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The Effect of Age on the B-Cell Repertoire

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Abstract

The antibody repertoire changes with age. This change reflects, in part, the age-associated impairment in the production of a diverse population of naive B cells in the bone marrow and, in part, by the decreased diversification of B cells in the germinal center where affinity maturation and isotype switching takes place. B cell number is strictly regulated and despite the decreased output of B cells by the bone marrow does not decline during aging. Self-renewal of peripheral B cells is sufficient to assure the stability of peripheral B cell number. However, when B cell production is stressed as, for example, following drug-induced lymphopenia, the rate of recovery of B cell number as well as of B cell diversity is compromised in old compared to young mice. Finally, aging is associated with the appearance of B cell clonal expansions which not only limit the diversity of the B cell repertoire but very likely give rise to monoclonal serum immunoglobulins and B cell neoplasms.

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REFERENCES

  1. Baumgartner L: Age and antibody production. Qualitative changes in antisera associated with aging. J Immunol 47:407, 1934.

    Google Scholar 

  2. Kyle RA, Rajkumar SV: Monoclonal gammopathies of undetermined significance. Hematol Oncol Clin North Am 13:1181-1202, 1999.

    Google Scholar 

  3. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA Koup RA: Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690-695, 1998.

    Google Scholar 

  4. Szabo P, Zhao K, Kirman I, Dyall R, Cruickshank W, Weksler ME: Maturation of B cell precursors is impaired in thymicdeprived nude and old mice. J Immunol 161:2248-2253, 1998.

    Google Scholar 

  5. Ben-Yehuda A, Szabo P, Dyall R, Weksler ME: Bone marrow declines as a site of B cell precursor differentiation with age: Relationship to thymus involution. Proc Natl Acad Sci USA 91:11988-11992, 1994.

    Google Scholar 

  6. Pillai S: The chosen few? Positive selection and the generation of naive B lymphocytes. Immunity 10:493-502, 1999.

    Google Scholar 

  7. Kirman I, Zhao K-S, Wang Y-F, Szabo P, Weksler ME: Increased apoptosis of bone marrow Pre-B cells in old mice associated with their low number. Int Immunol 10:1385-1392, 1998.

    Google Scholar 

  8. Stephan RP, Reilly CR, Witte PL: Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood 91:75-88, 1998.

    Google Scholar 

  9. Yehuda AB, Wirtheim E, Abdulhai A, Or R, Slavin S, Babaey S, Friedman GJ: Activation of the recombination activating gene 1 (RAG-1) transcript in bone marrow of senescent C57BL/6 mice by recombinant interleukin-7. Gerontol A Biol Sci Med Sci 54:B143-148, 1999.

    Google Scholar 

  10. Kline GH, Hayden TA, Klinman NR: B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. J Immunol 162:3342-3349, 1999.

    Google Scholar 

  11. Sprent J, Schaefer M, Hurd M, Surh CD, Ron Y: Mature murine B and T cells transferred to SCID mice can survive indefinitely and many maintain a virgin phenotype. J Exp Med 174:717-728, 1991.

    Google Scholar 

  12. Jin F, Li F, Freitas A, Szabo P, Weksler ME: Bone marrow loses capacity to generate a diverse B cell repertoire with age (submitted).

  13. Ben-Yehuda A, Szabo P, LeMaoult J, Manavalan JS, Weksler ME: Increased VH11 and VHQ52 gene use by splenic B cells in old mice associated with oligoclonal expansions of CD5 B cells. Mech Ageing Dev 103:111-121, 1998.

    Google Scholar 

  14. K Lam KP, Rajewsky K: B cell antigen receptor specificity and surface density together determine B-1 versus B-2 cell development. J Exp Med 90:471-477, 1999.

    Google Scholar 

  15. Hu A, Ehleiter D, Ben Yehuda, Schwab R, Russo C, Szabo P, Weksler ME: Effect of age on the expressed B cell repertoire: role of B cell subsets. Int Immunol 5:1035-1039, 1993.

    Google Scholar 

  16. Thomsen O, Kettel K: Die starke der menchlichen Isoagglutinine und entsperchenden Blutkorperchenrezeptoren in verchiende Lebensaltern, Z. Immunitatsforsch 63:67, 1929.

    Google Scholar 

  17. Rowley MJ, Buchanan H, Mackay IR: Reciprocal change with age in antibody to extrinsic and intrinsic antigens. Lancet 2:24-26, 1968.

    Google Scholar 

  18. Schwab R, Walters CA, Weksler ME: Host defense mechanisms and aging. Semin Oncol 16:20-27, 1989.

    Google Scholar 

  19. Goidl EA, Innes JB, Weksler ME: Immunological studies of aging. II. Loss of IgG and high avidity plaque-forming cells and increased suppressor cell activity in aging mice. J Exp Med 144:1037-1048, 1976.

    Google Scholar 

  20. Nicoletti C, Yang X, Cerny J: Repertoire diversity of antibody response to bacterial antigens in aged mice. III. Phosphorylcholine antibody from young and aged mice differ in structure and protective activity against infection with Streptococcus pneumoniae. J Immunol 150:543-549, 1993.

    Google Scholar 

  21. Musher DM, Chapman AJ, Goree A, Jonsson S, Briles D, Baughn RE: Natural and vaccine-related immunity to Streptococcus pneumoniae. J Infect Dis 154:245-256, 1986.

    Google Scholar 

  22. Zheng B, Han S, Takahashi Y, Kelsoe G: Immunosenescence and germinal center reaction. Immunol Rev 160:63-73, 1997.

    Google Scholar 

  23. Szewczuk MR, DeKruyff RH, Goidl EA, Weksler ME, Siskind GW: Ontogeny of B lymphocyte function. VIII. Failure of thymus cells from aged donors to induce the functional maturation of B lymphocytes from immature donors. Eur J Immunol 10:918-923, 1980.

    Google Scholar 

  24. Shen SS, Kim JS, Weksler ME: Effect of age on thymic development, T cell immunity, and helper T cell function. Rev Physiol Biochem Pharmacol 139:123-139, 1999.

    Google Scholar 

  25. Wang X, Stollar BD: Immunoglobulin VH gene expression in human aging. Clin Immunol 9:132-142, 1999.

    Google Scholar 

  26. 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 27:1381-1386, 1997.

    Google Scholar 

  27. Shapiro ED, Berg AT, Austrian R, Schroeder D, Parcells V, Margolis A, Adair RK, Clemens JD: The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 325:1453-1460, 1991.

    Google Scholar 

  28. LeMaoult J, Szabo P, Weksler ME: Effect of age on humoral immunity, selection of the B cell repertoire and B cell development. Immunol Rev 160:115-126, 1997.

    Google Scholar 

  29. Goidl EA, Stashak PW, Martin-McEvoy SSJ, Hiernaux JR: Age related changes in serum immunoglobulin isotypes and isotype subclass levels among standard long-lived and autoimmune and immunodeficient strains of mice: Serum Ig increases with age. Aging Immunol Infect Dis 1:227, 1989.

    Google Scholar 

  30. Rowley MJ, Buchanan H, Mackay IR, Mackay IR: Reciprocal change with age in antibody to extrinsic and intrinsic antigens. Lancet 2:24-26, 1968.

    Google Scholar 

  31. Hallgren HM, Buckley CE 3d, Gilbertsen VA, Yunis EJ: Lymphocyte phytohemagglutinin responsiveness, immunoglobulins and autoantibodies in aging humans. J Immunol 111:1101-1107, 1973.

    Google Scholar 

  32. Franceschi C, Monti D, Sansoni P, Cossarizza A: The immunology of exceptional individuals: The lesson of centenarians. Immunol Today 16:12-16, 1995.

    Google Scholar 

  33. Weksler ME, Schwab R, Huetz F, Kim YT, Coutinho A: Cellular basis for the age-associated increase in autoimmune reactions. Int Immunol 2:329-335, 1990.

    Google Scholar 

  34. Zhao K, Wang Y, Gueret R, Weksler ME: Dysregulation of the humoral immune response in old mice. Int Immunol 7:929-934, 1995.

    Google Scholar 

  35. Kirman I, Zhao K-S, Tschepen I, Szabo P, Richter G, Nguyen H, Weksler ME: Treatment of old mice with IL-2 corrects dysregulated IL-2 and IL-4 production. Int Immunol 8:1009-1015, 1996.

    Google Scholar 

  36. Crisi GM, Tsiagbe VK, Russo C, Basch RS, Thorbecke GJ: Evaluation of presence and functional activity of potentially self-reactive T cells in aged mice. Int Immunol 8:387-395, 1996.

    Google Scholar 

  37. Doria G, Mancini C, Utsuyama M, Frasca D, Hirokawa K: Aging of the recipients but not of the bone marrow donors enhances autoimmunity in syngeneic radiation chimeras. Mech Ageing Dev 95:131-142, 1997.

    Google Scholar 

  38. Welch MJ, Fong S, Vaughan J, Carson D: Increased frequency of rheumatoid factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Clin Exp Immunol 51:299-304, 1983.

    Google Scholar 

  39. Bovbjerg DH, Kim YT, Schwab R, Schmitt K, DeBlasio T, Weksler ME: “Cross-wiring” of the immune response in old mice: Increased autoantibody response despite reduced antibody response to nominal antigen. Cell Immunol 135:519-525, 1991.

    Google Scholar 

  40. Nobrega A, Haury M, Gueret R, Coutinho A, Weksler ME: The age-associated increase in autoreactivity reflects a global and progressive expansion of autoreactivity detectable in young mice. Scand J Immunol 44:437-443, 1996.

    Google Scholar 

  41. Lee JW, Jin F, Weksler ME: The nature and significance of age-associated autoimmunity. In The Molecular Pathology of Autoimmune Diseases, 2nd ed AN Theofilopoulos, C Bona (eds) (in press).

  42. Tsuda T, Kim YT, Siskind GW, Weksler ME: Old mice recover the ability to produce IgG and high avidity antibody following irradiation with partial bone marrow shielding. Proc Natl Acad Sci 85:1169-1173, 1988.

    Google Scholar 

  43. Weksler ME, Russo C, Siskind GW: Peripheral T cells select the B-cell repertoire in old mice. Immunol Rev 110:173-185, 1989.

    Google Scholar 

  44. Areaza EE, Gibbons JJ, Siskind GW, Weksler ME: Lower antibody response to tetanus toxoid associated with higher auto-antiidiotypic antibody in old compared with young humans. Clin Exp Immunol 92:169-173, 1993.

    Google Scholar 

  45. Nango K, Inaba M, Inaba K, Adachi Y, Than S, Ishida T, Kumamoto T, Uyama M, Ikehara S: Ontogeny of thymic B cells in normal mice. Cell Immunol 133:109-115, 1991.

    Google Scholar 

  46. Serrano D, Monteiro J, Allen SL, Kolitz J, Schulman P, Lichtman SM, Buchbinder A, Vinciguerra VP, Chiorazzi N, Gregersen PK: Clonal expansion within the CD41CD571 and CD81CD571 T cell subsets in chronic lymphocytic leukemia. J Immunol 158:1482-1489, 1997.

    Google Scholar 

  47. Fagerberg J, Yi Q, Gigliotti D, Harmenberg U, Ruden U, Persson B, Osterborg A, Mellstedt H: T-cell-epitope mapping of the idiotypic monoclonal IgG heavy and light chains in multiple myeloma. Int J Cancer 80:671-680, 1999

    Google Scholar 

  48. Wakabayashi A, Utsuyama M, Hosoda T, Sato K, Hirokawa K: Differential age effect of oral administration of an antigen on antibody response: An induction of tolerance in young mice but enhancement of immune response in old mice. Mech Ageing Dev 109:191-201, 1999.

    Google Scholar 

  49. Ben Yehuda A, Ehleiter D, Hu A, Weksler ME: Recombinant vaccinia virus expressing the PR/8 influenza hemagglutinin gene overcomes the impaired immune response and increased susceptibility of old mice to influenza infection. J Infect Dis 168:352-357, 1993.

    Google Scholar 

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  1. Weill Medical College, Cornell University, 1300 York Avenue, New York, New York, 10021

    Marc E. Weksler & Paul Szabo

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  1. Marc E. Weksler
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Weksler, M.E., Szabo, P. The Effect of Age on the B-Cell Repertoire. J Clin Immunol 20, 240–249 (2000). https://doi.org/10.1023/A:1006659401385

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