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Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus

  • Immunology in Colorado
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Abstract

Systemic lupus erythematosus is a severe autoimmune disease that affects multiple organ systems resulting in diverse symptoms and outcomes. It is characterized by antibody production to a variety of self-antigens, but it is specifically associated with those against anti-dsDNA. Anti-dsDNA antibodies are present before the onset of clinical disease and are associated with severe manifestations of lupus such as glomerulonephritis. Their levels fluctuate with changes in disease activity and, in combination with the levels of complement proteins C3 and C4, are strong indicators of disease flare and treatment response in patients with lupus. The decreased complement levels that are noted during flares of lupus activity are believed to be secondary to increased autoantibody production and immune complex formation that results in tissue damage; however, recent data suggest that complement activation can also drive development of these pathogenic autoantibodies. This review will explore the various roles of complement in the development and pathogenesis of anti-dsDNA antibodies.

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References

  1. Rahman A, Isenberg DA. Systemic lupus erythematosus. New Engl J Med. 2008;358(9):929–39.

    PubMed  CAS  Google Scholar 

  2. Diamond B, Bloom O, Al Abed Y, Kowal C, Huerta PT, Volpe BT. Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med. 2011;269(1):36–44.

    PubMed  CAS  Google Scholar 

  3. Isenberg DA, Shoenfeld Y, Walport M, Mackworth-Young C, Dudeney C, Todd-Pokropek A, et al. Detection of cross-reactive anti-DNA antibody idiotypes in the serum of systemic lupus erythematosus patients and of their relatives. Arthr Rheum. 1985;28(9):999–1007.

    CAS  Google Scholar 

  4. Holborow EJ, Weir DM, Johnson GD. A serum factor in lupus erythematosus with affinity for tissue nuclei. BMJ. 1957;2(5047):732–4.

    PubMed  CAS  Google Scholar 

  5. Koffler D, Schur PH, Kunkel HG. Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med. 1967;126(4):607–24.

    PubMed  CAS  Google Scholar 

  6. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. New Engl J Med. 2003;349(16):1526–33.

    PubMed  CAS  Google Scholar 

  7. Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T, et al. Relationship between anti–double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthr Rheum. 2005;52(4):1129–37.

    CAS  Google Scholar 

  8. Ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CGM. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. Arthr Rheum. 1990;33(5):634–43.

    Google Scholar 

  9. Ng KP, Manson JJ, Rahman A, Isenberg DA. Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus. Arthr Care Res. 2006;55(6):900–4.

    CAS  Google Scholar 

  10. Swaak AJ, Groenwold J, Bronsveld W. Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis. 1986;45(5):359–66.

    PubMed  CAS  Google Scholar 

  11. Hahn BH. Antibodies to DNA. New Engl J Med. 1998;338(19):1359–68.

    PubMed  CAS  Google Scholar 

  12. McCarty GA, Rice JR, Bembe ML, Pisetsky DS. Independent expression of autoantibodies in systemic lupus erythematosus. J Rheumatol. 1982;9:691–5.

    PubMed  CAS  Google Scholar 

  13. Cooper MD, Herrin BR. How did our complex immune system evolve? Nat Rev Immunol. 2011;10(1):2–3.

    Google Scholar 

  14. Racanelli V, Prete M, Musaraj G, Dammacco F, Perosa F. Autoantibodies to intracellular antigens: generation and pathogenetic role. Autoimmun Rev. 2011;10(8):503–8.

    PubMed  CAS  Google Scholar 

  15. Ehrenstein MR, Katz DR, Griffiths MH, Papadaki L, Winkler TH, Kalden JR, et al. Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kidney Int. 1995;48(3):705–11.

    PubMed  CAS  Google Scholar 

  16. Forger F, Matthias T, Oppermann M, Becker H, Helmke K. Clinical significance of anti-dsDNA antibody isotypes: IgG/IgM ratio of anti-dsDNA antibodies as a prognostic marker for lupus nephritis. Lupus. 2004;13(1):36–44.

    PubMed  CAS  Google Scholar 

  17. Baudino L, Azeredo da Silveira S, Nakata M, Izui S. Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin Immun. 2006;28(2):175–84.

    CAS  Google Scholar 

  18. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science. 2003;301(5638):1374–7.

    PubMed  CAS  Google Scholar 

  19. Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheum. 2008;4(9):491–8.

    CAS  Google Scholar 

  20. Zhou Z-H, Tzioufas AG, Notkins AL. Properties and function of polyreactive antibodies and polyreactive antigen-binding B cells. J Autoimmun. 2007;29(4):219–28.

    PubMed  CAS  Google Scholar 

  21. Zhou Z-H, Zhang Y, Hu Y-F, Wahl LM, Cisar JO, Notkins AL. The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies. Cell Host Microbe. 2007;1(1):51–61.

    PubMed  CAS  Google Scholar 

  22. Yurasov S, Nussenzweig MC. Regulation of autoreactive antibodies. Curr Opin Rheumatol. 2007;19:421–6.

    PubMed  CAS  Google Scholar 

  23. Lutz HU, Binder CJ, Kaveri S. Naturally occurring auto-antibodies in homeostasis and disease. Trends Immunol. 2009;30(1):43–51.

    PubMed  CAS  Google Scholar 

  24. Winkler TH, Jahn S, Kalden JR. IgG human monoclonal anti-DNA autoantibodies from patients with systemic lupus erythematosus. Clin Exp Immunol. 1991;85(3):379–85.

    PubMed  CAS  Google Scholar 

  25. Winkler TH, Fehr H, Kalden JR. Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas. Eur J Immunol. 1992;22(7):1719–28.

    PubMed  CAS  Google Scholar 

  26. 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 × NZW)F1 mice. J Exp Med. 1992;176(3):761–79.

    PubMed  CAS  Google Scholar 

  27. Shlomchik MJ, Aucoin AH, Pisetsky DS, Weigert MG. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc Natl Acad Sci USA. 1987;84(24):9150–4.

    PubMed  CAS  Google Scholar 

  28. Krishnan MR, Jou NT, Marion TN. Correlation between the amino acid position of arginine in VH-CDR3 and specificity for native DNA among autoimmune antibodies. J Immunol. 1996;157(6):2430–9.

    PubMed  CAS  Google Scholar 

  29. Radic MZ, Mackle J, Erikson J, Mol C, Anderson WF, Weigert M. Residues that mediate DNA binding of autoimmune antibodies. J Immunol. 1993;150(11):4966–77.

    PubMed  CAS  Google Scholar 

  30. Li Z, Schettino EW, Padlan EA, Ikematsu H, Casali P. Structure-function analysis of a lupus anti-DNA autoantibody: central role of the heavy chain complementarity-determining region 3 Arg in binding of double- and single-stranded DNA. Eur J Immunol. 2000;30(7):2015–26.

    PubMed  CAS  Google Scholar 

  31. Shlomchik M, Mascelli M, Shan H, Radic MZ, Pisetsky D, Marshak-Rothstein A, et al. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med. 1990;171(1):265–92.

    PubMed  CAS  Google Scholar 

  32. Desai DD, Krishnan MR, Swindle JT, Marion TN. Antigen-specific induction of antibodies against native mammalian DNA in nonautoimmune mice. J Immunol. 1993;151(3):1614–26.

    PubMed  CAS  Google Scholar 

  33. Desai DD, Marion TN. Induction of anti-DNA antibody with DNA-peptide complexes. Int Immunol. 2000;12(11):1569–78.

    PubMed  CAS  Google Scholar 

  34. 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. 1994;179(4):1317–30.

    PubMed  CAS  Google Scholar 

  35. Kruse K, Janko C, Urbonaviciute V, Mierke C, Winkler T, Voll R, et al. Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis. 2010;15(9):1098–113.

    PubMed  CAS  Google Scholar 

  36. Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, et al. SLE-a disease of clearance deficiency? Rheumatology. 2005;44(9):1101–7.

    PubMed  CAS  Google Scholar 

  37. Mevorach D, Zhou JL, Song X, Elkon KB. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J Exp Med. 1998;188(2):387–92.

    PubMed  CAS  Google Scholar 

  38. Oshima K, Aoki N, Kato T, Kitajima K, Matsuda T. Secretion of a peripheral membrane protein, MFG-E8, as a complex with membrane vesicles. Eur J Biochem. 2002;269(4):1209–18.

    PubMed  CAS  Google Scholar 

  39. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002;417(6885):182–7.

    PubMed  CAS  Google Scholar 

  40. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004;304(5674):1147–50.

    PubMed  CAS  Google Scholar 

  41. Gasser O, Schifferli Jr A. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood. 2004;104(8):2543–8.

    PubMed  CAS  Google Scholar 

  42. MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A. Rapid secretion of interleukin-1β by microvesicle shedding. Immunity. 2001;15(5):825–35.

    PubMed  CAS  Google Scholar 

  43. Mack M, Kleinschmidt A, Bruhl H, Klier C, Nelson PJ, Cihak J, et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med. 2000;6(7):769–75.

    PubMed  CAS  Google Scholar 

  44. Beyer C, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol. 2010;6(1):21–9.

    PubMed  CAS  Google Scholar 

  45. Thomas LM, Salter RD. Activation of macrophages by P2X7-induced microvesicles from myeloid cells is mediated by phospholipids and is partially dependent on TLR4. J Immunol. 2010;185(6):3740–9.

    PubMed  CAS  Google Scholar 

  46. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.

    PubMed  CAS  Google Scholar 

  47. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41.

    PubMed  CAS  Google Scholar 

  48. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463–9.

    PubMed  CAS  Google Scholar 

  49. Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol. 2011;13(2):170–80.

    PubMed  Google Scholar 

  50. Hakkim A, Funrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA. 2010;107(21):9813–8.

    PubMed  CAS  Google Scholar 

  51. Jeong SJ, Choi H, Lee HS, Han SH, Chin BS, Baek J-H, et al. Incidence and risk factors of infection in a single cohort of 110 adults with systemic lupus erythematosus. Scand J Infect Dis. 2009;41(4):268–74.

    PubMed  Google Scholar 

  52. James JA, Neas BR, Moser KL, Hall T, Bruner GR, Sestak AL, et al. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthr Rheum. 2001;44(5):1122–6.

    CAS  Google Scholar 

  53. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest. 1997;100(12):3019–26.

    PubMed  CAS  Google Scholar 

  54. Füst G. The role of the Epstein-Barr virus in the pathogenesis of some autoimmune disorders—similarities and differences. Eur J Microbiol Immunol. 2011;1(4):267–78.

    Google Scholar 

  55. Peters AL, Stunz LL, Meyerholz DK, Mohan C, Bishop GA. Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice. J Immunol. 2010;185(7):4053–62.

    PubMed  CAS  Google Scholar 

  56. Dykstra ML, Longnecker R, Pierce SK. Epstein-barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR. Immunity. 2001;14(1):57–67.

    PubMed  CAS  Google Scholar 

  57. Swanson-Mungerson M, Bultema R, Longnecker R. Epstein-barr virus LMP2A enhances B-cell responses in vivo and in vitro. J Virol. 2006;80(14):6764–70.

    PubMed  CAS  Google Scholar 

  58. Yadav P, Tran H, Ebegbe R, Gottlieb P, Wei H, Lewis RH, et al. Antibodies elicited in response to EBNA-1 may cross-react with dsDNA. PLoS ONE. 2011;6(1):e14488.

    PubMed  CAS  Google Scholar 

  59. Shoenfeld Y, Vilner Y, Coates ARM, Rauch J, Lavie G, Shaul D, et al. Monoclonal anti-tuberculosis antibodies react with DNA and monoclonal anti-DNA autoantibodies react with Mycobacterium tuberculosis. Clin Exp Immunol. 1986;66:1–265.

    Google Scholar 

  60. Sharma A, Isenberg DA, Diamond B. Crossreactivity of human anti-dsDNA antibodies to phosphorylcholine: clues to their origin. J Autoimmun. 2001;16(4):479–84.

    PubMed  CAS  Google Scholar 

  61. Zhang W, Reichlin M. A possible link between infection with Burkholderia bacteria and systemic lupus erythematosus based on epitope mimicry. Clin Dev Immunol. 2008. doi:10.1155/2008/683489.

  62. Naparstek Y, Plotz PH. The role of autoantibodies in autoimmune disease. Annu Rev Immunol. 1993;11:79–104.

    PubMed  CAS  Google Scholar 

  63. Ravirajan CT, Rowse L, MacGowan JR, Isenberg DA. An analysis of clinical disease activity and nephritis-associated serum autoantibody profiles in patients with systemic lupus erythematosus: a cross-sectional study. Rheumatology. 2001;40(12):1405–12.

    PubMed  CAS  Google Scholar 

  64. Isenberg DA, Garton M, Reichlin MW, Reichlin M. Long-term follow-up of autoantibody profiles in black female lupus patients and clinical comparison with Caucasian and Asian patients. Rheumatology. 1997;36(2):229–33.

    CAS  Google Scholar 

  65. Okamura M, Kanayama Y, Amastu K, Negoro N, Kohda S, Takeda T, et al. Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology. Ann Rheum Dis. 1993;52(1):14–20.

    PubMed  CAS  Google Scholar 

  66. Vlahakos D, Foster MH, Ucci AA, Barrett KJ, Datta SK, Madaio MP. Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo. J Am Soc Nephrol. 1992;2(8):1345–54.

    PubMed  CAS  Google Scholar 

  67. Zack DJ, Stempniak M, Wong AL, Taylor C, Weisbart RH. Mechanisms of cellular penetration and nuclear localization of an anti- double strand DNA autoantibody. J Immunol. 1996;157(5):2082–8.

    PubMed  CAS  Google Scholar 

  68. Ruiz-Arguelles A, Perez-Romano B, Llorente L, Alarcon-Segovia D, Castellanos JM. Penetration of anti-DNA antibodies into immature live cells. J Autoimmun. 1998;11(5):547–56.

    PubMed  CAS  Google Scholar 

  69. Madaio MP, Yanase K. Cellular penetration and nuclear localization of anti-DNA antibodies: mechanisms, consequences, implications and applications. J Autoimmun. 1998;11(5):535–8.

    PubMed  CAS  Google Scholar 

  70. Yanase K, Smith RM, Puccetti A, Jarett L, Madaio MP. Receptor-mediated cellular entry of nuclear localizing anti-DNA antibodies via myosin 1. J Clin Invest. 1997;100(1):25–31.

    PubMed  CAS  Google Scholar 

  71. Song Y-C, Sun G-H, Lee T-P, Huang JC, Yu C-L, Chen C-H, et al. Arginines in the CDR of anti-dsDNA autoantibodies facilitate cell internalization via electrostatic interactions. Eur J Immunol. 2008;38(11):3178–90.

    PubMed  CAS  Google Scholar 

  72. Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A. Fifty years of anti-ds DNA antibodies: are we approaching journey’s end? Rheumatology. 2007;46(7):1052–6.

    PubMed  CAS  Google Scholar 

  73. Renaudineau Y, Croquefer S, Jousse S, Renaudineau E, Devauchelle V, Guéguen P, et al. Association of α-actinin–binding anti–double-stranded DNA antibodies with lupus nephritis. Arthr Rheum. 2006;54(8):2523–32.

    CAS  Google Scholar 

  74. Mason LJ, Ravirajan CT, Rahman A, Putterman C, Isenberg DA. Is α-actinin a target for pathogenic anti-DNA antibodies in lupus nephritis? Arthr Rheum. 2004;50(3):866–70.

    CAS  Google Scholar 

  75. Zhao Z, Weinstein E, Tuzova M, Davidson A, Mundel P, Marambio P, et al. Cross-reactivity of human lupus anti-DNA antibodies with α-actinin and nephritogenic potential. Arthr Rheum. 2005;52(2):522–30.

    CAS  Google Scholar 

  76. Scherzer CR, Landwehrmeyer GB, Kerner JA, Counihan TJ, Kosinski CM, Standaert DG, et al. Expression of N-Methyl-D-Aspartate receptor subunit mRNAs in the human brain: Hippocampus and cortex. J Comp Neurol. 1998;390(1):75–90.

    PubMed  CAS  Google Scholar 

  77. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthr Rheum. 1999;42(4):599–8.

    Google Scholar 

  78. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23(1):155–84.

    PubMed  CAS  Google Scholar 

  79. Kowal C, DeGiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT, et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci USA. 2006;103(52):19854–9.

    PubMed  CAS  Google Scholar 

  80. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nat Rev Immunol. 2009;9(6):449–56.

    PubMed  CAS  Google Scholar 

  81. DeGiorgio LA. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001;7:1189–93.

    PubMed  CAS  Google Scholar 

  82. Bardana EJ, Harbeck RJ, Hoffman AA, Pirofsky B, Carr RI. The prognostic and therapeutic implications of DNA:anti-DNA immune complexes in systemic lupus erythematosus (SLE). Am J Med. 1975;59(4):515–22.

    PubMed  Google Scholar 

  83. Levinsky RJ, Cameron JS, Soothill JF. Serum immune complexes and disease activity in lupus nephritis. Lancet. 1977;309(8011):564–7.

    Google Scholar 

  84. Rumore PM, Steinman CR. Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest. 1990;86(1):69–74.

    PubMed  CAS  Google Scholar 

  85. Amoura Z, Piette J-C, Chabre H, Cacoub P, Papo T, Wechsler B, et al. Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus. Correlation with serum antinucleosome antibody titers and absence of clear association with disease activity. Arthr Rheum. 1997;40(12):2217–25.

    CAS  Google Scholar 

  86. Kramers C, Hylkema MN, van Bruggen MC, van de Lagemaat R, Dijkman HB, Assmann KJ, et al. Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo. J Clin Invest. 1994;94(2):568–77.

    PubMed  CAS  Google Scholar 

  87. Kalaaji M, Mortensen E, Jorgensen L, Olsen R, Rekvig OP. Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells. Am J Pathol. 2006;168(6):1779–92.

    PubMed  CAS  Google Scholar 

  88. Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol. 2006;7(1):49–56.

    PubMed  CAS  Google Scholar 

  89. Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, Luster AD. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest. 2005;115(2):407–17.

    PubMed  CAS  Google Scholar 

  90. Ronnblom L, Alm G. Systemic lupus erythematosus and the type I interferon system. Arthr Res Ther. 2003;5(2):68–75.

    Google Scholar 

  91. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3(73):73ra20.

    Google Scholar 

  92. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3(73):73ra19.

    Google Scholar 

  93. Lachmann PJ, Hughes-Jones NC. Initiation of complement activation. Springer Semin Immun. 1984;7(2):143–62.

    CAS  Google Scholar 

  94. Reid KBM, Turner MW. Mammalian lectins in activation and clearance mechanisms involving the complement system. Springer Semin Immun. 1994;15(4):307–26.

    CAS  Google Scholar 

  95. Muller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem. 1988;57(1):321–47.

    PubMed  CAS  Google Scholar 

  96. Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol. 2004;22(1):431–56.

    PubMed  CAS  Google Scholar 

  97. Molina H, Holers VM, Li B, Fung Y, Mariathasan S, Goellner J, et al. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc Natl Acad Sci USA. 1996;93(8):3357–61.

    PubMed  CAS  Google Scholar 

  98. Kaya Z, Afanasyeva M, Wang Y, Dohmen KM, Schlichting J, Tretter T, et al. Contribution of the innate immune system to autoimmune myocarditis: a role for complement. Nat Immunol. 2001;2(8):739–45.

    PubMed  CAS  Google Scholar 

  99. Holers VM. The complement system as a therapeutic target in autoimmunity. Clin Immunol. 2003;107(3):140–51.

    PubMed  CAS  Google Scholar 

  100. Stone NM, Williams A, Wilkinson JD, Bird G. Systemic lupus erythematosus with C1q deficiency. Brit J Dermatol. 2000;142(3):521–4.

    CAS  Google Scholar 

  101. Dragon-Durey MA, Quartier P, Fremeaux-Bacchi V, Blouin J, de Barace C. Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. J Immunol. 2001;166(12):7612–6.

    PubMed  CAS  Google Scholar 

  102. Rupert KL, Moulds JM, Yang Y, Arnett FC, Warren RW, Reveille JD, et al. The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes. J Immunol. 2002;169(3):1570–8.

    PubMed  CAS  Google Scholar 

  103. Kristjansdottir H, Saevarsdottir S, Gröndal G, Alarcón-Riquelme ME, Erlendsson K, Valdimarsson H, et al. Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in icelandic multicase systemic lupus erythematosus families. Arthr Rheum. 2008;58(12):3865–72.

    CAS  Google Scholar 

  104. Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998;188(12):2313–20.

    PubMed  CAS  Google Scholar 

  105. Botto M. Links between complement deficiency and apoptosis. Arthr Res. 2001;3(4):207–10.

    CAS  Google Scholar 

  106. Botto M, Dell’ Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998;19(1):56–9.

    PubMed  CAS  Google Scholar 

  107. Schifferli JA, Steiger G, Hauptmann G, Spaeth PJ, Sjoholm AG. Formation of soluble immune complexes by complement in sera of patients with various hypocomplementemic states. Difference between inhibition of immune precipitation and solubilization. J Clin Invest. 1985;76(6):2127–33.

    PubMed  CAS  Google Scholar 

  108. Watanabe H, Garnier G, Circolo A, Wetsel RA, Ruiz P, Holers VM, et al. Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B. J Immunol. 2000;164(2):786–94.

    PubMed  CAS  Google Scholar 

  109. Elliott MK, Jarmi T, Ruiz P, Xu Y, Holers VM, Gilkeson GS. Effects of complement factor D deficiency on the renal disease of MRL//lpr mice. Kidney Int. 2004;65(1):129–38.

    PubMed  CAS  Google Scholar 

  110. Harboe M, Ulvund G, Vien L, Fung M, Mollnes TE. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin Exp Immunol. 2004;138(3):439–46.

    PubMed  CAS  Google Scholar 

  111. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729–40.

    PubMed  CAS  Google Scholar 

  112. Bao L, Haas M, Quigg RJ. Complement factor H deficiency accelerates development of lupus nephritis. J Am Soc Nephrol. 2011;22(2):285–95.

    PubMed  Google Scholar 

  113. Zhao J, Wu H, Khosravi M, Cui H, Qian X, Kelly JA, et al. Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. PLoS Genet. 2011;7(5):e1002079.

    PubMed  CAS  Google Scholar 

  114. Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse H-M, Schirmer S, et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood. 2009;114(12):2439–47. doi:10.1182/blood-2009-02-205641.

    PubMed  CAS  Google Scholar 

  115. Fritsche LG, Lauer N, Hartmann A, Stippa S, Keilhauer CN, Oppermann M, et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum Mol Genet. 2010;19(23):4694–704. doi:10.1093/hmg/ddq399.

    PubMed  CAS  Google Scholar 

  116. Hebecker M, Jozsi M. Factor H-related protein 4 activates complement by serving as a platform for the assembly of alternative pathway C3 convertase via its interaction with C3b protein. J Biol Chem. 2012;287(23):19528–36. doi:10.1074/jbc.M112.364471.

    PubMed  CAS  Google Scholar 

  117. Dragon-Durey M-A, Loirat C, Cloarec S, Macher M-A, Blouin J, Nivet H, et al. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(2):555–63.

    PubMed  CAS  Google Scholar 

  118. Jozsi M, Strobel S, Dahse H-M, Liu W-S, Hoyer PF, Oppermann M, et al. Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood. 2007;110(5):1516–8.

    PubMed  CAS  Google Scholar 

  119. Nielsen CT, Østergaard O, Stener L, Iversen LV, Truedsson L, Gullstrand B, et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthr Rheum. 2012;64(4):1227–36.

    CAS  Google Scholar 

  120. Leffler J, Martin M, Gullstrand B, Tyden H, Lood C, Truedsson L, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol. 2012;188(7):3522–31.

    PubMed  CAS  Google Scholar 

  121. Henderson AL, Lindorfer MA, Kennedy AD, Foley PL, Taylor RP. Concerted clearance of immune complexes bound to the human erythrocyte complement receptor: development of a heterologous mouse model. J Immunol Methods. 2002;270(2):183–97.

    PubMed  CAS  Google Scholar 

  122. Iida K, Mornaghi R, Nussenzweig V. Complement receptor (CR1) deficiency in erythrocytes from patients with systemic lupus erythematosus. J Exp Med. 1982;155(5):1427–38.

    PubMed  CAS  Google Scholar 

  123. Wagner C, Hänsch GM, Stegmaier S, Denefleh B, Hug F, Schoels M. The complement receptor 3, CR3 (CD11b/CD18), on T lymphocytes: activation-dependent up-regulation and regulatory function. Eur J Immunol. 2001;31(4):1173–80.

    PubMed  CAS  Google Scholar 

  124. Ueda T, Rieu P, Brayer J, Arnaout MA. Identification of the complement iC3b binding site in the beta 2 integrin CR3 (CD11b/CD18). Proc Natl Acad Sci USA. 1994;91(22):10680–4.

    PubMed  CAS  Google Scholar 

  125. Nath SK, Han S, Kim-Howard X, Kelly JA, Viswanathan P, Gilkeson GS, et al. A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet. 2008;40(2):152–4.

    PubMed  CAS  Google Scholar 

  126. Kim-Howard X, Maiti AK, Anaya J-M, Bruner GR, Brown E, Merrill JT, et al. ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash and immunological manifestations in patients with systemic lupus erythematosus with European ancestry. Ann Rheum Dis. 2010;69(7):1329–32.

    PubMed  Google Scholar 

  127. Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Deicher H, et al. IgM anti-dsDNA antibodies in systemic lupus erythematosus: negative association with nephritis. Rheumatol Int. 1998;18(3):85–91.

    PubMed  CAS  Google Scholar 

  128. Buyon JP, Shadick N, Berkman R, Hopkins P, Dalton J, Weissmann G, et al. Surface expression of Gp 165/95, the complement receptor CR3, as a marker of disease activity in systemic lupus erythematosus. Clin Immunol Immunopathol. 1988;46:141–9.

    PubMed  CAS  Google Scholar 

  129. Camous L, Roumenina L, Bigot S, Brachemi S, Fremeaux-Bacchi V, Lesavre P, et al. Complement alternative pathway acts as a positive feedback amplification of neutrophil activation. Blood. 2011;117(4):1340–9.

    PubMed  CAS  Google Scholar 

  130. Carter RH, Spycher MO, Ng YC, Hoffman R, Fearon DT. Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J Immunol. 1988;141(2):457–63.

    PubMed  CAS  Google Scholar 

  131. Ross TM, Xu Y, Bright RA, Robinson HL. C3d enhancement of antibodies to hemagglutinin accelerates protection against influenza virus challenge. Nat Immunol. 2000;1(2):127–31.

    PubMed  CAS  Google Scholar 

  132. Lee Y, Haas KM, Gor DO, Ding X, Karp DR, Greenspan NS, et al. Complement component C3d-antigen complexes can either augment or inhibit B lymphocyte activation and humoral immunity in mice depending on the degree of CD21/CD19 complex engagement. J Immunol. 2005;175(12):8011–23.

    PubMed  CAS  Google Scholar 

  133. Chakravarty L, Zabel MD, Weis JJ, Weis JH. Depletion of Lyn kinase from the BCR complex and inhibition of B cell activation by excess CD21 ligation. Int Immunol. 2002;14(2):139–46.

    PubMed  CAS  Google Scholar 

  134. Tedder TF. Innate and adaptive receptors interact to balance humoral immunity. J Immunol. 2010;184(5):2231–2.

    PubMed  CAS  Google Scholar 

  135. Prodeus AP, Goerg S, Shen L-M, Pozdnyakova OO, Chu L, Alicot EM, et al. A critical role for complement in maintenance of self-tolerance. Immunity. 1998;9(5):721–31.

    PubMed  CAS  Google Scholar 

  136. Wu X, Jiang N, Deppong C, Singh J, Dolecki G, Mao D, et al. A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus. J Immunol. 2002;169(3):1587–92.

    PubMed  CAS  Google Scholar 

  137. Boackle SA, Holers VM, Chen X, Szakonyi G, Karp DR, Wakeland EK, et al. Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity. 2001;15(5):775–85.

    PubMed  CAS  Google Scholar 

  138. Giles BM, Tchepeleva SN, Kachinski JJ, Ruff K, Croker BP, Morel L, et al. Augmentation of NZB autoimmune phenotypes by the Sle1c murine lupus susceptibility interval. J Immunol. 2007;178(7):4667–75.

    PubMed  CAS  Google Scholar 

  139. Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, et al. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J Allergy Clin Immunol. 2012;129(3):801–10.

    PubMed  CAS  Google Scholar 

  140. Wu H, Boackle SA, Hanvivadhanakul P, Ulgiati D, Grossman JM, Lee Y, et al. Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus. Proc Natl Acad Sci USA. 2007;104(10):3961–6.

    PubMed  CAS  Google Scholar 

  141. Douglas KB, Windels DC, Zhao J, Gadeliya AV, Wu H, Kaufman KM, et al. Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing. Genes Immun. 2009;10(5):457–69.

    PubMed  CAS  Google Scholar 

  142. Liu Y-J, Xu J, de Bouteiller O, Parham CL, Grouard G, Djossou O, et al. Follicular dendritic cells specifically express the long CR2/CD21 isoform. J Exp Med. 1997;185(1):165–70. doi:10.1084/jem.185.1.165.

    PubMed  CAS  Google Scholar 

  143. Atkinson C, Qiao F, Song H, Gilkeson GS, Tomlinson S. Low-dose targeted complement inhibition protects against renal disease and other manifestations of autoimmune disease in MRL/lpr mice. J Immunol. 2008;180(2):1231–8.

    PubMed  CAS  Google Scholar 

  144. Sekine H, Kinser TTH, Qiao F, Martinez E, Paulling E, Ruiz P, et al. The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. Arthr Rheum. 2011;63(4):1076–85.

    CAS  Google Scholar 

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  1. Division of Rheumatology, Departments of Medicine and Immunology, University of Colorado School of Medicine, Mail Stop B-115, Aurora, CO, 80045, USA

    Brendan M. Giles & Susan A. Boackle

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Giles, B.M., Boackle, S.A. Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus. Immunol Res 55, 10–21 (2013). https://doi.org/10.1007/s12026-012-8345-z

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