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Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players

  • Clearance of dead cells: mechanisms, immune responses and implication in the development of diseases
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Abstract

Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease.

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References

  1. Lorenz HM, Grunke M, Hieronymus T, Herrmann M, Kuhnel A, Manger B, Kalden JR (1997) In vitro apoptosis and expression of apoptosis-related molecules in lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases. Arthritis Rheum 40:306–317

    PubMed  Google Scholar 

  2. Dillon SR, Constantinescu A, Schlissel MS (2001) Annexin V binds to positively selected B cells. J Immunol 166:58–71

    PubMed  Google Scholar 

  3. Appelt U, Sheriff A, Gaipl US, Kalden JR, Voll RE, Herrmann M (2005) Viable, apoptotic and necrotic monocytes expose phosphatidylserine: cooperative binding of the ligand Annexin V to dying but not viable cells and implications for PS-dependent clearance. Cell Death Differ 12:194–196

    PubMed  Google Scholar 

  4. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150

    PubMed  Google Scholar 

  5. Gaipl US, Kuenkele S, Voll RE, Beyer TD, Kolowos W, Heyder P, Kalden JR, Herrmann M (2001) Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death. Cell Death Differ 8:327–334

    PubMed  Google Scholar 

  6. Mevorach D, Mascarenhas JO, Gershov D, Elkon KB (1998) Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med 188:2313–2320

    PubMed  Google Scholar 

  7. Gaipl US, Beyer TD, Heyder P, Kuenkele S, Bottcher A, Voll RE, Kalden JR, Herrmann M (2004) Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin. Arthritis Rheum 50:640–649

    PubMed  Google Scholar 

  8. Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Ronnblom L, Sturfelt G, Eloranta ML, Bengtsson AA (2009) C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum 60:3081–3090

    PubMed  Google Scholar 

  9. Oshima K, Aoki N, Kato T, Kitajima K, Matsuda T (2002) Secretion of a peripheral membrane protein, MFG-E8, as a complex with membrane vesicles. Eur J Biochem 269:1209–1218

    PubMed  Google Scholar 

  10. Aoki N, Ishii T, Ohira S, Yamaguchi Y, Negi M, Adachi T, Nakamura R, Matsuda T (1997) Stage specific expression of milk fat globule membrane glycoproteins in mouse mammary gland: comparison of MFG-E8, butyrophilin, and CD36 with a major milk protein, beta-casein. Biochim Biophys Acta 1334:182–190

    PubMed  Google Scholar 

  11. Nakatani H, Aoki N, Nakagawa Y, Jin-No S, Aoyama K, Oshima K, Ohira S, Sato C, Nadano D, Matsuda T (2006) Weaning-induced expression of a milk-fat globule protein, MFG-E8, in mouse mammary glands, as demonstrated by the analyses of its mRNA, protein and phosphatidylserine-binding activity. Biochem J 395:21–30

    PubMed  Google Scholar 

  12. Oshima K, Aoki N, Negi M, Kishi M, Kitajima K, Matsuda T (1999) Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. Biochem Biophys Res Commun 254:522–528

    PubMed  Google Scholar 

  13. Burgess BL, Abrams TA, Nagata S, Hall MO (2006) MFG-E8 in the retina and retinal pigment epithelium of rat and mouse. Mol Vis 12:1437–1447

    PubMed  Google Scholar 

  14. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187

    PubMed  Google Scholar 

  15. Shi J, Gilbert GE (2003) Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites. Blood 101:2628–2636

    PubMed  Google Scholar 

  16. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216

    PubMed  Google Scholar 

  17. Miyasaka K, Hanayama R, Tanaka M, Nagata S (2004) Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur J Immunol 34:1414–1422

    PubMed  Google Scholar 

  18. Kranich J, Krautler NJ, Heinen E, Polymenidou M, Bridel C, Schildknecht A, Huber C, Kosco-Vilbois MH, Zinkernagel R, Miele G, Aguzzi A (2008) Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. J Exp Med 205:1293–1302

    PubMed  Google Scholar 

  19. Hanayama R, Tanaka M, Miwa K, Nagata S (2004) Expression of developmental endothelial locus-1 in a subset of macrophages for engulfment of apoptotic cells. J Immunol 172:3876–3882

    PubMed  Google Scholar 

  20. Hanayama R, Nagata S (2005) Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci USA 102:16886–16891

    PubMed  Google Scholar 

  21. Asano K, Miwa M, Miwa K, Hanayama R, Nagase H, Nagata S, Tanaka M (2004) Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med 200:459–467

    PubMed  Google Scholar 

  22. Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, Kirchner T, Kalden JR, Herrmann M (2002) Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum 46:191–201

    PubMed  Google Scholar 

  23. Wellmann U, Letz M, Herrmann M, Angermuller S, Kalden JR, Winkler TH (2005) The evolution of human anti-double-stranded DNA autoantibodies. Proc Natl Acad Sci USA 102:9258–9263

    PubMed  Google Scholar 

  24. Couto JR, Taylor MR, Godwin SG, Ceriani RL, Peterson JA (1996) Cloning and sequence analysis of human breast epithelial antigen BA46 reveals an RGD cell adhesion sequence presented on an epidermal growth factor-like domain. DNA Cell Biol 15:281–286

    PubMed  Google Scholar 

  25. Yamaguchi H, Takagi J, Miyamae T, Yokota S, Fujimoto T, Nakamura S, Ohshima S, Naka T, Nagata S (2008) Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus. J Leukoc Biol 83:1300–1307

    PubMed  Google Scholar 

  26. Hu CY, Wu CS, Tsai HF, Chang SK, Tsai WI, Hsu PN (2009) Genetic polymorphism in milk fat globule-EGF factor 8 (MFG-E8) is associated with systemic lupus erythematosus in human. Lupus 18:676–681

    PubMed  Google Scholar 

  27. Franz S, Frey B, Sheriff A, Gaipl US, Beer A, Voll RE, Kalden JR, Herrmann M (2006) Lectins detect changes of the glycosylation status of plasma membrane constituents during late apoptosis. Cytometry A 69:230–239

    PubMed  Google Scholar 

  28. Mierke CT, Kollmannsberger P, Zitterbart DP, Smith J, Fabry B, Goldmann WH (2008) Mechano-coupling and regulation of contractility by the vinculin tail domain. Biophys J 94:661–670

    PubMed  Google Scholar 

  29. Mierke CT, Zitterbart DP, Kollmannsberger P, Raupach C, Schlotzer-Schrehardt U, Goecke TW, Behrens J, Fabry B (2008) Breakdown of the endothelial barrier function in tumor cell transmigration. Biophys J 94:2832–2846

    PubMed  Google Scholar 

  30. Sheriff A, Gaipl US, Franz S, Heyder P, Voll RE, Kalden JR, Herrmann M (2004) Loss of GM1 surface expression precedes annexin V-phycoerythrin binding of neutrophils undergoing spontaneous apoptosis during in vitro aging. Cytometry A 62:75–80

    PubMed  Google Scholar 

  31. Raupach C, Zitterbart DP, Mierke CT, Metzner C, Muller FA, Fabry B (2007) Stress fluctuations and motion of cytoskeletal-bound markers. Phys Rev E Stat Nonlin Soft Matter Phys 76:011918

    PubMed  Google Scholar 

  32. Sessa L, Bianchi ME (2007) The evolution of High Mobility Group Box (HMGB) chromatin proteins in multicellular animals. Gene 387:133–140

    PubMed  Google Scholar 

  33. Thomas JO, Travers AA (2001) HMG1 and 2, and related ‘architectural’ DNA-binding proteins. Trends Biochem Sci 26:167–174

    PubMed  Google Scholar 

  34. Tsuda K, Kikuchi M, Mori K, Waga S, Yoshida M (1988) Primary structure of non-histone protein HMG1 revealed by the nucleotide sequence. Biochemistry 27:6159–6163

    PubMed  Google Scholar 

  35. Bianchi ME, Agresti A (2005) HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev 15:496–506

    PubMed  Google Scholar 

  36. Melvin VS, Edwards DP (1999) Coregulatory proteins in steroid hormone receptor action: the role of chromatin high mobility group proteins HMG-1 and -2. Steroids 64:576–586

    PubMed  Google Scholar 

  37. Melvin VS, Roemer SC, Churchill ME, Edwards DP (2002) The C-terminal extension (CTE) of the nuclear hormone receptor DNA binding domain determines interactions and functional response to the HMGB-1/-2 co-regulatory proteins. J Biol Chem 277:25115–25124

    PubMed  Google Scholar 

  38. Jayaraman L, Moorthy NC, Murthy KG, Manley JL, Bustin M, Prives C (1998) High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev 12:462–472

    PubMed  Google Scholar 

  39. Agresti A, Lupo R, Bianchi ME, Muller S (2003) HMGB1 interacts differentially with members of the Rel family of transcription factors. Biochem Biophys Res Commun 302:421–426

    PubMed  Google Scholar 

  40. Calogero S, Grassi F, Aguzzi A, Voigtlander T, Ferrier P, Ferrari S, Bianchi ME (1999) The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet 22:276–280

    PubMed  Google Scholar 

  41. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251

    PubMed  Google Scholar 

  42. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3:995–1001

    PubMed  Google Scholar 

  43. Chen G, Li J, Ochani M, Rendon-Mitchell B, Qiang X, Susarla S, Ulloa L, Yang H, Fan S, Goyert SM, Wang P, Tracey KJ, Sama AE, Wang H (2004) Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J Leukoc Biol 76:994–1001

    PubMed  Google Scholar 

  44. Dumitriu IE, Bianchi ME, Bacci M, Manfredi AA, Rovere-Querini P (2007) The secretion of HMGB1 is required for the migration of maturing dendritic cells. J Leukoc Biol 81:84–91

    PubMed  Google Scholar 

  45. Semino C, Angelini G, Poggi A, Rubartelli A (2005) NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 106:609–616

    PubMed  Google Scholar 

  46. Liu S, Stolz DB, Sappington PL, Macias CA, Killeen ME, Tenhunen JJ, Delude RL, Fink MP (2006) HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers. Am J Physiol Cell Physiol 290:C990–C999

    PubMed  Google Scholar 

  47. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195

    PubMed  Google Scholar 

  48. Bell CW, Jiang W, Reich CF III, Pisetsky DS (2006) The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol 291:C1318–C1325

    PubMed  Google Scholar 

  49. Urbonaviciute V, Furnrohr 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 (2008) Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 205:3007–3018

    PubMed  Google Scholar 

  50. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570

    PubMed  Google Scholar 

  51. Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, Dumitriu IE, Muller S, Iannacone M, Traversari C, Bianchi ME, Manfredi AA (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5:825–830

    PubMed  Google Scholar 

  52. Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P (2005) Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol 35:2184–2190

    PubMed  Google Scholar 

  53. Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G, Bierhaus A, Naworth P, Marshak-Rothstein A, Crow MK, Fitzgerald KA, Latz E, Kiener PA, Coyle AJ (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8:487–496

    PubMed  Google Scholar 

  54. Ivanov S, Dragoi AM, Wang X, Dallacosta C, Louten J, Musco G, Sitia G, Yap GS, Wan Y, Biron CA, Bianchi ME, Wang H, Chu WM (2007) A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 110:1970–1981

    PubMed  Google Scholar 

  55. Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, Savitsky D, Ronfani L, Akira S, Bianchi ME, Honda K, Tamura T, Kodama T, Taniguchi T (2009) HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462:99–103

    PubMed  Google Scholar 

  56. Youn JH, Oh YJ, Kim ES, Choi JE, Shin JS (2008) High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes. J Immunol 180:5067–5074

    PubMed  Google Scholar 

  57. Sha Y, Zmijewski J, Xu Z, Abraham E (2008) HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol 180:2531–2537

    PubMed  Google Scholar 

  58. Bianchi ME, Manfredi AA (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220:35–46

    PubMed  Google Scholar 

  59. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29:21–32

    PubMed  Google Scholar 

  60. Chen GY, Tang J, Zheng P, Liu Y (2009) CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323:1722–1725

    PubMed  Google Scholar 

  61. Kokkola R, Sundberg E, Ulfgren AK, Palmblad K, Li J, Wang H, Ulloa L, Yang H, Yan XJ, Furie R, Chiorazzi N, Tracey KJ, Andersson U, Harris HE (2002) High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum 46:2598–2603

    PubMed  Google Scholar 

  62. Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M, Inoue K, Yamada S, Ijiri K, Matsunaga S, Nakajima T, Komiya S, Maruyama I (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 48:971–981

    PubMed  Google Scholar 

  63. Popovic K, Ek M, Espinosa A, Padyukov L, Harris HE, Wahren-Herlenius M, Nyberg F (2005) Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum 52:3639–3645

    PubMed  Google Scholar 

  64. Barkauskaite V, Ek M, Popovic K, Harris HE, Wahren-Herlenius M, Nyberg F (2007) 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 16:794–802

    PubMed  Google Scholar 

  65. Fadok VA, McDonald PP, Bratton DL, Henson PM (1998) Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochem Soc Trans 26:653–656

    PubMed  Google Scholar 

  66. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351

    PubMed  Google Scholar 

  67. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250

    PubMed  Google Scholar 

  68. Hayashi A, Nagafuchi H, Ito I, Hirota K, Yoshida M, Ozaki S (2009) Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity. Mod Rheumatol 19:283–292

    PubMed  Google Scholar 

  69. Uesugi H, Ozaki S, Sobajima J, Osakada F, Shirakawa H, Yoshida M, Nakao K (1998) 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 25:703–709

    PubMed  Google Scholar 

  70. Urbonaviciute V, Furnrohr BG, Weber C, Haslbeck M, Wilhelm S, Herrmann M, Voll RE (2007) Factors masking HMGB1 in human serum and plasma. J Leukoc Biol 81:67–74

    PubMed  Google Scholar 

  71. Kushner I (1988) The acute phase response: an overview. Methods Enzymol 163:373–383

    PubMed  Google Scholar 

  72. Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74–80

    PubMed  Google Scholar 

  73. Zhang D, Jiang SL, Rzewnicki D, Samols D, Kushner I (1995) The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level. Biochem J 310(Pt 1):143–148

    PubMed  Google Scholar 

  74. Kleemann R, Gervois PP, Verschuren L, Staels B, Princen HM, Kooistra T (2003) Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. Blood 101:545–551

    PubMed  Google Scholar 

  75. Taylor AW, Ku NO, Mortensen RF (1990) Regulation of cytokine-induced human C-reactive protein production by transforming growth factor-beta. J Immunol 145:2507–2513

    PubMed  Google Scholar 

  76. Szalai AJ, Wu J, Lange EM, McCrory MA, Langefeld CD, Williams A, Zakharkin SO, George V, Allison DB, Cooper GS, Xie F, Fan Z, Edberg JC, Kimberly RP (2005) Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level. J Mol Med 83:440–447

    PubMed  Google Scholar 

  77. Garlanda C, Bottazzi B, Bastone A, Mantovani A (2005) Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 23:337–366

    PubMed  Google Scholar 

  78. Du Clos TW, Mold C (2004) C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res 30:261–277

    PubMed  Google Scholar 

  79. Motie M, Brockmeier S, Potempa LA (1996) Binding of model soluble immune complexes to modified C-reactive protein. J Immunol 156:4435–4441

    PubMed  Google Scholar 

  80. Potempa LA, Siegel JN, Fiedel BA, Potempa RT, Gewurz H (1987) Expression, detection and assay of a neoantigen (Neo-CRP) associated with a free, human C-reactive protein subunit. Mol Immunol 24:531–541

    PubMed  Google Scholar 

  81. Wang HW, Sui SF (2001) Dissociation and subunit rearrangement of membrane-bound human C-reactive proteins. Biochem Biophys Res Commun 288:75–79

    PubMed  Google Scholar 

  82. Diehl EE, Haines GK 3rd, Radosevich JA, Potempa LA (2000) Immunohistochemical localization of modified C-reactive protein antigen in normal vascular tissue. Am J Med Sci 319:79–83

    PubMed  Google Scholar 

  83. Heuertz RM, Schneider GP, Potempa LA, Webster RO (2005) Native and modified C-reactive protein bind different receptors on human neutrophils. Int J Biochem Cell Biol 37:320–335

    PubMed  Google Scholar 

  84. Devaraj S, Du Clos TW, Jialal I (2005) Binding and internalization of C-reactive protein by Fcgamma receptors on human aortic endothelial cells mediates biological effects. Arterioscler Thromb Vasc Biol 25:1359–1363

    PubMed  Google Scholar 

  85. Dobrinich R, Spagnuolo PJ (1991) Binding of C-reactive protein to human neutrophils. Inhibition of respiratory burst activity. Arthritis Rheum 34:1031–1038

    PubMed  Google Scholar 

  86. Zouki C, Haas B, Chan JS, Potempa LA, Filep JG (2001) Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion. J Immunol 167:5355–5361

    PubMed  Google Scholar 

  87. Potempa LA, Zeller JM, Fiedel BA, Kinoshita CM, Gewurz H (1988) Stimulation of human neutrophils, monocytes, and platelets by modified C-reactive protein (CRP) expressing a neoantigenic specificity. Inflammation 12:391–405

    PubMed  Google Scholar 

  88. Volanakis JE (2001) Human C-reactive protein: expression, structure, and function. Mol Immunol 38:189–197

    PubMed  Google Scholar 

  89. Hack CE, Wolbink GJ, Schalkwijk C, Speijer H, Hermens WT, van den Bosch H (1997) A role for secretory phospholipase A2 and C-reactive protein in the removal of injured cells. Immunol Today 18:111–115

    PubMed  Google Scholar 

  90. Pepys MB, Booth SE, Tennent GA, Butler PJ, Williams DG (1994) Binding of pentraxins to different nuclear structures: C-reactive protein binds to small nuclear ribonucleoprotein particles, serum amyloid P component binds to chromatin and nucleoli. Clin Exp Immunol 97:152–157

    PubMed  Google Scholar 

  91. Robey FA, Jones KD, Steinberg AD (1985) C-reactive protein mediates the solubilization of nuclear DNA by complement in vitro. J Exp Med 161:1344–1356

    PubMed  Google Scholar 

  92. Du Clos TW (1989) C-reactive protein reacts with the U1 small nuclear ribonucleoprotein. J Immunol 143:2553–2559

    PubMed  Google Scholar 

  93. Sheriff A, Gaipl US, Voll RE, Kalden JR, Herrmann M (2004) Apoptosis and systemic lupus erythematosus. Rheum Dis Clin North Am 30:505–527 viii-ix

    PubMed  Google Scholar 

  94. Li SH, Szmitko PE, Weisel RD, Wang CH, Fedak PW, Li RK, Mickle DA, Verma S (2004) C-reactive protein upregulates complement-inhibitory factors in endothelial cells. Circulation 109:833–836

    PubMed  Google Scholar 

  95. Gershov D, Kim S, Brot N, Elkon KB (2000) C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med 192:1353–1364

    PubMed  Google Scholar 

  96. Marnell L, Mold C, Du Clos TW (2005) C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 117:104–111

    PubMed  Google Scholar 

  97. Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M, Krausz T, Pepys MB (1999) C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 190:1733–1740

    PubMed  Google Scholar 

  98. Janko C, Schorn C, Weidner D, Sarter K, Chaurio R, Sheriff A, Schett G, Munoz LE (2009) Treatment with DNAse I fosters binding to nec PBMC of CRP. Autoimmunity 42:286–288

    PubMed  Google Scholar 

  99. Van Molle W, Denecker G, Rodriguez I, Brouckaert P, Vandenabeele P, Libert C (1999) Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins. J Immunol 163:5235–5241

    PubMed  Google Scholar 

  100. Szalai AJ (2004) C-reactive protein (CRP) and autoimmune disease: facts and conjectures. Clin Dev Immunol 11:221–226

    PubMed  Google Scholar 

  101. Nakayama S, Du Clos TW, Gewurz H, Mold C (1984) Inhibition of antibody responses to phosphocholine by C-reactive protein. J Immunol 132:1336–1340

    PubMed  Google Scholar 

  102. Xia D, Samols D (1997) Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia. Proc Natl Acad Sci USA 94:2575–2580

    PubMed  Google Scholar 

  103. Mold C, Rodriguez W, Rodic-Polic B, Du Clos TW (2002) C-reactive protein mediates protection from lipopolysaccharide through interactions with Fc gamma R. J Immunol 169:7019–7025

    PubMed  Google Scholar 

  104. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP (2006) Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440:1217–1221

    PubMed  Google Scholar 

  105. ter Borg EJ, Horst G, Limburg PC, van Rijswijk MH, Kallenberg CG (1990) C-reactive protein levels during disease exacerbations and infections in systemic lupus erythematosus: a prospective longitudinal study. J Rheumatol 17:1642–1648

    PubMed  Google Scholar 

  106. Pepys MB, Lanham JG, De Beer FC (1982) C-reactive protein in SLE. Clin Rheum Dis 8:91–103

    PubMed  Google Scholar 

  107. Russell AI, Cunninghame Graham DS, Shepherd C, Roberton CA, Whittaker J, Meeks J, Powell RJ, Isenberg DA, Walport MJ, Vyse TJ (2004) Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet 13:137–147

    PubMed  Google Scholar 

  108. Das T, Sen AK, Kempf T, Pramanik SR, Mandal C (2003) Induction of glycosylation in human C-reactive protein under different pathological conditions. Biochem J 373:345–355

    PubMed  Google Scholar 

  109. Rordorf C, Schnebli HP, Baltz ML, Tennent GA, Pepys MB (1982) The acute-phase response in (NZB X NZW)F1 and MRL/l MICE. J Exp Med 156:1268–1273

    PubMed  Google Scholar 

  110. Ogden CA, Elkon KB (2005) Single-dose therapy for lupus nephritis: C-reactive protein, nature’s own dual scavenger and immunosuppressant. Arthritis Rheum 52:378–381

    PubMed  Google Scholar 

  111. Rodriguez W, Mold C, Kataranovski M, Hutt J, Marnell LL, Du Clos TW (2005) Reversal of ongoing proteinuria in autoimmune mice by treatment with C-reactive protein. Arthritis Rheum 52:642–650

    PubMed  Google Scholar 

  112. Szalai AJ, Weaver CT, McCrory MA, van Ginkel FW, Reiman RM, Kearney JF, Marion TN, Volanakis JE (2003) Delayed lupus onset in (NZB x NZW)F1 mice expressing a human C-reactive protein transgene. Arthritis Rheum 48:1602–1611

    PubMed  Google Scholar 

  113. Du Clos TW, Zlock LT, Hicks PS, Mold C (1994) Decreased autoantibody levels and enhanced survival of (NZB × NZW) F1 mice treated with C-reactive protein. Clin Immunol Immunopathol 70:22–27

    PubMed  Google Scholar 

  114. Bell SA, Faust H, Schmid A, Meurer M (1998) Autoantibodies to C-reactive protein (CRP) and other acute-phase proteins in systemic autoimmune diseases. Clin Exp Immunol 113:327–332

    PubMed  Google Scholar 

  115. Sjowall C, Eriksson P, Almer S, Skogh T (2002) Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjogren’s syndrome, rheumatoid arthritis or inflammatory bowel disease. J Autoimmun 19:155–160

    PubMed  Google Scholar 

  116. Rosenau BJ, Schur PH (2006) Antibodies to C reactive protein. Ann Rheum Dis 65:674–676

    PubMed  Google Scholar 

  117. Clancy RM, Neufing PJ, Zheng P, O’Mahony M, Nimmerjahn F, Gordon TP, Buyon JP (2006) Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block. J Clin Invest 116:2413–2422

    PubMed  Google Scholar 

  118. Sjowall C, Bengtsson AA, Sturfelt G, Skogh T (2004) Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus. Arthritis Res Ther 6:R87–R94

    PubMed  Google Scholar 

  119. Dieker JW, van der Vlag J, Berden JH (2002) Triggers for anti-chromatin autoantibody production in SLE. Lupus 11:856–864

    PubMed  Google Scholar 

  120. Munoz LE, van Bavel C, Franz S, Berden J, Herrmann M, van der Vlag J (2008) Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus 17:371–375

    PubMed  Google Scholar 

  121. Radic M, Marion T, Monestier M (2004) Nucleosomes are exposed at the cell surface in apoptosis. J Immunol 172:6692–6700

    PubMed  Google Scholar 

  122. Casciola-Rosen LA, Anhalt G, Rosen A (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179:1317–1330

    PubMed  Google Scholar 

  123. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277

    PubMed  Google Scholar 

  124. Solomon DH, Kavanaugh AJ, Schur PH (2002) Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum 47:434–444

    PubMed  Google Scholar 

  125. Hahn BH (1998) Antibodies to DNA. N Engl J Med 338:1359–1368

    PubMed  Google Scholar 

  126. Swaak T, Smeenk R (1985) Detection of anti-dsDNA as a diagnostic tool: a prospective study in 441 non-systemic lupus erythematosus patients with anti-dsDNA antibody (anti-dsDNA). Ann Rheum Dis 44:245–251

    PubMed  Google Scholar 

  127. Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T (2005) Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis Rheum 52:1129–1137

    PubMed  Google Scholar 

  128. Winkler TH, Jahn S, Kalden JR (1991) IgG human monoclonal anti-DNA autoantibodies from patients with systemic lupus erythematosus. Clin Exp Immunol 85:379–385

    PubMed  Google Scholar 

  129. Winkler TH, Fehr H, Kalden JR (1992) Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas. Eur J Immunol 22:1719–1728

    PubMed  Google Scholar 

  130. Herrmann M, Winkler TH, Fehr H, Kalden JR (1995) Preferential recognition of specific DNA motifs by anti-double-stranded DNA autoantibodies. Eur J Immunol 25:1897–1904

    PubMed  Google Scholar 

  131. Koffler D, Schur PH, Kunkel HG (1967) Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126:607–624

    PubMed  Google Scholar 

  132. Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A (2007) Fifty years of anti-ds DNA antibodies: are we approaching journey’s end? Rheumatology (Oxford) 46:1052–1056

    Google Scholar 

  133. Raz E, Brezis M, Rosenmann E, Eilat D (1989) Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney. J Immunol 142:3076–3082

    PubMed  Google Scholar 

  134. Ehrenstein MR, Katz DR, Griffiths MH, Papadaki L, Winkler TH, Kalden JR, Isenberg DA (1995) Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kidney Int 48:705–711

    PubMed  Google Scholar 

  135. Mjelle JE, Kalaaji M, Rekvig OP (2009) Exposure of chromatin and not high affinity for dsDNA determines the nephritogenic impact of anti-dsDNA antibodies in (NZB × NZW)F1 mice. Autoimmunity 42:104–111

    PubMed  Google Scholar 

  136. Ravirajan CT, Rowse L, MacGowan JR, Isenberg DA (2001) An analysis of clinical disease activity and nephritis-associated serum autoantibody profiles in patients with systemic lupus erythematosus: a cross-sectional study. Rheumatology (Oxford) 40:1405–1412

    Google Scholar 

  137. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–1533

    PubMed  Google Scholar 

  138. ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CG (1990) Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum 33:634–643

    PubMed  Google Scholar 

  139. Mackworth-Young CG, Chan JK, Bunn CC, Hughes GR, Gharavi AE (1986) Complement fixation by anti-dsDNA antibodies in SLE: measurement by radioimmunoassay and relationship with disease activity. Ann Rheum Dis 45:314–318

    PubMed  Google Scholar 

  140. Kramers C, Hylkema MN, van Bruggen MC, van de Lagemaat R, Dijkman HB, Assmann KJ, Smeenk RJ, Berden JH (1994) Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo. J Clin Invest 94:568–577

    PubMed  Google Scholar 

  141. Zhao Z, Weinstein E, Tuzova M, Davidson A, Mundel P, Marambio P, Putterman C (2005) Cross-reactivity of human lupus anti-DNA antibodies with alpha-actinin and nephritogenic potential. Arthritis Rheum 52:522–530

    PubMed  Google Scholar 

  142. Jacob CO, Zang S, Li L, Ciobanu V, Quismorio F, Mizutani A, Satoh M, Koss M (2003) Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol 171:1564–1571

    PubMed  Google Scholar 

  143. Berkel AI, Petry F, Sanal O, Tinaztepe K, Ersoy F, Bakkaloglu A, Loos M (1997) Development of systemic lupus erythematosus in a patient with selective complete C1q deficiency. Eur J Pediatr 156:113–115

    PubMed  Google Scholar 

  144. Mevorach D (2000) Opsonization of apoptotic cells. Implications for uptake and autoimmunity. Ann N Y Acad Sci 926:226–235

    PubMed  Google Scholar 

  145. Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies [see comments]. Nat Genet 19:56–59

    PubMed  Google Scholar 

  146. Vlahakos D, Foster MH, Ucci AA, Barrett KJ, Datta SK, Madaio MP (1992) Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo. J Am Soc Nephrol 2:1345–1354

    PubMed  Google Scholar 

  147. Zack DJ, Stempniak M, Wong AL, Taylor C, Weisbart RH (1996) Mechanisms of cellular penetration and nuclear localization of an anti-double strand DNA autoantibody. J Immunol 157:2082–2088

    PubMed  Google Scholar 

  148. Rumore PM, Steinman CR (1990) Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest 86:69–74

    PubMed  Google Scholar 

  149. Munoz LE, Janko C, Grossmayer GE, Frey B, Voll RE, Kern P, Kalden JR, Schett G, Fietkau R, Herrmann M, Gaipl US (2009) Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus. Arthritis Rheum 60:1733–1742

    PubMed  Google Scholar 

  150. Frisoni L, McPhie L, Colonna L, Sriram U, Monestier M, Gallucci S, Caricchio R (2005) Nuclear autoantigen translocation and autoantibody opsonization lead to increased dendritic cell phagocytosis and presentation of nuclear antigens: a novel pathogenic pathway for autoimmunity? J Immunol 175:2692–2701

    PubMed  Google Scholar 

  151. Grossmayer GE, Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, Herrmann M (2005) Removal of dying cells and systemic lupus erythematosus. Mod Rheumatol 15:383–390

    PubMed  Google Scholar 

  152. Sarmiento LF, Munoz LE, Chirinos P, Bianco NE, Zabaleta-Lanz ME (2007) Opsonization by anti-dsDNA antibodies of apoptotic cells in systemic lupus erythematosus. Autoimmunity 40:337–339

    PubMed  Google Scholar 

  153. Grazia Cappiello M, Sutterwala FS, Trinchieri G, Mosser DM, Ma X (2001) Suppression of Il-12 transcription in macrophages following Fc gamma receptor ligation. J Immunol 166:4498–4506

    PubMed  Google Scholar 

  154. Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L (2004) Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 50:1861–1872

    PubMed  Google Scholar 

  155. Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443:998–1002

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by the “Deutsche Forschungsgemeinschaft” (HE 4490/3-1 and SFB 643-project B5), by the Training Grant SFB GK 643, by the Interdisciplinary Center for Clinical Research (IZKF) (N2) at the University Hospital of the Friedrich-Alexander University, by an intramural grant (ELAN-fonds M3-09.03.18.1) of the Medical Faculty of the Friedrich-Alexander University and by the K. und R. Wucherpfennigstiftung.

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Authors and Affiliations

  1. Department for Internal Medicine 3, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054, Erlangen, Germany

    Kristin Kruse, Christina Janko, Georg Schett, Luis E. Muñoz & Martin Herrmann

  2. IZKF Research Group N2, Nikolaus-Fiebiger-Center for Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, 91054, Erlangen, Germany

    Vilma Urbonaviciute & Reinhard E. Voll

  3. Hematopoiesis Unit, Department of Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, 91054, Erlangen, Germany

    Thomas H. Winkler

  4. Center of Medical Physics and Technology, Biophysics Group, Friedrich-Alexander University of Erlangen-Nuremberg, 91052, Erlangen, Germany

    Claudia T. Mierke

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  1. Kristin Kruse
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  2. Christina Janko
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  3. Vilma Urbonaviciute
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  7. Georg Schett
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  8. Luis E. Muñoz
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  9. Martin Herrmann
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Correspondence to Luis E. Muñoz.

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Luis E. Muñoz and Martin Herrmann equally contributed as senior authors.

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Kruse, K., Janko, C., Urbonaviciute, V. et al. Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis 15, 1098–1113 (2010). https://doi.org/10.1007/s10495-010-0478-8

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