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J Exp Med. 1993 May 1; 177(5): 1367–1381.
PMCID: PMC2191002

Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus


Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor beta chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that approximately 50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes--free DNA or histones by themselves-- could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4+ T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as 1 mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response.

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Selected References

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  • Lambert PH, Dixon FJ. Pathogenesis of the glomerulonephritis of NZB/W mice. J Exp Med. 1968 Mar 1;127(3):507–522. [PMC free article] [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]
  • Gauthier VJ, Mannik M. A small proportion of cationic antibodies in immune complexes is sufficient to mediate their deposition in glomeruli. J Immunol. 1990 Nov 15;145(10):3348–3352. [PubMed]
  • Vlahakos DV, Foster MH, Adams S, Katz M, Ucci AA, Barrett KJ, Datta SK, Madaio MP. Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites. Kidney Int. 1992 Jun;41(6):1690–1700. [PubMed]
  • Tsao BP, Ebling FM, Roman C, Panosian-Sahakian N, Calame K, Hahn BH. Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus. J Clin Invest. 1990 Feb;85(2):530–540. [PMC free article] [PubMed]
  • Shlomchik M, Mascelli M, Shan H, Radic MZ, Pisetsky D, Marshak-Rothstein A, Weigert M. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med. 1990 Jan 1;171(1):265–292. [PMC free article] [PubMed]
  • O'Keefe TL, Bandyopadhyay S, Datta SK, Imanishi-Kari T. V region sequences of an idiotypically connected family of pathogenic anti-DNA autoantibodies. J Immunol. 1990 Jun 1;144(11):4275–4283. [PubMed]
  • O'Keefe TL, Datta SK, Imanishi-Kari T. Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily. Eur J Immunol. 1992 Mar;22(3):619–624. [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]
  • Tillman DM, Jou NT, Hill RJ, Marion TN. Both IgM and IgG anti-DNA antibodies are the products of clonally selective B cell stimulation in (NZB x NZW)F1 mice. J Exp Med. 1992 Sep 1;176(3):761–779. [PMC free article] [PubMed]
  • Wofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med. 1985 Feb 1;161(2):378–391. [PMC free article] [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]
  • 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]
  • 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]
  • Santoro TJ, Portanova JP, Kotzin BL. The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice. J Exp Med. 1988 May 1;167(5):1713–1718. [PMC free article] [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]
  • Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. [PubMed]
  • Prud'Homme GJ, Park CL, Fieser TM, Kofler R, Dixon FJ, Theofilopoulos AN. Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype. J Exp Med. 1983 Feb 1;157(2):730–742. [PMC free article] [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]
  • Eastcott JW, Schwartz RS, Datta SK. Genetic analysis of the inheritance of B cell hyperactivity in relation to the development of autoantibodies and glomerulonephritis in NZB x SWR crosses. J Immunol. 1983 Nov;131(5):2232–2239. [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]
  • Adams S, Zordan T, Sainis K, Datta S. T cell receptor V beta genes expressed by IgG anti-DNA autoantibody-inducing T cells in lupus nephritis: forbidden receptors and double-negative T cells. Eur J Immunol. 1990 Jul;20(7):1435–1443. [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]
  • 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]
  • Madaio MP, Hodder S, Schwartz RS, Stollar BD. Responsiveness of autoimmune and normal mice to nucleic acid antigens. J Immunol. 1984 Feb;132(2):872–876. [PubMed]
  • Jorgensen JL, Esser U, Fazekas de St Groth B, Reay PA, Davis MM. Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics. Nature. 1992 Jan 16;355(6357):224–230. [PubMed]
  • Chesnut RW, Grey HM. Antigen presentation by B cells and its significance in T-B interactions. Adv Immunol. 1986;39:51–94. [PubMed]
  • Weiss S, Bogen B. MHC class II-restricted presentation of intracellular antigen. Cell. 1991 Feb 22;64(4):767–776. [PubMed]
  • Ozato K, Sachs DH. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed]
  • Payne J, Huber BT, Cannon NA, Schneider R, Schilham MW, Acha-Orbea H, MacDonald HR, Hengartner H. Two monoclonal rat antibodies with specificity for the beta-chain variable region V beta 6 of the murine T-cell receptor. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7695–7698. [PMC free article] [PubMed]
  • Ozato K, Mayer N, Sachs DH. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed]
  • Yager TD, McMurray CT, van Holde KE. Salt-induced release of DNA from nucleosome core particles. Biochemistry. 1989 Mar 7;28(5):2271–2281. [PubMed]
  • Atkinson MJ, Bell DA, Singhal SK. A naturally occurring polyclonal B cell activator of normal and autoantibody responses. J Immunol. 1985 Oct;135(4):2524–2533. [PubMed]
  • Bell DA, Morrison B, VandenBygaart P. Immunogenic DNA-related factors. Nucleosomes spontaneously released from normal murine lymphoid cells stimulate proliferation and immunoglobulin synthesis of normal mouse lymphocytes. J Clin Invest. 1990 May;85(5):1487–1496. [PMC free article] [PubMed]
  • Simon RH, Felsenfeld G. A new procedure for purifying histone pairs H2A + H2B and H3 + H4 from chromatin using hydroxylapatite. Nucleic Acids Res. 1979 Feb;6(2):689–696. [PMC free article] [PubMed]
  • Sette A, Buus S, Appella E, Smith JA, Chesnut R, Miles C, Colon SM, Grey HM. Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proc Natl Acad Sci U S A. 1989 May;86(9):3296–3300. [PMC free article] [PubMed]
  • Anker R, Zavala F, Pollok BA. VH and VL region structure of antibodies that recognize the (NANP)3 dodecapeptide sequence in the circumsporozoite protein of Plasmodium falciparum. Eur J Immunol. 1990 Dec;20(12):2757–2761. [PubMed]
  • Sherman DH, Hochman PS, Dick R, Tizard R, Ramachandran KL, Flavell RA, Huber BT. Molecular analysis of antigen recognition by insulin-specific T-cell hybridomas from B6 wild-type and bm12 mutant mice. Mol Cell Biol. 1987 May;7(5):1865–1872. [PMC free article] [PubMed]
  • Bradley LM, Atkins GG, Swain SL. Long-term CD4+ memory T cells from the spleen lack MEL-14, the lymph node homing receptor. J Immunol. 1992 Jan 15;148(2):324–331. [PubMed]
  • Germain RN, Ashwell JD, Lechler RI, Margulies DH, Nickerson KM, Suzuki G, Tou JY. "Exon-shuffling" maps control of antibody- and T-cell-recognition sites to the NH2-terminal domain of the class II major histocompatibility polypeptide A beta. Proc Natl Acad Sci U S A. 1985 May;82(9):2940–2944. [PMC free article] [PubMed]
  • Ziegler HK, Unanue ER. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. Proc Natl Acad Sci U S A. 1982 Jan;79(1):175–178. [PMC free article] [PubMed]
  • Takahashi H, Cease KB, Berzofsky JA. Identification of proteases that process distinct epitopes on the same protein. J Immunol. 1989 Apr 1;142(7):2221–2229. [PubMed]
  • Rekvig OP, Hannestad K. Human autoantibodies that react with both cell nuclei and plasma membranes display specificity for the octamer of histones H2A, H2B, H3, and H4 in high salt. J Exp Med. 1980 Dec 1;152(6):1720–1733. [PMC free article] [PubMed]
  • Rubin RL, Bell SA, Burlingame RW. Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. J Clin Invest. 1992 Jul;90(1):165–173. [PMC free article] [PubMed]
  • Losman MJ, Fasy TM, Novick KE, Monestier M. Monoclonal autoantibodies to subnucleosomes from a MRL/Mp(-)+/+ mouse. Oligoclonality of the antibody response and recognition of a determinant composed of histones H2A, H2B, and DNA. J Immunol. 1992 Mar 1;148(5):1561–1569. [PubMed]
  • Ghatak S, Sainis K, Owen FL, Datta SK. T-cell-receptor beta- and I-A beta-chain genes of normal SWR mice are linked with the development of lupus nephritis in NZB x SWR crosses. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6850–6853. [PMC free article] [PubMed]
  • Termaat RM, Brinkman K, Nossent JC, Swaak AJ, Smeenk RJ, Berden JH. Anti-heparan sulphate reactivity in sera from patients with systemic lupus erythematosus with renal or non-renal manifestations. Clin Exp Immunol. 1990 Nov;82(2):268–274. [PMC free article] [PubMed]
  • Noonan DM, Horigan EA, Ledbetter SR, Vogeli G, Sasaki M, Yamada Y, Hassell JR. Identification of cDNA clones encoding different domains of the basement membrane heparan sulfate proteoglycan. J Biol Chem. 1988 Nov 5;263(31):16379–16387. [PubMed]
  • Gavalchin J, Nicklas JA, Eastcott JW, Madaio MP, Stollar BD, Schwartz RS, Datta SK. Lupus prone (SWR x NZB)F1 mice produce potentially nephritogenic autoantibodies inherited from the normal SWR parent. J Immunol. 1985 Feb;134(2):885–894. [PubMed]
  • Rumore PM, Steinman CR. Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest. 1990 Jul;86(1):69–74. [PMC free article] [PubMed]
  • Carson DA. The specificity of anti-DNA antibodies in systemic lupus erythematosus. J Immunol. 1991 Jan 1;146(1):1–2. [PubMed]
  • Schmiedeke TM, Stöckl FW, Weber R, Sugisaki Y, Batsford SR, Vogt A. Histones have high affinity for the glomerular basement membrane. Relevance for immune complex formation in lupus nephritis. J Exp Med. 1989 Jun 1;169(6):1879–1894. [PMC free article] [PubMed]
  • Fournié GJ, Lulé J, Dueymes JM, Laval F, Delobbe I, Vernier I, Pourrat JP. Plasma DNA in patients undergoing hemodialysis or hemofiltration: cytolysis in artificial kidney is responsible for the release of DNA in circulation. Am J Nephrol. 1989;9(5):384–391. [PubMed]
  • Stollar BD. Immunochemistry of DNA. Int Rev Immunol. 1989;5(1):1–22. [PubMed]
  • Einck L, Dibble R, Frado LY, Woodcock CL. Nucleosomes as antigens. Characterization of determinants and cross-reactivity. Exp Cell Res. 1982 May;139(1):101–110. [PubMed]
  • Atanassov C, Briand JP, Bonnier D, Van Regenmortel MH, Muller S. New Zealand white rabbits immunized with RNA-complexed total histones develop an autoimmune-like response. Clin Exp Immunol. 1991 Oct;86(1):124–133. [PMC free article] [PubMed]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Herron LR, Coffman RL, Bond MW, Kotzin BL. Increased autoantibody production by NZB/NZW B cells in response to IL-5. J Immunol. 1988 Aug 1;141(3):842–848. [PubMed]
  • Deusch K, Fernandez-Botran R, Konstadoulakis M, Baur K, Schwartz RS, Madaio MP. Autoreactive T cells from MRL-lpr/lpr mice secrete multiple lymphokines and induce the production of IgG anti-DNA antibodies. J Autoimmun. 1991 Aug;4(4):563–576. [PubMed]
  • Hefeneider SH, Cornell KA, Brown LE, Bakke AC, McCoy SL, Bennett RM. Nucleosomes and DNA bind to specific cell-surface molecules on murine cells and induce cytokine production. Clin Immunol Immunopathol. 1992 Jun;63(3):245–251. [PubMed]
  • Ozaki S, Berzofsky JA. Antibody conjugates mimic specific B cell presentation of antigen: relationship between T and B cell specificity. J Immunol. 1987 Jun 15;138(12):4133–4142. [PubMed]
  • Hardin JA, Thomas JO. Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histones H1 and H2B. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7410–7414. [PMC free article] [PubMed]
  • Portanova JP, Arndt RE, Kotzin BL. Selective production of autoantibodies in graft-vs-host-induced and spontaneous murine lupus. Predominant reactivity with histone regions accessible in chromatin. J Immunol. 1988 Feb 1;140(3):755–760. [PubMed]
  • Panina-Bordignon P, Tan A, Termijtelen A, Demotz S, Corradin G, Lanzavecchia A. Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol. 1989 Dec;19(12):2237–2242. [PubMed]
  • Valmori D, Pessi A, Bianchi E, Corradin G. Use of human universally antigenic tetanus toxin T cell epitopes as carriers for human vaccination. J Immunol. 1992 Jul 15;149(2):717–721. [PubMed]
  • Lundberg AS, McDevitt HO. Evolution of major histocompatibility complex class II allelic diversity: direct descent in mice and humans. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6545–6549. [PMC free article] [PubMed]
  • Kaye J, Vasquez NJ, Hedrick SM. Involvement of the same region of the T cell antigen receptor in thymic selection and foreign peptide recognition. J Immunol. 1992 Jun 1;148(11):3342–3353. [PubMed]
  • Taylor AH, Haberman AM, Gerhard W, Caton AJ. Structure-function relationships among highly diverse T cells that recognize a determinant from influenza virus hemagglutinin. J Exp Med. 1990 Dec 1;172(6):1643–1651. [PMC free article] [PubMed]
  • Jacob L, Viard JP, Allenet B, Anin MF, Slama FB, Vandekerckhove J, Primo J, Markovits J, Jacob F, Bach JF, et al. A monoclonal anti-double-stranded DNA autoantibody binds to a 94-kDa cell-surface protein on various cell types via nucleosomes or a DNA-histone complex. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4669–4673. [PMC free article] [PubMed]
  • Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93–151. [PubMed]

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