Skip to main content
SpringerLink
Log in

Transcription Factors in Mature B-Cells During Aging

  • Chapter
Handbook on Immunosenescence

  • 1821 Accesses

Abstract

The purpose of this chapter is to give an overview of the age-related changes in the expression and function of the major transcription factors regulating mature B-cells. We also summarize our recent work and show that the age-related defects in Ig class switch are directly related to the decrease in the transcription factor E47 which controls the expression of AID, needed for CSR. The age-associated effects on the expression and function of the transcription factors NF-κ B and Pax-5 are also described. Blimp-1 seems not to be modified by aging. For other transcription factors relevant for mature B-cell functions, such and IRF4 and Notch2, no effects of aging have been reported so far. The defects presented herein for aged B-cells should allow the discovery of mechanisms to improve humoral immune responses in both humans and mice in the near future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Anspach J, Poulsen G, Kaattari I, Pollock R, Zwollo P (2001) Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice. J Immunol 166:2617–2626

    PubMed  CAS  Google Scholar 

  • Bergler W, Adam S, Gross HJ, Hormann K, Schwartz-Albiez R (1999) Age-dependent altered proportions in subpopulations of tonsillar lymphocytes. Clin Exp Immunol 116:9–18

    Article  PubMed  CAS  Google Scholar 

  • Bevilacqua A, Ceriani MC, Capaccioli S, Nicolin A (2003) Post-transcriptional regulation of gene expression by degradation of messenger RNAs. J Cell Physiol 195:356–372

    Article  PubMed  CAS  Google Scholar 

  • Calame KL, Lin KI, Tunyaplin C (2003) Regulatory mechanisms that determine the development and function of plasma cells. Ann Rev Immunol 21:205–230

    Article  CAS  Google Scholar 

  • Cao H, Deterding LJ, Venable JD, Kennington EA, Yates JR 3rd, Tomer KB, Blackshear PJ (2006) Identification of the anti-inflammatory protein tristetraprolin as a hyperphosphorylated protein by mass spectrometry and site-directed mutagenesis. Biochem J 394:285–297

    Article  PubMed  CAS  Google Scholar 

  • Carballo E, Cao H, Lai WS, Kennington EA, Campbell D, Blackshear PJ (2001) Decreased sensitivity of tristetraprolin-deficient cells to p38 inhibitors suggests the involvement of tristetraprolin in the p38 signaling pathway. J Biol Chem 276: 42580–42587

    Article  PubMed  CAS  Google Scholar 

  • Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, Bram RJ, Jabara H, Geha RS (2005) TACI and BAFF-R mediate isotype switching in B cells. J Exp Med 201:35–39

    Article  PubMed  CAS  Google Scholar 

  • Chen CY, Shyu AB (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20:465–470

    Article  PubMed  CAS  Google Scholar 

  • Chrestensen CA, Schroeder MJ, Shabanowitz J, Hunt DF, Pelo JW, Worthington MT, Sturgill TW (2004) MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem 279:10176–10184

    Article  PubMed  CAS  Google Scholar 

  • Dedeoglu F, Horwitz B, Chaudhuri J, Alt FW, Geha RS (2004) Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol 16:395–404

    Article  PubMed  CAS  Google Scholar 

  • Ephrussi A, Church GM, Tonegawa S, Gilbert W (1985) B lineage—specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science 227:134–140

    Article  PubMed  CAS  Google Scholar 

  • Frasca D, Nguyen D, Riley RL, Blomberg BB (2003) Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the spleen of aged mice. J Immunol 170:719–726

    PubMed  CAS  Google Scholar 

  • Frasca D, Van Der Put E, Riley RL, Blomberg BB (2004a) Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J Immunol 172: 2155–2162

    CAS  Google Scholar 

  • Frasca D, Riley RL, Blomberg BB (2004b) Effect of age on the immunoglobulin class switch. Crit Rev Immunol 24:297–320

    Article  CAS  Google Scholar 

  • Frasca D, Riley RL, Blomberg BB (2005a) Humoral immune response and B-cell functions including immunoglobulin class switch are downregulated in aged mice and humans. Semin Immunol 17:378–384

    Article  CAS  Google Scholar 

  • Frasca D, Van Der Put E, Landin AM, Gong D, Riley RL, Blomberg BB (2005b) RNA stability of the E2A-encoded transcription factor E47 is lower in splenic activated B cells from aged mice. J Immunol 175:6633–6644

    CAS  Google Scholar 

  • Frasca D, Riley RL, Blomberg BB (2007a) Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF. Exp Gerontol 42:192–203

    Article  CAS  Google Scholar 

  • Frasca D, Landin AM, Alvarez JP, Blackshear PJ, Riley RL, Blomberg BB (2007b) Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of e47 mRNA. J Immunol 179:918–927

    CAS  Google Scholar 

  • Gonda H, Sugai M, Nambu Y, Katakai T, Agata Y, Mori KJ, Yokota Y, Shimizu A (2003) The balance between Pax5 and Id2 activities is the key to AID gene expression. J Exp Med 198: 1427–1437

    Article  PubMed  CAS  Google Scholar 

  • Han S, Yang K, Ozen Z, Peng W, Marinova E, Kelsoe G, Zheng B (2003) Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice. J Immunol 170:1267–1273

    PubMed  CAS  Google Scholar 

  • Henthorn P, Kiledjian M, Kadesch T (1990) Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science 247:467–470

    Article  PubMed  CAS  Google Scholar 

  • Huang LE Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 95:7987–7992

    Article  PubMed  CAS  Google Scholar 

  • Huggins GS, Chin MT, Sibinga NE, Lee SL, Haber E, Lee ME (1999) Characterization of the mUBC9-binding sites required for E2A protein degradation. J Biol Chem 274:28690–28696

    Article  PubMed  CAS  Google Scholar 

  • Iida S, Rao PH, Butler M, Corradini P, Boccadoro M, Klein B, Chaganti RS, Dalla-Favera R (1997) Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet 17:226–230

    Article  PubMed  CAS  Google Scholar 

  • Jeppson JD, Patel HR, Sakata N, Domenico J, Terada N, Gelfand EW (1998) Requirement for dual signals by anti-CD40 and IL-4 for the induction of nuclear factor-kappa B, IL-6, and IgE in human B lymphocytes. J Immunol 161:1738–1742

    PubMed  CAS  Google Scholar 

  • Johnson K, Calame K (2003) Transcription factors controlling the beginning and end of B-cell differentiation. Curr Opin Genet Dev 13:522–528

    Article  PubMed  CAS  Google Scholar 

  • Kaku H, Horikawa K, Obata Y, Kato I, Okamoto H, Sakaguchi N, Gerondakis S, Takatsu K (2002) NF-kappaB is required for CD38-mediated induction of C(gamma)1 germline transcripts in murine B lymphocytes. Int Immunol 14:1055–1064

    Article  PubMed  CAS  Google Scholar 

  • Kee BL, Bain G, Murre C (2002) IL-7Ralpha and E47: independent pathways required for development of multipotent lymphoid progenitors. EMBO J 21:103–113

    Article  PubMed  CAS  Google Scholar 

  • Kee BL, Murre C (1998) Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12. J Exp Med 188:699–713

    Article  PubMed  CAS  Google Scholar 

  • Kho CJ, Huggins GS, Endege WO, Hsieh CM, Lee ME, Haber E (1997) Degradation of E2A proteins through a ubiquitin-conjugating enzyme, UbcE2A. J Biol Chem 272:3845–3851

    Article  PubMed  CAS  Google Scholar 

  • King AM, Van Der Put E, Blomberg BB, Riley RL (2007) Accelerated Notch-dependent degradation of E47 proteins in aged B cell precursors is associated with increased ERK MAPK activation. J Immunol 178:3521–3529

    PubMed  CAS  Google Scholar 

  • Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, Ludwig T, Rajewsky K, Dalla-Favera R (2006) Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol 7:773–782.

    Article  PubMed  CAS  Google Scholar 

  • Knodel M, Kuss AW, Berberich I, Schimpl A (2001) Blimp-1 over-expression abrogates IL-4- and CD40-mediated suppression of terminal B cell differentiation but arrests isotype switching. Eur J Immunol 31:1972–1980

    Article  PubMed  CAS  Google Scholar 

  • Kozmik Z, Wang S, Dorfler P, Adams B, Busslinger M (1992) The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP. Mol Cell Biol 12:2662–2672

    PubMed  CAS  Google Scholar 

  • Kuroda K, Han H, Tani S, Tanigaki K, Tun T, Furukawa T, Taniguchi Y, Kurooka H, Hamada Y, Toyokuni S, Honjo T (2003) Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18:301–312

    Article  PubMed  CAS  Google Scholar 

  • Lauring J, Schlissel MS (1999) Distinct factors regulate the murine RAG-2 promoter in B- and T-cell lines. Mol Cell Biol 19:2601–2612

    PubMed  CAS  Google Scholar 

  • Lin KI, Angelin-Duclos C, Kuo TC, Calame K (2002) Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol 22:4771–4780

    Article  PubMed  CAS  Google Scholar 

  • Lin KI, Tunyaplin C, Calame, K (2003) Transcriptional regulatory cascades controlling plasma cell differentiation. Immunol Rev 194:19–28

    Article  PubMed  CAS  Google Scholar 

  • Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822–829

    Article  PubMed  CAS  Google Scholar 

  • Lu R, Medina KL, Lancki DW, Singh H (2003) IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development. Genes Dev 17:1703–1708

    Article  PubMed  CAS  Google Scholar 

  • Maillard I, Fang T, Pear WS (2005) Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 23:945–974

    Article  PubMed  CAS  Google Scholar 

  • Massari ME, Murre C (2000) Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20:429–440

    Article  PubMed  CAS  Google Scholar 

  • Max EE, Wakatsuki Y, Neurath MF, Strober W (1995) The role of BSAP in immunoglobulin isotype switching and B-cell proliferation. Curr Top Microbiol Immunol 194:449–458

    PubMed  CAS  Google Scholar 

  • Michaelson JS, Singh M, Birshtein BK (1996) B cell lineage-specific activator protein (BSAP). A player at multiple stages of B cell development. J Immunol 156:2349–2351

    PubMed  CAS  Google Scholar 

  • Murre C, McCaw PS, Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56:777–783

    Article  PubMed  CAS  Google Scholar 

  • Neurath MF, Strober W, Wakatsuki Y (1994) The murine Ig 3’ alpha enhancer is a target site with repressor function for the B cell lineage-specific transcription factor BSAP (NF-HB, S alpha- BP). J Immunol 153:730–742

    PubMed  CAS  Google Scholar 

  • Nutt SL, Morrison AM, Dorfler P, Rolink A, Busslinger M (1998) Identification of BSAP (Pax-5) target genes in early B-cell development by loss- and gain-of-function experiments. EMBO J 17:2319–2333

    Article  PubMed  CAS  Google Scholar 

  • Nutt SL, Heavey B, Rolink AG, Busslinger M (1999) Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401:556–562

    Article  PubMed  CAS  Google Scholar 

  • O’Riordan M, Grosschedl R (1999) Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. Immunity 11:21–31

    Article  PubMed  CAS  Google Scholar 

  • Pioli C, Gatta L, Ubaldi V, Doria G (2000) Inhibition of IgG1 and IgE production by stimulation of the B cell CTLA-4 receptor. J Immunol 165:5530–5536

    PubMed  CAS  Google Scholar 

  • Quong MW, Harris DP, Swain SL, Murre C (1999) E2A activity is induced during B-cell activation to promote immunoglobulin class switch recombination. EMBO J 18:6307–6318

    Article  PubMed  CAS  Google Scholar 

  • Quong MW, Romanow WJ, Murre C (2002) E protein function in lymphocyte development. Annu Rev Immunol 20:301–322

    Article  PubMed  CAS  Google Scholar 

  • Riley RL, Van Der Put E, King AM, Frasca D, Blomberg, BB (2005) Deficient B lymphopoiesis in murine senescence: potential roles for dysregulation of E2A, Pax-5, and STAT5. Semin Immunol 17:330–336

    Article  PubMed  CAS  Google Scholar 

  • Rivera R, Murre C (2001) The regulation and function of the Id proteins in lymphocyte development. Oncogene 20:8308–8316

    Article  PubMed  CAS  Google Scholar 

  • Roberts EC, Deed RW, Inoue T, Norton JD, Sharrocks AD (2001) Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding. Mol Cell Biol 21:524–533

    Article  PubMed  CAS  Google Scholar 

  • Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto G, Seo S, Kumano K, Nakagami-Yamaguchi E, Hamada Y, Aizawa S, Hirai H (2003) Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18:675–685

    Article  PubMed  CAS  Google Scholar 

  • Sayegh CE, Quong MW, Agata Y, Murre C (2003) E-proteins directly regulate expression of activation- induced deaminase in mature B cells. Nat Immunol 4:586–593

    Article  PubMed  CAS  Google Scholar 

  • Schlissel M, Voronova A, Baltimore D (1991) Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line. Genes Dev 5:1367–1376

    Article  PubMed  CAS  Google Scholar 

  • Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A, Giltnane JM, Yang L, Zhao H, Calame K, Staudt LM (2002) Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51–62

    Article  PubMed  CAS  Google Scholar 

  • Shen C-P, Kadesch T (1995) B-cell-specific DNA binding by an E47 homodimer. Mol Cell Biol 15:4518–4524

    PubMed  CAS  Google Scholar 

  • Sigvardsson M, O’Riordan M, Grosschedl R (1997) EBF and E47 collaborate to induce expression of the endogenous immunoglobulin surrogate light chain genes. Immunity 7:25–36

    Article  PubMed  CAS  Google Scholar 

  • Smith AM (1976) The effects of age on the immune response to type III pneumococcal polysaccharide (SIII) and bacterial lipopolysaccharide (LPS) in BALB/c, SJL/J, and C3H mice. J Immunol 116:469–474

    PubMed  CAS  Google Scholar 

  • Snapper CM, Zelazowski P, Rosas FR, Kehry MR, Tian M, Baltimore D, Sha, WC (1996) B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J Immunol 156:183–191

    PubMed  CAS  Google Scholar 

  • Song H, Price PW, Cerny J (1997) Age-related changes in antibody repertoire: contribution from T cells. Immunol Rev 160:55–62

    Article  PubMed  CAS  Google Scholar 

  • Sugai M, Gonda H, Kusunoki T, Katakai T, Yokota Y, Shimizu A (2003) Essential role of Id2 in negative regulation of IgE class switching. Nat Immunol 4:25–30

    Article  PubMed  CAS  Google Scholar 

  • Tell G, Scaloni A, Pellizzari L, Formisano S, Pucillo C, Damante G (1998) Redox potential controls the structure and DNA binding activity of the paired domain. J Biol Chem 273:25062–25072

    Article  PubMed  CAS  Google Scholar 

  • Tinnell SB, Jacobs-Helber SM, Sterneck E, Sawyer ST, Conrad DH (1998) STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production. Int Immunol 10:1529–1538

    Article  PubMed  CAS  Google Scholar 

  • Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL (2004) Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 173:1158–1165

    PubMed  CAS  Google Scholar 

  • Van Der Put E, Frasca D, King AM, Blomberg BB, Riley RL (2004) Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover. J Immunol 173:818–827

    PubMed  CAS  Google Scholar 

  • Weksler MC, Innes JD, Goldstein G (1978) Immunological studies of aging. IV. The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin32- 36. J Exp Med 148:996–1006

    Article  PubMed  CAS  Google Scholar 

  • Whisler RL, Williams JW, Jr, Newhouse YG (1991) Human B cell proliferative responses during aging. Reduced RNA synthesis and DNA replication after signal transduction by surface immunoglobulins compared to B cell antigenic determinants CD20 and CD40. Mech Ageing Dev 61:209–222

    Article  PubMed  CAS  Google Scholar 

  • Yamada T, Zhang K, Yamada A, Zhu D, Saxon A (2005) B lymphocyte stimulator activates p38 mitogen-activated protein kinase in human Ig class switch recombination. Am J Respir Cell Mol Biol 32:388–394

    Article  PubMed  CAS  Google Scholar 

  • Zheng B, Han S, Takahashi Y, Kelsoe G (1997) Immunosenescence and germinal center reaction. Immunol Rev 160:63–77

    Article  PubMed  CAS  Google Scholar 

  • Zwollo P, Desiderio S (1994) Specific recognition of the blk promoter by the B-lymphoid transcription factor B-cell-specific activator protein. J Biol Chem 269:15310–15317

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 016960 (R-138), 33101, Miami, USA

    Daniela Frasca, Richard L. Riley & Bonnie B. Blomberg

  2. Graduate School of Cell Biology and Development, University of Rome La Sapienza, Rome, Italy

    Daniela Frasca

Authors
  1. Daniela Frasca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard L. Riley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bonnie B. Blomberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, 1036 Rue Belvedere, J1H 4C4, Sherbrooke, Quebec, Canada

    Tamas Fulop

  2. Department of Experimental Pathalogy, CIG Interdepartmental Center “L. Galvani” University of Bologna, Via San Giacomo 12, 40126, Bologna, Italy

    Claudio Franceschi

  3. Institute for Health and Life Sciences, 4-6-22 Kohinato, Bunkyo-ku, Tokyo, 112-0006, Japan

    Katsuiku Hirokawa

  4. ZMF - Zentrum Med. Forschung Abt. Transplant./ Immunologie, University of Tübingen, Waldhörnlestr. 22, 72072, Tübingen, Germany

    Graham Pawelec

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Frasca, D., Riley, R.L., Blomberg, B.B. (2009). Transcription Factors in Mature B-Cells During Aging. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook on Immunosenescence. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9063-9_19

Download citation

Publish with us

Policies and ethics

Search

Navigation