Histone-specific Th0 and Th1 clones derived from systemic lupus erythematosus patients induce double-stranded DNA antibody production
Reinhard E. Voll MD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorEdith A. Roth
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorIrute Girkontaite PhD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorMartin Herrmann PhD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorHanns-Martin Lorenz MD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorCorresponding Author
Joachim R. Kalden MD
Friedrich-Alexander-University, Erlangen, Germany
Director, Department of Internal Medicine III, Krankenhausstrasse 12, 91054 Erlangen, GermanySearch for more papers by this authorReinhard E. Voll MD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorEdith A. Roth
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorIrute Girkontaite PhD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorMartin Herrmann PhD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorHanns-Martin Lorenz MD
Friedrich-Alexander-University, Erlangen, Germany
Search for more papers by this authorCorresponding Author
Joachim R. Kalden MD
Friedrich-Alexander-University, Erlangen, Germany
Director, Department of Internal Medicine III, Krankenhausstrasse 12, 91054 Erlangen, GermanySearch for more papers by this authorAbstract
Objective. To investigate whether histone-specific T helper (Th) cells that are able to induce anti-doublestranded DNA (anti-dsDNA) antibodies can be isolated from patients with systemic lupus erythematosus (SLE) and to characterize the cytokine secretion pattern of such Th clones.
Methods. Peripheral blood mononuclear cells from SLE patients and healthy donors were stimulated with autologous apoptotic cell material or purified histones, expanded with interleukin-2 (IL-2), and cloned by limiting dilution. Histone reactivity of clones was examined by histone-specific proliferation and cytokine release. Cytokines were determined by enzyme-linked immunosorbent assay (ELISA) and CTLL-2 bioassay. Induction of anti-dsDNA antibodies was measured in cocultures of autologous B cells and Th clones by ELISA.
Results. Numerous histone-specific T cell receptor (TCR) α/β+ Th clones were established from 2 of 3 patients with active SLE and from 1 of 2 healthy individuals. Most Th clones secreted IL-2, interferon-γ (IFNγ), and IL-4, whereas some produced predominantly IL-2 and lFNγ. Th clones that could stimulate the production of anti-dsDNA antibodies were derived from SLE patients and from a healthy individual.
Conclusion. Th cells specific for histones may play an important role in the pathogenesis of SLE by inducing autoantibodies to dsDNA. Both Th1 and Th2 cytokines may be involved in the pathogenesis of SLE. The presence of histone-specific Th cells in a healthy individual indicates the importance of peripheral tolerance for preventing autoimmunity to nuclear antigens.
Reference
- 1 Tan EM: Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 44: 93–151, 1989
- 2 Isenberg DA, Ehrenstein MR, Longhurst C, Kalsi JK: The origin, sequence, structure, and consequences of developing anti-DNA antibodies: a human perspective. Arthritis Rheum 37: 169–180, 1994
- 3 Gavalchin J, Datta SK: The NZB x SWR model of lupus nephritis. II. Autoantibodies deposited in renal lesions show a restricted isotype diversity. J Immunol 138: 138–148, 1987
- 4 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 41: 1690–1700, 1992
- 5 Okamura M, Kanayama Y, Amastu K, Negoru N, Kohda S, Takeda T, Inue T: Significance of enzyme linked immunosorbent assay for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology. Ann Rheum Dis 52: 14–20, 1993
- 6 Van Es JH, Gmelig Meyling FH, van der Akker MR, Aanstoot H, Derksen RH, Logtenberg T: Somatic mutations in the variable regions of a human IgG anti-double stranded DNA autoantibody suggests a role for antigen in the induction of systemic lupus erythematosus. J Exp Med 173: 461–470, 1991
- 7 Winkler TH, Fehr H, Kalden JR: Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas. Eur J Immunol 22: 1719–1728, 1992
- 8 Kasaian MT, Ikematsu H, Balow JE, Casali P: Structure of the VH and VL segments of monoreactive and polyreactive IgA autoantibodies to DNA in patients with systemic lupus erythematosus. J Immunol 152: 3137–3151, 1994
- 9 Madaio MP, Hodder S, Schwartz RS, Stollar BD: Responsiveness of autoimmune and normal mice to nucleic acid antigens. J Immunol 132: 872–876, 1984
- 10 Mohan C, Adams S, Stanik V, Datta SK: Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 177: 1367–1381, 1993
- 11 Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179: 1317–1330, 1994
- 12 Bell DA, Morrison B: The spontaneous apoptotic cell death of normal human lymphocytes in vitro: the release of, and immunoproliferative response to, nucleosomes in vitro. Clin Immunol Immunopathol 60: 13–26, 1991
- 13 Shivakumar S, Tsokos GC, Datta SK: T cell receptor α/β 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 143: 103–112, 1989
- 14 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 γδ T-cell antigen receptor. Proc Natl Acad Sci U S A 87: 7020–7024, 1990
- 15 Street NE, Mosmann TR: Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J 5: 171–177, 1991
- 16 Romagnani S: Lymphokine production by human T cells in disease states. Annu Rev Immunol 12: 227–257, 1994
- 17 Caligaris-Cappio F, Bertero MT, Converso M, Stacchini A, Vinante F, Romagnani S, Pizzolo G: Circulating levels of soluble CD30, a marker of cells producing Th2-type cytokines, are increased in patients with systemic lupus erythematosus and correlate with disease activity. Clin Exp Rheumatol 13: 339–343, 1995
- 18 Horwitz DA, Wang H, Gray JD: Cytokine gene profile in circulating blood mononuclear cells from patients with systemic lupus erythematosus: increased interleukin-2 but not interleukin 4 mRNA. Lupus 3: 423–428, 1994
- 19 Del Prete GF, De Carli M, Mastromauro C, Biagotti R, Macchia D, Falagiani P, Ricci M, Romagnani S: Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest 88: 346–350, 1991
- 20 Winkler TH, Jahn S, Kalden JR: IgG human monoclonal anti-DNA autoantibodies from patients with systemic lupus erythematosus. Clin Exp Immunol 85: 379–385, 1991
- 21 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 95: 531–541, 1995
- 22 Bustos A, Boimorto R, Subiza JL, Pereira LF, Marco M, Figueredo MA, Del La Concha EG: Inhibition of histone/antihistone reactivity by histone-binding serum components; differential effect on anti-H1 versus anti-H2B antibodies. Clin Exp Immunol 95: 408–414, 1994
- 23 Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA: T cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 347: 183–187, 1990
- 24 Yan T, Burkhardt H, Ritter T, Bröker B, Mann KH, Bertling WM, von der Mark K, Emmrich F: Specificity and T cell receptor beta chain usage of a human collagen type II-reactive T cell clone derived from a healthy individual. Eur J Immunol 22: 51–56, 1992
- 25 Filion MC, Bradly AJ, Devine DV, Decary F, Chartrand P: Autoreactive T cells in healthy individuals show tolerance in vitro with characteristics similar but distinct from clonal anergy. Eur J Immunol 25: 3123–3127, 1995
- 26 Del Prete G, Maggi E, Pizzolo G, Romagnani S: CD30, Th2 cytokines and HIV infection: a complex and fascinating link. Immunol Today 16: 76–80, 1995
- 27 Linker-Israeli M: Cytokine abnormalities in human lupus. Clin Immunol Immunopathol 63: 10–12, 1992
- 28 Prud'Homme GJ, Kono DH, Theofilopoulos AN: Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1β, interleukin-10 and interferon-γ mRNA in the lymph nodes of lupus-prone mice. Mol Immunol 32: 495–503, 1995
- 29 Volk H-D, Sonnichsen N, Jahn S, Hiepe F, Apostoloff E, von Baehr R, Diezel W: The influence of interferon-γ, interleukin-2, prostaglandin E2, and cyclosporine on the polyclonal and anti-DNA antibody secretion in lymphocyte cultures derived from patients with systemic lupus erythematosus. Arch Dermatol Res 279: 92–96, 1987
- 30 Ozmen L, Roman D, Fountoulakis M, Schmid G, Ryffel B, Garotta G: Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-γ receptor inhibits the onset of glomerulonephritis. Eur J Immunol 25: 6–12, 1995
- 31 Gharavi AE, Harris EN, Lockshin MD, Hughes GRV, Elkon KB: IgG subclass and light chain distribution of anticardiolipin and anti-DNA antibodies in systemic lupus erythematosus. Ann Rheum Dis 47: 286–290, 1988
- 32 Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Morel-Fourrier B, Brouet JC, Alarcon-Segovia D, Galanaud P, Emilie D: Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 181: 839–844, 1995
- 33 Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S: Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 150: 353–360, 1993
- 34 Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM, Galanaud P, Emilie D: In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus: a potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 37: 1647–1655, 1994
- 35 Rumore PM, Steinman CR: Endogenous circulating DNA in systemic lupus erythematosus: occurrence as multimeric complexes bound to histone. J Clin Invest 86: 69–74, 1990
- 36 Herrmann M, Zoller OM, Hagenhofer M, Voll R, Kalden JR: What triggers anti-dsDNA antibodies? Mol Biol Rep 23: 265–267, 1996
