had a reduced cell population of naïve B cells than that of EBV-B young cells. Furthermore, HLA-DR expression, which is important for antigen presentation, was decreased in the EBV-B old cells. Comparative microarray analysis between EBV-B young and old cells also showed decreased expression of antibody genes, such as those of the heavy chain and light chain (κ chain). These results suggest that cellular senescence and decreased gene expression are responsible, at least in part, for the decline in B cell function and antigen sensitization capacity with aging, which ultimately impairs the function of the acquired immune system.
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The data and materials that support the findings of this study are available from the corresponding author upon reasonable request.
References
Acosta JC, Banito A, Wuestefeld T et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990. https://doi.org/10.1038/ncb2784
Bolstad BM, Irizarry RA, Åstrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19:185–193. https://doi.org/10.1093/bioinformatics/19.2.185
Coppé JP, Rodier F, Patil CK et al (2011) Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 286:36396–36403. https://doi.org/10.1074/jbc.M111.257071
DiLillo DJ, Matsushita T, Tedder TF (2010) B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci 1183:38–57. https://doi.org/10.1111/j.1749-6632.2009.05137.x
Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367. https://doi.org/10.1073/pnas.92.20.9363
Dorshkind K, Swain S (2009) Age-associated declines in immune system development and function: causes, consequences, and reversal. Curr Opin Immunol 21:404–407. https://doi.org/10.1016/j.coi.2009.07.001
Franceschi C, Bonafè M, Valensin S et al (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
Frasca D, Blomberg BB (2011) Aging affects human B cell responses. J Clin Immunol 31:430–435. https://doi.org/10.1007/s10875-010-9501-7
Frasca D, Riley RL, Blomberg BB (2004) Effect of age on the immunoglobulin class switch. Crit Rev Immunol 24:297–320. https://doi.org/10.1615/critrevimmunol.v24.i5.10
Garg M, Luo W, Kaplan AM, Bondada S (1996) Cellular basis of decreased immune response to pneumococcal vaccines in aged mice. Infect Immun 64:4456–4462. https://doi.org/10.1128/iai.64.11.4456-4462.1996
Goronzy JJ, Lee WW, Weyand CM (2007) Aging and T-cell diversity. Exp Gerontol 42:400–406. https://doi.org/10.1016/j.exger.2006.11.016
Gri G, Savio D, Trinchieri G, Ma X (1998) Synergistic regulation of the human interleukin-12 p40 promoter by NFkappaB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages. J Biol Chem 273:6431–6438. https://doi.org/10.1074/jbc.273.11.6431
Ichihara Y, Okano M, Nishioka K et al (2009) Aging exacerbates restraint stress-induced inhibition of antigen-specific antibody production in mice. Allergol Int 58:119–124. https://doi.org/10.2332/allergolint.O-08-535
Labrie JE, Sah AP, Allman DM et al (2004) Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. J Exp Med 200:411–423. https://doi.org/10.1084/jem.20040845
Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133–139. https://doi.org/10.1038/ni1033
Miller JP, Allman D (2003) The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 171:2326–2330. https://doi.org/10.4049/jimmunol.171.5.2326
Miller RA (1991) Aging and immune function. Int Rev Cytol 124:187–215. https://doi.org/10.1016/S0074-7696(08)61527-2
Muñoz-Espín D, Cañamero M, Maraver A et al (2013) Programmed cell senescence during mammalian embryonic development. Cell 155:1104–1118. https://doi.org/10.1016/j.cell.2013.10.019
Pawelec G, Hirokawa K, Fülöp T (2001) Altered T cell signalling in ageing. Mech Ageing Dev 122:1613–1637. https://doi.org/10.1016/s0047-6374(01)00290-1
Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192:547–556. https://doi.org/10.1083/jcb.201009094
Shi Y, Yamazaki T, Okubo Y et al (2005) Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol 175:3262–3267. https://doi.org/10.4049/jimmunol.175.5.3262
Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18:1613–1620. https://doi.org/10.1016/s0264-410x(99)00495-8
Stephan RP, Lill-Elghanian DA, Witte PL (1997) Development of B cells in aged mice: decline in the ability of pro-B cells to respond to IL-7 but not to other growth factors. J Immunol 158:1598–1609
Tsaknaridis L, Spencer L, Culbertson N et al (2003) Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res 74:296–308. https://doi.org/10.1002/jnr.10766
Veldhoen M, Hocking RJ, Atkins CJ et al (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189. https://doi.org/10.1016/j.immuni.2006.01.001
Yang NC, Hu ML (2005) The limitations and validities of se nescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol 40:813–819. https://doi.org/10.1016/j.exger.2005.07.011
Yang G, Rosen DG, Zhang Z et al (2006) The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci U S A 103:16472–16477. https://doi.org/10.1073/pnas.0605752103
Zhao D, Hajiaghamohseni LK, Lu X et al (2020) Inhibition of acid ceramidase regulates MHC class II antigen presentation and suppression of autoimmune arthritis. Cytokine 135:155219. https://doi.org/10.1016/j.cyto.2020.155219
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The authors would like to thank K. Yasuda (Cell Innovator, Fukuoka, Japan) for her assistance with the microarray analysis.
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Fujiki, T., Matsumoto, SE., Kishihara, K. et al. Age-related functional decline of human B cells. Cytotechnology 74, 319–327 (2022). https://doi.org/10.1007/s10616-021-00513-z
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DOI: https://doi.org/10.1007/s10616-021-00513-z