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Proc Natl Acad Sci U S A. May 10, 1994; 91(10): 4392–4396.

Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions.


B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses.

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  • Hodgkin PD, Yamashita LC, Coffman RL, Kehry MR. Separation of events mediating B cell proliferation and Ig production by using T cell membranes and lymphokines. J Immunol. 1990 Oct 1;145(7):2025–2034. [PubMed]
  • Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, Anderson DM, Gimpel SD, Davis-Smith T, Maliszewski CR, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80–82. [PubMed]
  • Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550–6554. [PMC free article] [PubMed]
  • Lane P, Traunecker A, Hubele S, Inui S, Lanzavecchia A, Gray D. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. Eur J Immunol. 1992 Oct;22(10):2573–2578. [PubMed]
  • Parker DC. T cell-dependent B cell activation. Annu Rev Immunol. 1993;11:331–360. [PubMed]
  • Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985 Apr 11;314(6011):537–539. [PubMed]
  • Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. [PubMed]
  • Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993 Nov 5;262(5135):905–907. [PubMed]
  • Freeman GJ, Borriello F, Hodes RJ, Reiser H, Hathcock KS, Laszlo G, McKnight AJ, Kim J, Du L, Lombard DB, et al. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science. 1993 Nov 5;262(5135):907–909. [PubMed]
  • Mond JJ, Seghal E, Kung J, Finkelman FD. Increased expression of I-region-associated antigen (Ia) on B cells after cross-linking of surface immunoglobulin. J Immunol. 1981 Sep;127(3):881–888. [PubMed]
  • Freedman AS, Freeman G, Horowitz JC, Daley J, Nadler LM. B7, a B-cell-restricted antigen that identifies preactivated B cells. J Immunol. 1987 Nov 15;139(10):3260–3267. [PubMed]
  • Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714–2722. [PubMed]
  • Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K, et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 1988 Aug 25;334(6184):676–682. [PubMed]
  • Mason DY, Jones M, Goodnow CC. Development and follicular localization of tolerant B lymphocytes in lysozyme/anti-lysozyme IgM/IgD transgenic mice. Int Immunol. 1992 Feb;4(2):163–175. [PubMed]
  • Brink R, Goodnow CC, Crosbie J, Adams E, Eris J, Mason DY, Hartley SB, Basten A. Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen. J Exp Med. 1992 Oct 1;176(4):991–1005. [PMC free article] [PubMed]
  • Adams E, Basten A, Goodnow CC. Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/anti-lysozyme double-transgenic mice. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5687–5691. [PMC free article] [PubMed]
  • Basten A, Brink R, Peake P, Adams E, Crosbie J, Hartley S, Goodnow CC. Self tolerance in the B-cell repertoire. Immunol Rev. 1991 Aug;122:5–19. [PubMed]
  • Allen PM, Matsueda GR, Evans RJ, Dunbar JB, Jr, Marshall GR, Unanue ER. Identification of the T-cell and Ia contact residues of a T-cell antigenic epitope. Nature. 327(6124):713–715. [PubMed]
  • Rojo JM, Janeway CA., Jr The biologic activity of anti-T cell receptor V region monoclonal antibodies is determined by the epitope recognized. J Immunol. 1988 Feb 15;140(4):1081–1088. [PubMed]
  • Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. [PMC free article] [PubMed]
  • O'Garra A, Barbis D, Wu J, Hodgkin PD, Abrams J, Howard M. The BCL1 B lymphoma responds to IL-4, IL-5, and GM-CSF. Cell Immunol. 1989 Oct 1;123(1):189–200. [PubMed]
  • Brian AA. Stimulation of B-cell proliferation by membrane-associated molecules from activated T cells. Proc Natl Acad Sci U S A. 1988 Jan;85(2):564–568. [PMC free article] [PubMed]
  • Castle BE, Kishimoto K, Stearns C, Brown ML, Kehry MR. Regulation of expression of the ligand for CD40 on T helper lymphocytes. J Immunol. 1993 Aug 15;151(4):1777–1788. [PubMed]
  • Lane P, Brocker T, Hubele S, Padovan E, Lanzavecchia A, McConnell F. Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation. J Exp Med. 1993 Apr 1;177(4):1209–1213. [PMC free article] [PubMed]
  • Lane P, Gerhard W, Hubele S, Lanzavecchia A, McConnell F. Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1. Immunology. 1993 Sep;80(1):56–61. [PMC free article] [PubMed]
  • Hodgkin PD, Hapel AJ, Johnson RM, Young IG, Lafferty KJ. Blocking of delivery of the antigen-mediated signal to the nucleus of T cells by cyclosporine. Transplantation. 1987 May;43(5):685–692. [PubMed]
  • Stall AM, Loken MR. Allotypic specificities of murine IgD and IgM recognized by monoclonal antibodies. J Immunol. 1984 Feb;132(2):787–795. [PubMed]
  • Ohara J, Paul WE. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. [PubMed]
  • Goodnow CC, Brink R, Adams E. Breakdown of self-tolerance in anergic B lymphocytes. Nature. 1991 Aug 8;352(6335):532–536. [PubMed]
  • Chesnut RW, Colon SM, Grey HM. Antigen presentation by normal B cells, B cell tumors, and macrophages: functional and biochemical comparison. J Immunol. 1982 Apr;128(4):1764–1768. [PubMed]
  • Lanzavecchia A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu Rev Immunol. 1990;8:773–793. [PubMed]
  • Goodnow CC, Crosbie J, Jorgensen H, Brink RA, Basten A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature. 1989 Nov 23;342(6248):385–391. [PubMed]
  • Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561–569. [PMC free article] [PubMed]
  • Nossal GJ. Cellular and molecular mechanisms of B lymphocyte tolerance. Adv Immunol. 1992;52:283–331. [PubMed]
  • Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. [PubMed]
  • Fuchs EJ, Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992 Nov 13;258(5085):1156–1159. [PubMed]
  • Goodnow CC, Adelstein S, Basten A. The need for central and peripheral tolerance in the B cell repertoire. Science. 1990 Jun 15;248(4961):1373–1379. [PubMed]

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