Immunologic Research

, Volume 55, Issue 1–3, pp 10–21

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

Immunology in Colorado

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.

Keywords

SLE Autoantibodies Anti-dsDNA antibodies Complement Clearance 

References

  1. 1.
    Rahman A, Isenberg DA. Systemic lupus erythematosus. New Engl J Med. 2008;358(9):929–39.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.Google Scholar
  4. 4.
    Holborow EJ, Weir DM, Johnson GD. A serum factor in lupus erythematosus with affinity for tissue nuclei. BMJ. 1957;2(5047):732–4.PubMedGoogle Scholar
  5. 5.
    Koffler D, Schur PH, Kunkel HG. Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med. 1967;126(4):607–24.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 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.Google Scholar
  8. 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. 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.Google Scholar
  10. 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.PubMedGoogle Scholar
  11. 11.
    Hahn BH. Antibodies to DNA. New Engl J Med. 1998;338(19):1359–68.PubMedGoogle Scholar
  12. 12.
    McCarty GA, Rice JR, Bembe ML, Pisetsky DS. Independent expression of autoantibodies in systemic lupus erythematosus. J Rheumatol. 1982;9:691–5.PubMedGoogle Scholar
  13. 13.
    Cooper MD, Herrin BR. How did our complex immune system evolve? Nat Rev Immunol. 2011;10(1):2–3.Google Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.Google Scholar
  18. 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.PubMedGoogle Scholar
  19. 19.
    Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheum. 2008;4(9):491–8.Google Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 22.
    Yurasov S, Nussenzweig MC. Regulation of autoreactive antibodies. Curr Opin Rheumatol. 2007;19:421–6.PubMedGoogle Scholar
  23. 23.
    Lutz HU, Binder CJ, Kaveri S. Naturally occurring auto-antibodies in homeostasis and disease. Trends Immunol. 2009;30(1):43–51.PubMedGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 33.
    Desai DD, Marion TN. Induction of anti-DNA antibody with DNA-peptide complexes. Int Immunol. 2000;12(11):1569–78.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 41.
    Gasser O, Schifferli Jr A. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood. 2004;104(8):2543–8.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 44.
    Beyer C, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol. 2010;6(1):21–9.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.Google Scholar
  53. 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.PubMedGoogle Scholar
  54. 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. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.PubMedGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 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. 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.PubMedGoogle Scholar
  61. 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. 62.
    Naparstek Y, Plotz PH. The role of autoantibodies in autoimmune disease. Annu Rev Immunol. 1993;11:79–104.PubMedGoogle Scholar
  63. 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.PubMedGoogle Scholar
  64. 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.Google Scholar
  65. 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.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedGoogle Scholar
  69. 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.PubMedGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 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.PubMedGoogle Scholar
  73. 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.Google Scholar
  74. 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.Google Scholar
  75. 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.Google Scholar
  76. 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.PubMedGoogle Scholar
  77. 77.
    The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthr Rheum. 1999;42(4):599–8.Google Scholar
  78. 78.
    LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23(1):155–84.PubMedGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 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.PubMedGoogle Scholar
  81. 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.PubMedGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 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. 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.PubMedGoogle Scholar
  85. 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.Google Scholar
  86. 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.PubMedGoogle Scholar
  87. 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.PubMedGoogle Scholar
  88. 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.PubMedGoogle Scholar
  89. 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.PubMedGoogle Scholar
  90. 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. 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. 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. 93.
    Lachmann PJ, Hughes-Jones NC. Initiation of complement activation. Springer Semin Immun. 1984;7(2):143–62.Google Scholar
  94. 94.
    Reid KBM, Turner MW. Mammalian lectins in activation and clearance mechanisms involving the complement system. Springer Semin Immun. 1994;15(4):307–26.Google Scholar
  95. 95.
    Muller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem. 1988;57(1):321–47.PubMedGoogle Scholar
  96. 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.PubMedGoogle Scholar
  97. 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.PubMedGoogle Scholar
  98. 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.PubMedGoogle Scholar
  99. 99.
    Holers VM. The complement system as a therapeutic target in autoimmunity. Clin Immunol. 2003;107(3):140–51.PubMedGoogle Scholar
  100. 100.
    Stone NM, Williams A, Wilkinson JD, Bird G. Systemic lupus erythematosus with C1q deficiency. Brit J Dermatol. 2000;142(3):521–4.Google Scholar
  101. 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.PubMedGoogle Scholar
  102. 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.PubMedGoogle Scholar
  103. 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.Google Scholar
  104. 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.PubMedGoogle Scholar
  105. 105.
    Botto M. Links between complement deficiency and apoptosis. Arthr Res. 2001;3(4):207–10.Google Scholar
  106. 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.PubMedGoogle Scholar
  107. 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.PubMedGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 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.PubMedGoogle Scholar
  110. 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.PubMedGoogle Scholar
  111. 111.
    Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729–40.PubMedGoogle Scholar
  112. 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.PubMedGoogle Scholar
  113. 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.PubMedGoogle Scholar
  114. 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.PubMedGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedGoogle Scholar
  117. 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.PubMedGoogle Scholar
  118. 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.PubMedGoogle Scholar
  119. 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.Google Scholar
  120. 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.PubMedGoogle Scholar
  121. 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.PubMedGoogle Scholar
  122. 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.PubMedGoogle Scholar
  123. 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.PubMedGoogle Scholar
  124. 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.PubMedGoogle Scholar
  125. 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.PubMedGoogle Scholar
  126. 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.PubMedGoogle Scholar
  127. 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.PubMedGoogle Scholar
  128. 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.PubMedGoogle Scholar
  129. 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.PubMedGoogle Scholar
  130. 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.PubMedGoogle Scholar
  131. 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.PubMedGoogle Scholar
  132. 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.PubMedGoogle Scholar
  133. 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.PubMedGoogle Scholar
  134. 134.
    Tedder TF. Innate and adaptive receptors interact to balance humoral immunity. J Immunol. 2010;184(5):2231–2.PubMedGoogle Scholar
  135. 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.PubMedGoogle Scholar
  136. 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.PubMedGoogle Scholar
  137. 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.PubMedGoogle Scholar
  138. 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.PubMedGoogle Scholar
  139. 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.PubMedGoogle Scholar
  140. 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.PubMedGoogle Scholar
  141. 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.PubMedGoogle Scholar
  142. 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.PubMedGoogle Scholar
  143. 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.PubMedGoogle Scholar
  144. 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.Google Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Rheumatology, Departments of Medicine and ImmunologyUniversity of Colorado School of MedicineAuroraUSA

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