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J Clin Invest. May 1, 1996; 97(9): 2063–2073.
PMCID: PMC507281

Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production.


We investigated the role of the costimulatory molecules, CD40 and its ligand CD40L, in the pathogenesis of human SLE. In comparison to normal subjects or patients in remission, PBMC from active lupus patients had a 21-fold increase in the frequency of CD40L-expressing, CD4+T cells. However, the expression of CD40L induced in either lupus or normal T cells by mitogenic stimulation could be down-regulated equally well by CD40 molecules on autologous B cells. Active lupus patients also had a 22-fold increase in percentage of CD8+ T cells expressing CD40L, consistent with their unusual helper activity in SLE. Surprisingly, patients with active lupus had a 20.5-fold increase in B cells that spontaneously expressed high levels of CD40L, as strongly as their T cells. Although lupus patients in remission had low levels of CD40L+ cells in the range of normal subjects, mitogen-induced upregulation of CD40L expression in the T and B cells was markedly greater than normal, suggesting an intrinsic defect. A mAb to CD40L blocked significantly the ability of lymphocytes from lupus patients with active and established disease to produce the pathogenic variety of antinuclear autoantibodies in vitro, bolstering the possibility of anti-CD40L immunotherapy for lupus. Future studies on the hyperexpression of CD40L could elucidate a regulatory defect in the pathogenic T and B cells of lupus.

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  • Rothfield NF, Stollar BD. The relation of immunoglobulin class, pattern of anti-nuclear antibody, and complement-fixing antibodies to DNA in sera from patients with systemic lupus erythematosus. J Clin Invest. 1967 Nov;46(11):1785–1794. [PMC free article] [PubMed]
  • Burlingame RW, Boey ML, Starkebaum G, Rubin RL. The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest. 1994 Jul;94(1):184–192. [PMC free article] [PubMed]
  • Suzuki N, Harada T, Mizushima Y, Sakane T. Possible pathogenic role of cationic anti-DNA autoantibodies in the development of nephritis in patients with systemic lupus erythematosus. J Immunol. 1993 Jul 15;151(2):1128–1136. [PubMed]
  • Suenaga R, Abdou NI. Cationic and high affinity serum IgG anti-dsDNA antibodies in active lupus nephritis. Clin Exp Immunol. 1993 Dec;94(3):418–422. [PMC free article] [PubMed]
  • Diamond B, Katz JB, Paul E, Aranow C, Lustgarten D, Scharff MD. The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol. 1992;10:731–757. [PubMed]
  • Sabbaga J, Pankewycz OG, Lufft V, Schwartz RS, Madaio MP. Cross-reactivity distinguishes serum and nephritogenic anti-DNA antibodies in human lupus from their natural counterparts in normal serum. J Autoimmun. 1990 Apr;3(2):215–235. [PubMed]
  • Rubin RL, Burlingame RW, Arnott JE, Totoritis MC, McNally EM, Johnson AD. IgG but not other classes of anti-[(H2A-H2B)-DNA] is an early sign of procainamide-induced lupus. J Immunol. 1995 Mar 1;154(5):2483–2493. [PubMed]
  • Gavalchin J, Datta SK. The NZB X SWR model of lupus nephritis. II. Autoantibodies deposited in renal lesions show a distinctive and restricted idiotypic diversity. J Immunol. 1987 Jan 1;138(1):138–148. [PubMed]
  • Burlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN. Genesis and evolution of antichromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. J Clin Invest. 1993 Apr;91(4):1687–1696. [PMC free article] [PubMed]
  • Di Valerio R, Bernstein KA, Varghese E, Lefkowith JB. Murine lupus glomerulotropic monoclonal antibodies exhibit differing specificities but bind via a common mechanism. J Immunol. 1995 Aug 15;155(4):2258–2268. [PubMed]
  • Datta SK, Patel H, Berry D. Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis. J Exp Med. 1987 May 1;165(5):1252–1268. [PMC free article] [PubMed]
  • Sainis K, Datta SK. CD4+ T cell lines with selective patterns of autoreactivity as well as CD4- CD8- T helper cell lines augment the production of idiotypes shared by pathogenic anti-DNA autoantibodies in the NZB x SWR model of lupus nephritis. J Immunol. 1988 Apr 1;140(7):2215–2224. [PubMed]
  • Shivakumar S, Tsokos GC, Datta SK. T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol. 1989 Jul 1;143(1):103–112. [PubMed]
  • Rajagopalan S, Zordan T, Tsokos GC, Datta SK. Pathogenic anti-DNA autoantibody-inducing T helper cell lines from patients with active lupus nephritis: isolation of CD4-8- T helper cell lines that express the gamma delta T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7020–7024. [PMC free article] [PubMed]
  • Desai-Mehta A, Mao C, Rajagopalan S, Robinson T, Datta SK. Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus. J Clin Invest. 1995 Feb;95(2):531–541. [PMC free article] [PubMed]
  • Adams S, Leblanc P, Datta SK. Junctional region sequences of T-cell receptor beta-chain genes expressed by pathogenic anti-DNA autoantibody-inducing helper T cells from lupus mice: possible selection by cationic autoantigens. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11271–11275. [PMC free article] [PubMed]
  • Mao C, Osman GE, Adams S, Datta SK. T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice. J Immunol. 1994 Feb 1;152(3):1462–1470. [PubMed]
  • Mohan C, Adams S, Stanik V, Datta SK. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med. 1993 May 1;177(5):1367–1381. [PMC free article] [PubMed]
  • Ando DG, Sercarz EE, Hahn BH. Mechanisms of T and B cell collaboration in the in vitro production of anti-DNA antibodies in the NZB/NZW F1 murine SLE model. J Immunol. 1987 May 15;138(10):3185–3190. [PubMed]
  • Naiki M, Chiang BL, Cawley D, Ansari A, Rozzo SJ, Kotzin BL, Zlotnik A, Gershwin ME. Generation and characterization of cloned T helper cell lines for anti-DNA responses in NZB.H-2bm12 mice. J Immunol. 1992 Dec 15;149(12):4109–4115. [PubMed]
  • Linker-Israeli M, Quismorio FP, Jr, Horwitz DA. CD8+ lymphocytes from patients with systemic lupus erythematosus sustain, rather than suppress, spontaneous polyclonal IgG production and synergize with CD4+ cells to support autoantibody synthesis. Arthritis Rheum. 1990 Aug;33(8):1216–1225. [PubMed]
  • Crow MK, DelGiudice-Asch G, Zehetbauer JB, Lawson JL, Brot N, Weissbach H, Elkon KB. Autoantigen-specific T cell proliferation induced by the ribosomal P2 protein in patients with systemic lupus erythematosus. J Clin Invest. 1994 Jul;94(1):345–352. [PMC free article] [PubMed]
  • Kuwana M, Medsger TA, Jr, Wright TM. T and B cell collaboration is essential for the autoantibody response to DNA topoisomerase I in systemic sclerosis. J Immunol. 1995 Sep 1;155(5):2703–2714. [PubMed]
  • Mamula MJ, Fatenejad S, Craft J. B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol. 1994 Feb 1;152(3):1453–1461. [PubMed]
  • Sobel ES, Kakkanaiah VN, Kakkanaiah M, Cheek RL, Cohen PL, Eisenberg RA. T-B collaboration for autoantibody production in lpr mice is cognate and MHC-restricted. J Immunol. 1994 Jun 15;152(12):6011–6016. [PubMed]
  • Klinman DM, Steinberg AD. Systemic autoimmune disease arises from polyclonal B cell activation. J Exp Med. 1987 Jun 1;165(6):1755–1760. [PMC free article] [PubMed]
  • Reininger L, Radaszkiewicz T, Kosco M, Melchers F, Rolink AG. Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells. J Exp Med. 1992 Nov 1;176(5):1343–1353. [PMC free article] [PubMed]
  • Datta SK, Owen FL, Womack JE, Riblet RJ. Analysis of recombinant inbred lines derived from "autoimmune" (NZB) and "high leukemia" (C58) strains: independent multigenic systems control B cell hyperactivity, retrovirus expression, and autoimmunity. J Immunol. 1982 Oct;129(4):1539–1544. [PubMed]
  • Merino R, Iwamoto M, Fossati L, Izui S. Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice. J Immunol. 1993 Dec 1;151(11):6509–6516. [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]
  • Lederman S, Yellin MJ, Inghirami G, Lee JJ, Knowles DM, Chess L. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. J Immunol. 1992 Dec 15;149(12):3817–3826. [PubMed]
  • Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature. 1994 Feb 3;367(6462):425–428. [PubMed]
  • Roy M, Waldschmidt T, Aruffo A, Ledbetter JA, Noelle RJ. The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol. 1993 Sep 1;151(5):2497–2510. [PubMed]
  • Ren CL, Morio T, Fu SM, Geha RS. Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2. J Exp Med. 1994 Feb 1;179(2):673–680. [PMC free article] [PubMed]
  • Faris M, Gaskin F, Parsons JT, Fu SM. CD40 signaling pathway: anti-CD40 monoclonal antibody induces rapid dephosphorylation and phosphorylation of tyrosine-phosphorylated proteins including protein tyrosine kinase Lyn, Fyn, and Syk and the appearance of a 28-kD tyrosine phosphorylated protein. J Exp Med. 1994 Jun 1;179(6):1923–1931. [PMC free article] [PubMed]
  • Banchereau J, Bazan F, Blanchard D, Brière F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881–922. [PubMed]
  • Spriggs MK, Armitage RJ, Strockbine L, Clifford KN, Macduff BM, Sato TA, Maliszewski CR, Fanslow WC. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992 Dec 1;176(6):1543–1550. [PMC free article] [PubMed]
  • Lederman S, Yellin MJ, Cleary AM, Pernis A, Inghirami G, Cohn LE, Covey LR, Lee JJ, Rothman P, Chess L. T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death. J Immunol. 1994 Mar 1;152(5):2163–2171. [PubMed]
  • Foy TM, Laman JD, Ledbetter JA, Aruffo A, Claassen E, Noelle RJ. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med. 1994 Jul 1;180(1):157–163. [PMC free article] [PubMed]
  • Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. [PubMed]
  • Tsubata T, Wu J, Honjo T. B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40. Nature. 1993 Aug 12;364(6438):645–648. [PubMed]
  • Wang Z, Karras JG, Howard RG, Rothstein TL. Induction of bcl-x by CD40 engagement rescues sIg-induced apoptosis in murine B cells. J Immunol. 1995 Oct 15;155(8):3722–3725. [PubMed]
  • Liang MH, Socher SA, Larson MG, Schur PH. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum. 1989 Sep;32(9):1107–1118. [PubMed]
  • Grammer AC, Bergman MC, Miura Y, Fujita K, Davis LS, Lipsky PE. The CD40 ligand expressed by human B cells costimulates B cell responses. J Immunol. 1995 May 15;154(10):4996–5010. [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]
  • Yellin MJ, Sippel K, Inghirami G, Covey LR, Lee JJ, Sinning J, Clark EA, Chess L, Lederman S. CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule/CD40-L. Potential role in regulating helper effector function. J Immunol. 1994 Jan 15;152(2):598–608. [PubMed]
  • van Kooten C, Gaillard C, Galizzi JP, Hermann P, Fossiez F, Banchereau J, Blanchard D. B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40. Eur J Immunol. 1994 Apr;24(4):787–792. [PubMed]
  • Mohan C, Shi Y, Laman JD, Datta SK. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995 Feb 1;154(3):1470–1480. [PubMed]
  • Gyllensten UB, Erlich HA. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. [PMC free article] [PubMed]
  • Nonoyama S, Penix LA, Edwards CP, Lewis DB, Ito S, Aruffo A, Wilson CB, Ochs HD. Diminished expression of CD40 ligand by activated neonatal T cells. J Clin Invest. 1995 Jan;95(1):66–75. [PMC free article] [PubMed]
  • Vassilopoulos D, Kovacs B, Tsokos GC. TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus. J Immunol. 1995 Aug 15;155(4):2269–2281. [PubMed]
  • Kammer GM, Khan IU, Malemud CJ. Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymphocytes. J Clin Invest. 1994 Jul;94(1):422–430. [PMC free article] [PubMed]
  • Maggi E, Giudizi MG, Biagiotti R, Annunziato F, Manetti R, Piccinni MP, Parronchi P, Sampognaro S, Giannarini L, Zuccati G, et al. Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection. J Exp Med. 1994 Aug 1;180(2):489–495. [PMC free article] [PubMed]
  • Buhlmann JE, Foy TM, Aruffo A, Crassi KM, Ledbetter JA, Green WR, Xu JC, Shultz LD, Roopesian D, Flavell RA, et al. In the absence of a CD40 signal, B cells are tolerogenic. Immunity. 1995 Jun;2(6):645–653. [PubMed]
  • Tsitsikov EN, Ramesh N, Geha RS. Structure of the murine CD40 ligand gene. Mol Immunol. 1994 Aug;31(12):895–900. [PubMed]
  • Facchetti F, Appiani C, Salvi L, Levy J, Notarangelo LD. Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells. J Immunol. 1995 Jun 15;154(12):6624–6633. [PubMed]
  • Ware CF, Crowe PD, Vanarsdale TL, Andrews JL, Grayson MH, Jerzy R, Smith CA, Goodwin RG. Tumor necrosis factor (TNF) receptor expression in T lymphocytes. Differential regulation of the type I TNF receptor during activation of resting and effector T cells. J Immunol. 1991 Dec 15;147(12):4229–4238. [PubMed]
  • Ranheim EA, Kipps TJ. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993 Apr 1;177(4):925–935. [PMC free article] [PubMed]
  • Kennedy MK, Mohler KM, Shanebeck KD, Baum PR, Picha KS, Otten-Evans CA, Janeway CA, Jr, Grabstein KH. Induction of B cell costimulatory function by recombinant murine CD40 ligand. Eur J Immunol. 1994 Jan;24(1):116–123. [PubMed]
  • Singh RR, Kumar V, Ebling FM, Southwood S, Sette A, Sercarz EE, Hahn BH. T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus. J Exp Med. 1995 Jun 1;181(6):2017–2027. [PMC free article] [PubMed]
  • Sercarz EE, Datta SK. Mechanisms of autoimmunization: perspective from the mid-90s. Curr Opin Immunol. 1994 Dec;6(6):875–881. [PubMed]
  • Gleichmann E, Van Elven EH, Van der Veen JP. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol. 1982 Feb;12(2):152–159. [PubMed]
  • James JA, Gross T, Scofield RH, Harley JB. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med. 1995 Feb 1;181(2):453–461. [PMC free article] [PubMed]
  • Desai DD, Krishnan MR, Swindle JT, Marion TN. Antigen-specific induction of antibodies against native mammalian DNA in nonautoimmune mice. J Immunol. 1993 Aug 1;151(3):1614–1626. [PubMed]
  • Moens U, Seternes OM, Hey AW, Silsand Y, Traavik T, Johansen B, Rekvig OP. In vivo expression of a single viral DNA-binding protein generates systemic lupus erythematosus-related autoimmunity to double-stranded DNA and histones. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12393–12397. [PMC free article] [PubMed]
  • Schattner EJ, Elkon KB, Yoo DH, Tumang J, Krammer PH, Crow MK, Friedman SM. CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway. J Exp Med. 1995 Nov 1;182(5):1557–1565. [PMC free article] [PubMed]
  • Finck BK, Linsley PS, Wofsy D. Treatment of murine lupus with CTLA4Ig. Science. 1994 Aug 26;265(5176):1225–1227. [PubMed]
  • Klaus SJ, Pinchuk LM, Ochs HD, Law CL, Fanslow WC, Armitage RJ, Clark EA. Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction. J Immunol. 1994 Jun 15;152(12):5643–5652. [PubMed]
  • Datta SK, Mohan C, Desai-Mehta A. Mechanisms of the pathogenic autoimmune response in lupus: prospects for specific immunotherapy. Immunol Res. 1995;14(2):132–147. [PubMed]

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