Abstract
Our laboratory has contributed to the areas of B cell receptor (BCR) and pre-BCR gene identification and transcription and has focused on the problem of the aged immune system in mice and humans for the last 15 years. We have found biomarkers for the decrease in B cell function in aged mice and humans. These include decreases in immunoglobulin (Ig) class switch (e.g., IgM to IgG), decreases in the enzyme AID (activation-induced cytidine deaminase) and decreases in the transcription factor E47. The E47 mRNA stability is decreased in old B cells due to decreased phospho-MAPKinase and phospho-TTP (tristetraprolin). Inflammation, e.g., TNF-α, which increases with age, impacts B cells directly by increasing their TNF-α and NF-κB and leads to the above decreased pathway. Both class switch and affinity maturation are decreased in elderly responses to the influenza vaccine and biomarkers we have found (numbers and percentages of switched memory B cells and AID in stimulated B cells in culture) can predict a beneficial or decreased immune response to the vaccine. Current and future avenues to improve the humoral immune response in the elderly are discussed.
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References
Hodes RJ. Aging and the immune system. Immunol Rev. 1997;160:5–8.
LeMaoult J, Szabo P, Weksler ME. Effect of age on humoral immunity, selection of the B-cell repertoire and B-cell development. Immunol Rev. 1997;160:115–26.
Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004;5(2):133–9. doi:10.1038/ni1033.
Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, et al. T cells and aging, January 2002 update. Front Biosci J virtual Library. 2002;7:d1056–183.
Sadighi Akha AA, Miller RA. Signal transduction in the aging immune system. Curr Opin Immunol. 2005;17(5): 486–91. doi: 10.1016/j.coi.2005.07.004.
Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci USA. 2003;100(25):15053–8. doi:10.1073/pnas.2433717100.
Pawelec G, Derhovanessian E. Role of CMV in immune senescence. Virus Res. 2011;157(2):175–9. doi:10.1016/j.virusres.2010.09.010.
Kosco MH, Burton GF, Kapasi ZF, Szakal AK, Tew JG. Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing. Immunology. 1989;68(3):312–8.
van Dijk-Hard I, Soderstrom I, Feld S, Holmberg D, Lundkvist I. Age-related impaired affinity maturation and differential D-JH gene usage in human VH6-expressing B lymphocytes from healthy individuals. Eur J Immunol. 1997;27(6):1381–6. doi:10.1002/eji.1830270613.
Zheng B, Han S, Takahashi Y, Kelsoe G. Immunosenescence and germinal center reaction. Immunol Rev. 1997;160:63–77.
Wang X, Stollar BD. Immunoglobulin VH gene expression in human aging. Clin Immunol. 1999;93(2):132–42. doi:10.1006/clim 1999.4781.
Yang X, Stedra J, Cerny J. Repertoire diversity of antibody response to bacterial antigens in aged mice. IV. Study of VH and VL gene utilization in splenic antibody foci by in situ hybridization. J Immunol. 1994;152(5):2214–21.
Frasca D, Landin AM, Alvarez JP, Blackshear PJ, Riley RL, Blomberg BB. Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of E47 mRNA. J Immunol. 2007;179(2):918–27.
Frasca D, Riley RL, Blomberg BB. Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF. Exp Gerontol. 2007;42(3):192–203.
Frasca D, Romero M, Landin AM, Diaz A, Riley RL, Blomberg BB. Protein phosphatase 2A (PP2A) is increased in old murine B cells and mediates p38 MAPK/tristetraprolin dephosphorylation and E47 mRNA instability. Mech Ageing Dev. 2010;131(5):306–14. doi:10.1016/j.mad.2010.02.002.
Frasca D, Van der Put E, Landin AM, Gong D, Riley RL, Blomberg BB. RNA stability of the E2A-encoded transcription factor E47 is lower in splenic activated B cells from aged mice. J Immunol. 2005;175(10):6633–44.
Frasca D, Van der Put E, Riley RL, Blomberg BB. Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J Immunol. 2004;172(4):2155–62.
Frasca D, Diaz A, Romero M, Landin AM, Phillips M, Lechner SC, et al. Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans. Vaccine. 2010;28(51):8077–84. doi:10.1016/j.vaccine.2010.10.023.
Frasca D, Diaz A, Romero M, Mendez NV, Landin AM, Ryan JG, et al. Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine. Vaccine. 2013. doi:10.1016/j.vaccine.2013.05.003.
Frasca D, Diaz A, Romero M, Phillips M, Mendez NV, Landin AM, et al. Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine. Int Immunol. 2012;24(3):175–82. doi:10.1093/intimm/dxr123.
Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol. 2008;180(8):5283–90.
Nussenzweig MC, Alt FW. Antibody diversity: one enzyme to rule them all. Nat Med. 2004;10(12):1304–5. doi:10.1038/nm1204-1304.
Okazaki IM, Kinoshita K, Muramatsu M, Yoshikawa K, Honjo T. The AID enzyme induces class switch recombination in fibroblasts. Nature. 2002;416(6878):340–5. doi:10.1038/nature727.
Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol: CB. 2002;12(20):1748–55.
Durandy A. Hyper-IgM syndromes: a model for studying the regulation of class switch recombination and somatic hypermutation generation. Biochem Soc Trans. 2002;30(4):815–8. doi:10.1042bst0300815/.
Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch recombination. J Allergy Clin Immunol. 2006;117(4):855–64. doi:10.1016/j.jaci.2006.01.043.
Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L, et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA. 1998;95(20):11816–21.
Dorsett Y, Robbiani DF, Jankovic M, Reina-San-Martin B, Eisenreich TR, Nussenzweig MC. A role for AID in chromosome translocations between c-myc and the IgH variable region. J Exp Med. 2007;204(9):2225–32. doi:10.1084/jem.20070884.
Sayegh CE, Quong MW, Agata Y, Murre C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat Immunol. 2003;4(6):586–93. doi:10.1038/ni923.
Tran TH, Nakata M, Suzuki K, Begum NA, Shinkura R, Fagarasan S, et al. B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nat Immunol. 2010;11(2):148–54. doi:10.1038/ni.1829.
Ephrussi A, Church GM, Tonegawa S, Gilbert W. B lineage–specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science. 1985;227(4683):134–40.
Henthorn P, Kiledjian M, Kadesch T. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science. 1990;247(4941):467–70.
Quong MW, Romanow WJ, Murre C. E protein function in lymphocyte development. Annu Rev Immunol. 2002;20:301–22. doi:10.1146/annurev.immunol.20.092501.162048.
Massari ME, Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol. 2000;20(2):429–40.
Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989;56(5):777–83.
Schlissel M, Voronova A, Baltimore D. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line. Genes Dev. 1991;5(8):1367–76.
Sigvardsson M, O’Riordan M, Grosschedl R. EBF and E47 collaborate to induce expression of the endogenous immunoglobulin surrogate light chain genes. Immunity. 1997;7(1):25–36.
Anspach J, Poulsen G, Kaattari I, Pollock R, Zwollo P. Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice. J Immunol. 2001;166(4):2617–26.
Frasca D, Romero M, Diaz A, Alter-Wolf S, Ratliff M, Landin AM, et al. A molecular mechanism for TNF-alpha-mediated downregulation of B cell responses. J Immunol. 2012;188(1):279–86. doi:10.4049/jimmunol.1003964.
Frasca D, Nguyen D, Riley RL, Blomberg BB. Effects of aging on proliferation and E47 transcription factor activity induced by different stimuli in murine splenic B cells. Mech Ageing Dev. 2003;124(4):361–9.
Frasca D, Nguyen D, Riley RL, Blomberg BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the spleen of aged mice. J Immunol. 2003;170(2):719–26.
Quong MW, Harris DP, Swain SL, Murre C. E2A activity is induced during B-cell activation to promote immunoglobulin class switch recombination. EMBO J. 1999;18(22):6307–18. doi:10.1093/emboj/18.22.6307.
Van der Put E, Frasca D, King AM, Blomberg BB, Riley RL. Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover. J Immunol. 2004;173(2):818–27.
King AM, Van der Put E, Blomberg BB, Riley RL. Accelerated Notch-dependent degradation of E47 proteins in aged B cell precursors is associated with increased ERK MAPK activation. J Immunol. 2007;178(6):3521–9.
Huggins GS, Chin MT, Sibinga NE, Lee SL, Haber E, Lee ME. Characterization of the mUBC9-binding sites required for E2A protein degradation. J Biol Chem. 1999;274(40):28690–6.
Kho CJ, Huggins GS, Endege WO, Hsieh CM, Lee ME, Haber E. Degradation of E2A proteins through a ubiquitin-conjugating enzyme, UbcE2A. J Biol Chem. 1997;272(6):3845–51.
Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1 alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA. 1998;95(14):7987–92.
Bevilacqua A, Ceriani MC, Capaccioli S, Nicolin A. Post-transcriptional regulation of gene expression by degradation of messenger RNAs. J Cell Physiol. 2003;195(3):356–72. doi:10.1002/jcp.10272.
Chen CY, Shyu AB. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci. 1995;20(11):465–70.
DuBois RN, McLane MW, Ryder K, Lau LF, Nathans D. A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence. J Biol Chem. 1990;265(31):19185–91.
Lai WS, Stumpo DJ, Blackshear PJ. Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein. J Biol Chem. 1990;265(27):16556–63.
Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998;281(5379):1001–5.
Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, et al. A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity. 1996;4(5):445–54.
Carballo E, Cao H, Lai WS, Kennington EA, Campbell D, Blackshear PJ. Decreased sensitivity of tristetraprolin-deficient cells to p38 inhibitors suggests the involvement of tristetraprolin in the p38 signaling pathway. J Biol Chem. 2001;276(45):42580–7. doi:10.1074/jbc.M104953200.
Chrestensen CA, Schroeder MJ, Shabanowitz J, Hunt DF, Pelo JW, Worthington MT, et al. MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem. 2004;279(11):10176–84. doi:10.1074/jbc.M310486200.
Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 2009;1795(1):1–15. doi:10.1016/j.bbcan.2008.05.005.
Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 1999;24(5):186–91.
Landin AM, Frasca D, Harrison P, Scallan M, Riley RL, Blomberg BB. E47 retroviral rescue of intrinsic B-cell defects in senescent mice. Aging Cell. 2011;10(2):327–37. doi:10.1111/j.1474-9726.2011.00673.x.
Ademokun A, Wu YC, Dunn-Walters D. The ageing B cell population: composition and function. Biogerontology. 2010;11(2):125–37. doi:10.1007/s10522-009-9256-9.
Colonna-Romano G, Bulati M, Aquino A, Pellicano M, Vitello S, Lio D, et al. A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people. Mech Ageing Dev. 2009;130(10):681–90. doi:10.1016/j.mad.2009.08.003.
Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev. 2011;10(3):330–5. doi:10.1016/j.arr.2010.08.004.
Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K. Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol. 2005;175(5):3262–7.
Buffa S, Pellicano M, Bulati M, Martorana A, Goldeck D, Caruso C, et al. A novel B cell population revealed by a CD38/CD24 gating strategy: CD38(-)CD24 (-) B cells in centenarian offspring and elderly people. Age (Dordr). 2013;35(5):2009–24. doi:10.1007/s11357-012-9488-5.
Duggal NA, Upton J, Phillips AC, Sapey E, Lord JM. An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity. Aging Cell. 2013;12(5):873–81. doi:10.1111/acel.12114.
Derhovanessian E, Theeten H, Hahnel K, Van Damme P, Cools N, Pawelec G. Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Vaccine. 2013;31(4):685–90. doi:10.1016/j.vaccine.2012.11.041.
McElhaney JE. Influenza vaccine responses in older adults. Ageing Res Rev. 2011;10(3):379–88. doi:10.1016/j.arr.2010.10.008.
Murasko DM, Bernstein ED, Gardner EM, Gross P, Munk G, Dran S, et al. Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly. Exp Gerontol. 2002;37(2–3):427–39.
Frasca D, Blomberg BB. Aging affects human B cell responses. J Clin Immunol. 2011;31(3):430–5. doi:10.1007/s10875-010-9501-7.
Khurana S, Frasca D, Blomberg B, Golding H. AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in vivo following pandemic 2009-H1N1 vaccination in humans. PLoS Pathog. 2012;8(9):e1002920. doi:10.1371/journal.ppat.1002920.
Andrisani G, Frasca D, Romero M, Armuzzi A, Felice C, Marzo M, et al. Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-alpha agents: effects of combined therapy with immunosuppressants. J Crohns Colitis. 2013;7(4):301–7. doi:10.1016/j.crohns.2012.05.011.
Frasca D, Andrisani G, Diaz A, Felice C, Guidi L, Blomberg BB. AID in aging and autoimmune diseases. Autoimmunity. 2013;46(2):168–75. doi:10.3109/08916934.2012.750300.
Agrawal S, Gupta S. TLR1/2, TLR7, and TLR9 signals directly activate human peripheral blood naive and memory B cell subsets to produce cytokines, chemokines, and hematopoietic growth factors. J Clin Immunol. 2011;31(1):89–98. doi:10.1007/s10875-010-9456-8.
Acknowledgments
This study was supported by the following NIH grants: AG-17618 and AG-28586 (to BBB); AI096446-01A1 and AG042826-01A1 (to BBB and DF).
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Blomberg, B.B., Frasca, D. Age effects on mouse and human B cells. Immunol Res 57, 354–360 (2013). https://doi.org/10.1007/s12026-013-8440-9
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DOI: https://doi.org/10.1007/s12026-013-8440-9