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PMID: 19064698 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE.

The Journal of experimental medicine ·Vol. 205 ·No. 13 ·2008-12-22 ·Pages 3007-18

Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, Bianchi ME, Kirschning C, Wagner H, Manfredi AA, Kalden JR, Schett G, Rovere-Querini P, Herrmann M, Voll RE

Abstract

Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box protein 1 (HMGB1) is tightly attached to the chromatin of apoptotic cells. We demonstrate that HMGB1 remains bound to nucleosomes released from late apoptotic cells in vitro. HMGB1-nucleosome complexes were also detected in plasma from SLE patients. HMGB1-containing nucleosomes from apoptotic cells induced secretion of interleukin (IL) 1beta, IL-6, IL-10, and tumor necrosis factor (TNF) alpha and expression of costimulatory molecules in macrophages and dendritic cells (DC), respectively. Neither HMGB1-free nucleosomes from viable cells nor nucleosomes from apoptotic cells lacking HMGB1 induced cytokine production or DC activation. HMGB1-containing nucleosomes from apoptotic cells induced anti-dsDNA and antihistone IgG responses in a Toll-like receptor (TLR) 2-dependent manner, whereas nucleosomes from living cells did not. In conclusion, HMGB1-nucleosome complexes activate antigen presenting cells and, thereby, may crucially contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA.

MeSH Terms
Animals Apoptosis/physiology Autoantibodies/immunology Cell Line Cytokines/immunology Female HMGB1 Protein/genetics,immunology Humans Immune System Phenomena/physiology Inflammation/immunology Lupus Erythematosus, Systemic/immunology,physiopathology Mice Mice, Inbred BALB C Mice, Knockout Myeloid Differentiation Factor 88/genetics,immunology Nucleosomes/immunology Receptor for Advanced Glycation End Products Receptors, Immunologic/immunology Toll-Like Receptor 2/immunology Toll-Like Receptor 4/immunology Toll-Like Receptor 9/immunology
Chemicals
Autoantibodies Cytokines HMGB1 Protein Myd88 protein, mouse Myeloid Differentiation Factor 88 Nucleosomes Receptor for Advanced Glycation End Products Receptors, Immunologic Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptor 9
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Urbonaviciute Vilma
Interdisciplinary Center of Clinical Research (IZKF), Research Group N2, Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.
Fürnrohr Barbara G
Meister Silke
Munoz Luis
Heyder Petra
De Marchis Francesco
Bianchi Marco E
Kirschning Carsten
Wagner Hermann
Manfredi Angelo A
Kalden Joachim R
Schett Georg
Rovere-Querini Patrizia
Herrmann Martin
Voll Reinhard E
References (74)
74 references, click to expand
  1. Immunochemical determination of DNA in immune complexes present in the circulation of patients with systemic lupus erythematosus.
    J Autoimmun. 1998 Oct;11(5):489-93 PMID: 9802934
  2. Pathogenesis of systemic lupus erythematosus.
    J Clin Pathol. 2003 Jul;56(7):481-90 PMID: 12835292
  3. Toll-like receptors in the induction of the innate immune response.
    Nature. 2000 Aug 17;406(6797):782-7 PMID: 10963608
  4. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus.
    Immunity. 2006 Sep;25(3):417-28 PMID: 16973389
  5. Cytokine production, serum levels and disease activity in systemic lupus erythematosus.
    Clin Exp Rheumatol. 2000 Sep-Oct;18(5):565-70 PMID: 11072595
  6. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages.
    Scand J Immunol. 2005 Jan;61(1):1-9 PMID: 15644117
  7. Detection of nucleosome particles in serum and plasma from patients with systemic lupus erythematosus using monoclonal antibody 4H7.
    J Rheumatol. 2001 Jan;28(1):81-94 PMID: 11196548
  8. TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus.
    Infect Genet Evol. 2008 Sep;8(5):541-4 PMID: 18417424
  9. Endonuclease activation and chromosomal DNA fragmentation during apoptosis in leukemia cells.
    Int J Hematol. 2006 Jul;84(1):31-7 PMID: 16867899
  10. A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA.
    Blood. 2007 Sep 15;110(6):1970-81 PMID: 17548579
  11. Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus.
    Lupus. 2007;16(10):794-802 PMID: 17895302
  12. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization.
    J Immunol. 2004 Jul 1;173(1):307-13 PMID: 15210788
  13. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.
    Arthritis Rheum. 2003 Apr;48(4):971-81 PMID: 12687539
  14. High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis.
    Arthritis Rheum. 2002 Oct;46(10):2598-603 PMID: 12384917
  15. Dendritic cells and the control of immunity.
    Nature. 1998 Mar 19;392(6673):245-52 PMID: 9521319
  16. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes.
    J Exp Med. 2000 Aug 21;192(4):565-70 PMID: 10952726
  17. Dendritic cell biology.
    Adv Immunol. 2005;88:193-233 PMID: 16227091
  18. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.
    J Clin Invest. 2005 Feb;115(2):407-17 PMID: 15668740
  19. Recognizing death: the phagocytosis of apoptotic cells.
    Trends Cell Biol. 1998 Sep;8(9):365-72 PMID: 9728398
  20. Cross-regulation of TNF and IFN-alpha in autoimmune diseases.
    Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3372-7 PMID: 15728381
  21. Effects of immobilized immune complexes on Fc- and complement-receptor function in resident and thioglycollate-elicited mouse peritoneal macrophages.
    J Exp Med. 1979 Sep 19;150(3):607-21 PMID: 383878
  22. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus.
    Arthritis Rheum. 1998 Jul;41(7):1241-50 PMID: 9663482
  23. HMG-1 as a late mediator of endotoxin lethality in mice.
    Science. 1999 Jul 9;285(5425):248-51 PMID: 10398600
  24. Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies.
    Arthritis Rheum. 1998 Feb;41(2):205-14 PMID: 9485078
  25. 30-kDa heparin-binding protein of brain (amphoterin) involved in neurite outgrowth. Amino acid sequence and localization in the filopodia of the advancing plasma membrane.
    J Biol Chem. 1991 Sep 5;266(25):16722-9 PMID: 1885601
  26. Responsiveness of autoimmune and normal mice to nucleic acid antigens.
    J Immunol. 1984 Feb;132(2):872-6 PMID: 6690621
  27. A Toll-like receptor recognizes bacterial DNA.
    Nature. 2000 Dec 7;408(6813):740-5 PMID: 11130078
  28. Cellular recognition of trimyristoylated peptide or enterobacterial lipopolysaccharide via both TLR2 and TLR4.
    J Biol Chem. 2007 May 4;282(18):13190-8 PMID: 17353199
  29. The role of tumor necrosis factor-alpha in systemic lupus erythematosus.
    Arthritis Res Ther. 2008;10(1):202 PMID: 18226185
  30. Apoptotic cell clearance in systemic lupus erythematosus. II. Role of beta2-glycoprotein I.
    Arthritis Rheum. 1998 Feb;41(2):215-23 PMID: 9485079
  31. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein.
    J Biol Chem. 2004 Feb 27;279(9):7370-7 PMID: 14660645
  32. Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation.
    J Immunol. 2005 Mar 15;174(6):3326-34 PMID: 15749864
  33. DNase I mediates internucleosomal DNA degradation in human cells undergoing drug-induced apoptosis.
    Eur J Immunol. 2001 Mar;31(3):743-51 PMID: 11241278
  34. Binding properties of human anti-DNA antibodies to cloned human DNA fragments.
    Scand J Immunol. 1989 Jul;30(1):51-63 PMID: 2787927
  35. Reversing established sepsis with antagonists of endogenous high-mobility group box 1.
    Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):296-301 PMID: 14695889
  36. Endogenous ligands of Toll-like receptors.
    J Leukoc Biol. 2004 Sep;76(3):514-9 PMID: 15178705
  37. HMG1 and 2, and related 'architectural' DNA-binding proteins.
    Trends Biochem Sci. 2001 Mar;26(3):167-74 PMID: 11246022
  38. Prevalence and characterization of novel pANCA, antibodies to the high mobility group non-histone chromosomal proteins HMG1 and HMG2, in systemic rheumatic diseases.
    J Rheumatol. 1998 Apr;25(4):703-9 PMID: 9558172
  39. Autoantibodies in SLE but not in scleroderma react with protein-stripped nucleosomes.
    J Autoimmun. 2004 Jun;22(4):325-34 PMID: 15120756
  40. Involvement of phosphatidylserine, alphavbeta3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages.
    Arthritis Rheum. 2006 Mar;54(3):927-38 PMID: 16508977
  41. Time between onset of apoptosis and release of nucleosomes from apoptotic cells: putative implications for systemic lupus erythematosus.
    Ann Rheum Dis. 2003 Jan;62(1):10-4 PMID: 12480662
  42. Evolution of antinuclear antibodies and clinical patterns in patients with active rheumatoid arthritis with longterm infliximab therapy.
    J Rheumatol. 2006 Jan;33(1):24-30 PMID: 16395746
  43. Toll-like receptors; their physiological role and signal transduction system.
    Int Immunopharmacol. 2001 Apr;1(4):625-35 PMID: 11357875
  44. Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice.
    J Leukoc Biol. 2007 Jan;81(1):100-7 PMID: 16935945
  45. Nucleosome autoantibodies.
    Clin Chim Acta. 2006 Apr;366(1-2):48-60 PMID: 16364274
  46. Factors masking HMGB1 in human serum and plasma.
    J Leukoc Biol. 2007 Jan;81(1):67-74 PMID: 17060363
  47. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response.
    J Clin Invest. 2004 Jun;113(11):1641-50 PMID: 15173891
  48. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
    Immunity. 1998 Jul;9(1):143-50 PMID: 9697844
  49. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.
    J Exp Med. 1994 Apr 1;179(4):1317-30 PMID: 7511686
  50. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE.
    Nat Immunol. 2007 May;8(5):487-96 PMID: 17417641
  51. Expression of high mobility group protein 1 in the sera of patients and mice with systemic lupus erythematosus.
    Ann Rheum Dis. 2008 May;67(5):727-8 PMID: 18408114
  52. HMGB1 is an endogenous immune adjuvant released by necrotic cells.
    EMBO Rep. 2004 Aug;5(8):825-30 PMID: 15272298
  53. Antigen presentation and immune regulatory capacity of immature and mature-enriched antigen presenting (dendritic) cells derived from human bone marrow.
    Hum Immunol. 2004 Feb;65(2):93-103 PMID: 14969764
  54. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes.
    J Exp Med. 2004 Jun 21;199(12):1631-40 PMID: 15197227
  55. Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice.
    Kidney Int. 1995 Sep;48(3):705-11 PMID: 7474655
  56. Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis.
    J Clin Invest. 1977 Jan;59(1):90-6 PMID: 299748
  57. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus.
    Science. 2001 Nov 16;294(5546):1540-3 PMID: 11711679
  58. The expression of plasma nucleosomes in mice undergoing in vivo apoptosis.
    Clin Immunol. 2003 Feb;106(2):139-47 PMID: 12672404
  59. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins.
    Mol Cell Biol. 1999 Aug;19(8):5237-46 PMID: 10409715
  60. The key role of nucleosomes in lupus.
    Arthritis Rheum. 1999 May;42(5):833-43 PMID: 10323438
  61. An Ig mu-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice.
    Int Immunol. 2001 Dec;13(12):1461-9 PMID: 11717187
  62. Systemic exposure to irradiated apoptotic cells induces autoantibody production.
    J Exp Med. 1998 Jul 20;188(2):387-92 PMID: 9670050
  63. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus.
    Arthritis Rheum. 2005 Nov;52(11):3639-45 PMID: 16255056
  64. Immunosuppressive effects of apoptotic cells.
    Nature. 1997 Nov 27;390(6658):350-1 PMID: 9389474
  65. Deoxybonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus.
    J Clin Invest. 1966 Nov;45(11):1732-40 PMID: 4959277
  66. The extracellular release of HMGB1 during apoptotic cell death.
    Am J Physiol Cell Physiol. 2006 Dec;291(6):C1318-25 PMID: 16855214
  67. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice.
    Nat Genet. 1999 Jul;22(3):276-80 PMID: 10391216
  68. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.
    Nature. 2002 Jul 11;418(6894):191-5 PMID: 12110890
  69. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus.
    Arthritis Rheum. 2002 Jan;46(1):191-201 PMID: 11817590
  70. HMG proteins: dynamic players in gene regulation and differentiation.
    Curr Opin Genet Dev. 2005 Oct;15(5):496-506 PMID: 16102963
  71. What triggers anti-dsDNA antibodies?
    Mol Biol Rep. 1996;23(3-4):265-7 PMID: 9112239
  72. Interleukin-10 (IL-10) secretion in systemic lupus erythematosus and rheumatoid arthritis: IL-10-dependent CD4+CD45RO+ T cell-B cell antibody synthesis.
    J Clin Immunol. 1996 Jul;16(4):198-207 PMID: 8840221
  73. Antibodies to DNA.
    N Engl J Med. 1998 May 7;338(19):1359-68 PMID: 9571257
  74. Requirements for proteolysis during apoptosis.
    Mol Cell Biol. 1997 Nov;17(11):6502-7 PMID: 9343413
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20081165
Published
2008-12-22
Epub
2008-00-08
Pages
3007-18
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2605236
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20081165 PMC Full Text View journal details
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