Skip to main content

Advertisement

Log in

Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Systemic lupus erythematosus (SLE) is a remarkably complex and heterogeneous systemic autoimmune disease. Disease complexity within individuals and heterogeneity among individuals, even genetically identical individuals, is driven by stochastic execution of a complex inherited program. Genome-wide association studies (GWAS) have progressively improved understanding of which genes are most critical to the potential for SLE and provided illuminating insight about the immune mechanisms that are engaged in SLE. What initiates expression of the genetic program to cause SLE within an individual and how that program is initiated remains poorly understood. If we extrapolate from all of the different experimental mouse models for SLE, we can begin to appreciate why SLE is so heterogeneous and consequently why prediction of disease outcome is so difficult. In this review, we critically evaluate extrinsic versus intrinsic cellular functions in the clearance and elimination of cellular debris and how dysfunction in that system may promote autoimmunity to nuclear antigens. We also examine several mouse models genetically prone to SLE either because of natural inheritance or inheritance of induced mutations to illustrate how different immune mechanisms may initiate autoimmunity and affect disease pathogenesis. Finally, we describe the heterogeneity of disease manifestations in SLE and discuss the mechanisms of disease pathogenesis with emphasis on glomerulonephritis. Particular attention is given to discussion of how anti-DNA autoantibody initiates experimental lupus nephritis (LN) in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kotzin BL (1996) Systemic lupus erythematosus. Cell 85(3):303–306

    PubMed  CAS  Google Scholar 

  2. Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y (2004) Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34(2):501–537

    PubMed  CAS  Google Scholar 

  3. Guidelines ACoRAHCoSLE (1999) Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum 42(9):1785–1796

    Google Scholar 

  4. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725. doi:10.1002/1529-0131(199709)40:9<1725::AID-ART29>3.0.CO;2-Y

    PubMed  CAS  Google Scholar 

  5. Stoll T, Seifert B, Isenberg DA (1996) SLICC/ACR Damage Index is valid, and renal and pulmonary organ scores are predictors of severe outcome in patients with systemic lupus erythematosus. Br J Rheumatol 35(3):248–254

    PubMed  CAS  Google Scholar 

  6. 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(11):1271–1277

    PubMed  CAS  Google Scholar 

  7. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sanchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG Jr, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G Jr, Magder LS (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64(8):2677–2686. doi:10.1002/art.34473

    PubMed  PubMed Central  Google Scholar 

  8. Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM, American College of R (2012) American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 64(6):797–808. doi:10.1002/acr.21664

    Google Scholar 

  9. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, Urowitz M, Fortin PR, Petri M, Barr S, Gordon C, Bae SC, Isenberg D, Zoma A, Aranow C, Dooley MA, Nived O, Sturfelt G, Steinsson K, Alarcon G, Senecal JL, Zummer M, Hanly J, Ensworth S, Pope J, Edworthy S, Rahman A, Sibley J, El-Gabalawy H, McCarthy T, St Pierre Y, Clarke A, Ramsey-Goldman R (2006) Mortality in systemic lupus erythematosus. Arthritis Rheum 54(8):2550–2557. doi:10.1002/art.21955

    PubMed  CAS  Google Scholar 

  10. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ (2005) Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 202(2):321–331. doi:10.1084/jem.20050338

    PubMed  CAS  PubMed Central  Google Scholar 

  11. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ (2006) Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25(3):417–428

    PubMed  CAS  Google Scholar 

  12. Shlomchik M, Mascelli M, Shan H, Radic MZ, Pisetsky D, Marshak-Rothstein A, Weigert M (1990) Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med 171:265–297

    PubMed  CAS  Google Scholar 

  13. Tillman DM, Jou NT, Hill RJ, Marion TN (1992) Both IgM and IgG anti-DNA antibodies are the products of clonally selective B cell stimulation in (NZB x NZW)F1 mice. J Exp Med 176(3):761–779

    PubMed  CAS  Google Scholar 

  14. Tan EM (1989) Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 44:93–151

    PubMed  CAS  Google Scholar 

  15. Petri M (2006) Systemic lupus erythematosus: 2006 update. J Clin Rheumatol 12(1):37–40. doi:10.1097/01.rhu.0000200420.67262.04

    PubMed  Google Scholar 

  16. Ward MM (2004) Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third national health and nutrition examination survey. J Womens Health (Larchmt) 13(6):713–718. doi:10.1089/1540999041783208

    Google Scholar 

  17. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, National Arthritis Data W (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I Arthritis Rheum 58(1):15–25. doi:10.1002/art.23177

    Google Scholar 

  18. McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK (1995) Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum 38(9):1260–1270

    PubMed  CAS  Google Scholar 

  19. Contreras G, Lenz O, Pardo V, Borja E, Cely C, Iqbal K, Nahar N, de La Cuesta C, Hurtado A, Fornoni A, Beltran-Garcia L, Asif A, Young L, Diego J, Zachariah M, Smith-Norwood B (2006) Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int 69(10):1846–1851. doi:10.1038/sj.ki.5000243

    PubMed  CAS  Google Scholar 

  20. Franco C, Yoo W, Franco D, Xu Z (2010) Predictors of end stage renal disease in African Americans with lupus nephritis. Bull NYU Hosp Jt Dis 68(4):251–256

    PubMed  Google Scholar 

  21. Klein-Gitelman MS (2011) Pediatric systemic lupus erythematosus. Medscape Reference. http://emedicine.medscape.com/article/1008066-overview-a0101.

  22. Tucker LB, Menon S, Schaller JG, Isenberg DA (1995) Adult- and childhood-onset systemic lupus erythematosus: a comparison of onset, clinical features, serology, and outcome. Br J Rheumatol 34(9):866–872

    PubMed  CAS  Google Scholar 

  23. Brunner HI, Huggins J, Klein-Gitelman MS (2011) Pediatric SLE—towards a comprehensive management plan. Nat Rev Rheumatol 7(4):225–233. doi:10.1038/nrrheum.2011.15

    PubMed  CAS  Google Scholar 

  24. Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ, Murphy ED, Roths JB, Dixon FJ (1978) Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148(5):1198–1215

    PubMed  CAS  Google Scholar 

  25. Rudofsky UH, Evans BD, Balaban SL, Mottironi VD, Gabrielsen AE (1993) Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization. Lab Invest 68(4):419–426

    PubMed  CAS  Google Scholar 

  26. Wakeland EK, Liu K, Graham RR, Behrens TW (2001) Delineating the genetic basis of systemic lupus erythematosus. Immunity 15(3):397–408

    PubMed  CAS  Google Scholar 

  27. Howie JB, Helyer BJ (1968) The immunology and pathology of NZB mice. Adv Immunol 9:215–266

    PubMed  CAS  Google Scholar 

  28. Helyer BJ, Howie JB (1963) Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice. Nature 197:197

    PubMed  CAS  Google Scholar 

  29. Drake CG, Babcock SK, Palmer E, Kotzin BL (1994) Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB x NZW)F1 mice. Proc Natl Acad Sci U S A 91(9):4062–4066

    PubMed  CAS  PubMed Central  Google Scholar 

  30. Knight JG, Adams DD (1978) Three genes for lupus nephritis in NZB x NZW mice. J Exp Med 147:1653–1660

    PubMed  CAS  Google Scholar 

  31. Kono DH, Burlingame RW, Owens DG, Kuramochi A, Balderas RS, Balomenos D, Theofilopoulos AN (1994) Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci U S A 91(21):10168–10172

    PubMed  CAS  PubMed Central  Google Scholar 

  32. Kotzin BL, Palmer E (1987) The contribution of NZW genes to lupus-like disease in (NZB x NZW)F1 mice. J Exp Med 165:1237–1251

    PubMed  CAS  Google Scholar 

  33. Morel L, Wakeland EK (1998) Susceptibility to lupus nephritis in the NZB/W model system. Curr Opin Immunol 10(6):718–725

    PubMed  CAS  Google Scholar 

  34. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK (1994) Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1(3):219–229

    PubMed  CAS  Google Scholar 

  35. Perry D, Sang A, Yin Y, Zheng YY, Morel L (2011) Murine models of systemic lupus erythematosus. J Biomed Biotechnol 2011:271694. doi:10.1155/2011/271694

    PubMed  PubMed Central  Google Scholar 

  36. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20. doi:10.1038/83707

    PubMed  CAS  Google Scholar 

  37. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21. doi:10.1038/83713

    PubMed  CAS  Google Scholar 

  38. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17(4):393–398. doi:10.1038/ng1297-393

    PubMed  CAS  Google Scholar 

  39. Finnish-German AC (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 17(4):399–403. doi:10.1038/ng1297-399

    Google Scholar 

  40. Ahonen P (1985) Autoimmune polyendocrinopathy–candidosis–ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin Genet 27(6):535–542

    PubMed  CAS  Google Scholar 

  41. Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, Caeiro F, Massardo L, Villa AR, Pons-Estel BA, Grupo Latinoamericano de Estudio del Lupus E (2005) Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 52(4):1138–1147. doi:10.1002/art.20999

    PubMed  Google Scholar 

  42. Harley IT, Kaufman KM, Langefeld CD, Harley JB, Kelly JA (2009) Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet 10(5):285–290. doi:10.1038/nrg2571

    PubMed  CAS  PubMed Central  Google Scholar 

  43. Block SR, Winfield JB, Lockshin MD, D'Angelo WA, Christian CL (1975) Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets. Am J Med 59(4):533–552

    PubMed  CAS  Google Scholar 

  44. Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, Walker A, Mack TM (1992) A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 35(3):311–318

    PubMed  CAS  Google Scholar 

  45. Boackle SA (2013) Advances in lupus genetics. Curr Opin Rheumatol 25(5):561–568. doi:10.1097/BOR.0b013e328363eb4e

    PubMed  CAS  Google Scholar 

  46. Deng Y, Tsao BP (2010) Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6(12):683–692. doi:10.1038/nrrheum.2010.176

    PubMed  CAS  PubMed Central  Google Scholar 

  47. So HC, Gui AH, Cherny SS, Sham PC (2011) Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet Epidemiol 35(5):310–317. doi:10.1002/gepi.20579

    PubMed  Google Scholar 

  48. Vaughn SE, Kottyan LC, Munroe ME, Harley JB (2012) Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways. J Leukoc Biol 92(3):577–591. doi:10.1189/jlb.0212095

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Connolly JJ, Hakonarson H (2012) Role of cytokines in systemic lupus erythematosus: recent progress from GWAS and sequencing. J Biomed Biotechnol 2012:798924. doi:10.1155/2012/798924

    PubMed  PubMed Central  Google Scholar 

  50. Eisenberg RA, Craven SY, Warren RW, Cohen PL (1987) Stochastic control of anti-Sm autoantibodies in MRL/Mp-lpr/lpr mice. J Clin Invest 80(3):691–697

    PubMed  CAS  PubMed Central  Google Scholar 

  51. Gray-McGuire C, Moser KL, Gaffney PM, Kelly J, Yu H, Olson JM, Jedrey CM, Jacobs KB, Kimberly RP, Neas BR, Rich SS, Behrens TW, Harley JB (2000) Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2. Am J Hum Genet 67(6):1460–1469. doi:10.1086/316891

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Hughes T, Adler A, Kelly JA, Kaufman KM, Williams AH, Langefeld CD, Brown EE, Alarcon GS, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Boackle SA, Stevens AM, Reveille JD, Sanchez E, Martin J, Niewold TB, Vila LM, Scofield RH, Gilkeson GS, Gaffney PM, Criswell LA, Moser KL, Merrill JT, Jacob CO, Tsao BP, James JA, Vyse TJ, Alarcon-Riquelme ME, Network B, Harley JB, Richardson BC, Sawalha AH (2012) Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum 64(2):485–492. doi:10.1002/art.33354

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Castillejo-Lopez C, Delgado-Vega AM, Wojcik J, Kozyrev SV, Thavathiru E, Wu YY, Sanchez E, Pollmann D, Lopez-Egido JR, Fineschi S, Dominguez N, Lu R, James JA, Merrill JT, Kelly JA, Kaufman KM, Moser KL, Gilkeson G, Frostegard J, Pons-Estel BA, D'Alfonso S, Witte T, Callejas JL, Harley JB, Gaffney PM, Martin J, Guthridge JM, Alarcon-Riquelme ME (2012) Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Ann Rheum Dis 71(1):136–142. doi:10.1136/annrheumdis-2011-200085

    PubMed  CAS  PubMed Central  Google Scholar 

  54. Dang J, Shan S, Li J, Zhao H, Xin Q, Liu Y, Bian X, Liu Q (2014) Gene-gene interactions of IRF5, STAT4, IKZF1 and ETS1 in systemic lupus erythematosus. Tissue Antigens 83(6):401–408. doi:10.1111/tan.12349

    PubMed  CAS  Google Scholar 

  55. Leng RX, Wang W, Cen H, Zhou M, Feng CC, Zhu Y, Yang XK, Yang M, Zhai Y, Li BZ, Wang XS, Li R, Chen GM, Chen H, Pan HF, Ye DQ (2012) Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus. PLoS ONE 7(12):e51090. doi:10.1371/journal.pone.0051090

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreno L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E (2010) Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 20(2):170–179. doi:10.1101/gr.100289.109

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Ballestar E, Esteller M, Richardson BC (2006) The epigenetic face of systemic lupus erythematosus. J Immunol 176(12):7143–7147

    PubMed  CAS  Google Scholar 

  58. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB (1997) An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest 100(12):3019–3026. doi:10.1172/JCI119856

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Botto M, Walport MJ (2002) C1q, autoimmunity and apoptosis. Immunobiology 205(4–5):395–406. doi:10.1078/0171-2985-00141

    PubMed  CAS  Google Scholar 

  60. 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. Nat Genet 19(1):56–59. doi:10.1038/ng0598-56

    PubMed  CAS  Google Scholar 

  61. Mazur DJ, Perrino FW (1999) Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3′→5′ exonucleases. J Biol Chem 274(28):19655–19660

    PubMed  CAS  Google Scholar 

  62. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C, Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt RE, Dominiczak AF, Gahr M, Hollis T, Perrino FW, Lieberman J, Hubner N (2007) Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39(9):1065–1067. doi:10.1038/ng2091

    PubMed  CAS  Google Scholar 

  63. Shaw EA, Stevens AM (2008) Are pediatric autoimmune diseases primarily genetic diseases? Curr Opin Rheumatol 20(5):589–594. doi:10.1097/BOR.0b013e328307f283

    PubMed  Google Scholar 

  64. Hashimoto H, Tsuda H, Matsumoto T, Nasu H, Takasaki Y, Shokawa Y, Hirose S, Terasaki PI, Iwaki Y (1985) HLA antigens associated with systemic lupus erythematosus in Japan. J Rheumatol 12(5):919–923

    PubMed  CAS  Google Scholar 

  65. Yuan YJ, Luo XB, Shen N (2010) Current advances in lupus genetic and genomic studies in Asia. Lupus 19(12):1374–1383. doi:10.1177/0961203310376639

    PubMed  CAS  Google Scholar 

  66. Arason GJ, Jorgensen GH, Ludviksson BR (2010) Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol 71(5):317–328. doi:10.1111/j.1365-3083.2010.02386.x

    PubMed  CAS  Google Scholar 

  67. Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76:227–324

    PubMed  CAS  Google Scholar 

  68. Sullivan KE (1998) Complement deficiency and autoimmunity. Curr Opin Pediatr 10(6):600–606

    PubMed  CAS  Google Scholar 

  69. Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647. doi:10.1146/annurev.immunol.25.022106.141618

    PubMed  CAS  PubMed Central  Google Scholar 

  70. Marnell L, Mold C, Du Clos TW (2005) C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 117(2):104–111. doi:10.1016/j.clim.2005.08.004

    PubMed  CAS  Google Scholar 

  71. Fernando MM, Stevens CR, Sabeti PC, Walsh EC, McWhinnie AJ, Shah A, Green T, Rioux JD, Vyse TJ (2007) Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS Genet 3(11):e192. doi:10.1371/journal.pgen.0030192

    PubMed  PubMed Central  Google Scholar 

  72. Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT, Ortmann WA, Jacob CO, Alarcon-Riquelme ME, Tsao BP, Harley JB, Gaffney PM, Moser KL, Petri M, Demirci FY, Kamboh MI, Manzi S, Gregersen PK, Langefeld CD, Behrens TW, Criswell LA (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet 7(3):e1001323. doi:10.1371/journal.pgen.1001323

    PubMed  CAS  PubMed Central  Google Scholar 

  73. Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Leung AM, Li XP, Avihingsanon Y, Wong CM, Lee TL, Ho MH, Lee PP, Chang YK, Li PH, Li RJ, Zhang L, Wong WH, Ng IO, Lau CS, Sham PC, Lau YL (2010) Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 6(2):e1000841. doi:10.1371/journal.pgen.1000841

    PubMed  PubMed Central  Google Scholar 

  74. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H, Baechler EC, Li QZ, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40(2):204–210. doi:10.1038/ng.81

    PubMed  CAS  PubMed Central  Google Scholar 

  75. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira RC, Pant PV, Ballinger DG, Kosoy R, Demirci FY, Kamboh MI, Kao AH, Tian C, Gunnarsson I, Bengtsson AA, Rantapaa-Dahlqvist S, Petri M, Manzi S, Seldin MF, Ronnblom L, Syvanen AC, Criswell LA, Gregersen PK, Behrens TW (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358(9):900–909. doi:10.1056/NEJMoa0707865

    PubMed  CAS  Google Scholar 

  76. Sekine H, Ferreira RC, Pan-Hammarstrom Q, Graham RR, Ziemba B, de Vries SS, Liu J, Hippen K, Koeuth T, Ortmann W, Iwahori A, Elliott MK, Offer S, Skon C, Du L, Novitzke J, Lee AT, Zhao N, Tompkins JD, Altshuler D, Gregersen PK, Cunningham-Rundles C, Harris RS, Her C, Nelson DL, Hammarstrom L, Gilkeson GS, Behrens TW (2007) Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci U S A 104(17):7193–7198. doi:10.1073/pnas.0700815104

    PubMed  CAS  PubMed Central  Google Scholar 

  77. Emamian ES, Leon JM, Lessard CJ, Grandits M, Baechler EC, Gaffney PM, Segal B, Rhodus NL, Moser KL (2009) Peripheral blood gene expression profiling in Sjogren's syndrome. Genes and Immunity 10(4):285–296. doi:10.1038/gene.2009.20

    PubMed  CAS  PubMed Central  Google Scholar 

  78. Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, Tawil R, Barohn RJ, Saperstein DS, Briemberg HR, Ericsson M, Park P, Amato AA (2005) Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 57(5):664–678. doi:10.1002/ana.20464

    PubMed  CAS  Google Scholar 

  79. Baechler EC, Bauer JW, Slattery CA, Ortmann WA, Espe KJ, Novitzke J, Ytterberg SR, Gregersen PK, Behrens TW, Reed AM (2007) An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity. Mol Med 13(1–2):59–68. doi:10.2119/2006-00085.Baechler

    PubMed  CAS  PubMed Central  Google Scholar 

  80. Braunstein I, Klein R, Okawa J, Werth VP (2012) The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. Br J Dermatol 166(5):971–975. doi:10.1111/j.1365-2133.2012.10825.x

    PubMed  CAS  PubMed Central  Google Scholar 

  81. Irvine KM, Gallego P, An X, Best SE, Thomas G, Wells C, Harris M, Cotterill A, Thomas R (2012) Peripheral blood monocyte gene expression profile clinically stratifies patients with recent-onset type 1 diabetes. Diabetes 61(5):1281–1290. doi:10.2337/db11-1549

    PubMed  CAS  PubMed Central  Google Scholar 

  82. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100(5):2610–2615. doi:10.1073/pnas.0337679100

    PubMed  CAS  PubMed Central  Google Scholar 

  83. Bronson PG, Chaivorapol C, Ortmann W, Behrens TW, Graham RR (2012) The genetics of type I interferon in systemic lupus erythematosus. Curr Opin Immunol 24(5):530–537. doi:10.1016/j.coi.2012.07.008

    PubMed  CAS  Google Scholar 

  84. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT (2012) PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev 249(1):158–175. doi:10.1111/j.1600-065X.2012.01146.x

    PubMed  CAS  PubMed Central  Google Scholar 

  85. Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5(5):375–386. doi:10.1038/nri1604

    PubMed  CAS  Google Scholar 

  86. Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503–514. doi:10.1016/j.immuni.2012.03.013

    PubMed  CAS  PubMed Central  Google Scholar 

  87. Morimoto AM, Flesher DT, Yang J, Wolslegel K, Wang X, Brady A, Abbas AR, Quarmby V, Wakshull E, Richardson B, Townsend MJ, Behrens TW (2011) Association of endogenous anti-interferon-alpha autoantibodies with decreased interferon-pathway and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 63(8):2407–2415. doi:10.1002/art.30399

    PubMed  CAS  PubMed Central  Google Scholar 

  88. Cunninghame Graham DS, Graham RR, Manku H, Wong AK, Whittaker JC, Gaffney PM, Moser KL, Rioux JD, Altshuler D, Behrens TW, Vyse TJ (2008) Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat Genet 40(1):83–89. doi:10.1038/ng.2007.47

    PubMed  CAS  PubMed Central  Google Scholar 

  89. Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse G (1997) Expression and function of OX40 ligand on human dendritic cells. J Immunol 159(8):3838–3848

    PubMed  CAS  Google Scholar 

  90. Latza U, Durkop H, Schnittger S, Ringeling J, Eitelbach F, Hummel M, Fonatsch C, Stein H (1994) The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen. Eur J Immunol 24(3):677–683. doi:10.1002/eji.1830240329

    PubMed  CAS  Google Scholar 

  91. Jacob CO, McDevitt HO (1988) Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature 331(6154):356–358. doi:10.1038/331356a0

    PubMed  CAS  Google Scholar 

  92. Chong WP, Ip WK, Wong WH, Lau CS, Chan TM, Lau YL (2004) Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes and Immunity 5(6):484–492. doi:10.1038/sj.gene.6364119

    PubMed  CAS  Google Scholar 

  93. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW (1998) Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci U S A 95(16):9465–9470

    PubMed  CAS  PubMed Central  Google Scholar 

  94. Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, Hutchinson IV (1997) Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 24(12):2314–2317

    PubMed  CAS  Google Scholar 

  95. Sawalha AH, Webb R, Han S, Kelly JA, Kaufman KM, Kimberly RP, Alarcon-Riquelme ME, James JA, Vyse TJ, Gilkeson GS, Choi CB, Scofield RH, Bae SC, Nath SK, Harley JB (2008) Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 3(3):e1727. doi:10.1371/journal.pone.0001727

    PubMed  PubMed Central  Google Scholar 

  96. Hughes T, Kim-Howard X, Kelly JA, Kaufman KM, Langefeld CD, Ziegler J, Sanchez E, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Reveille JD, Martin J, Brown EE, Vila LM, Alarcon GS, James JA, Gilkeson GS, Moser KL, Gaffney PM, Merrill JT, Vyse TJ, Alarcon-Riquelme ME, Network B, Nath SK, Harley JB, Sawalha AH (2011) Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21. Arthritis Rheum 63(6):1689–1697. doi:10.1002/art.30320

    PubMed  CAS  PubMed Central  Google Scholar 

  97. Cunninghame Graham DS, Wong AK, McHugh NJ, Whittaker JC, Vyse TJ (2006) Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study. Hum Mol Genet 15(21):3195–3205. doi:10.1093/hmg/ddl395

    PubMed  CAS  Google Scholar 

  98. Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, Alarcon-Riquelme ME, Gallant CJ, Boackle SA, Criswell LA, Kimberly RP, Brown E, Edberg J, Stevens AM, Jacob CO, Tsao BP, Gilkeson GS, Kamen DL, Merrill JT, Petri M, Goldman RR, Vila LM, Anaya JM, Niewold TB, Martin J, Pons-Estel BA, Sabio JM, Callejas JL, Vyse TJ, Bae SC, Perrino FW, Freedman BI, Scofield RH, Moser KL, Gaffney PM, James JA, Langefeld CD, Kaufman KM, Harley JB, Atkinson JP (2011) Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12(4):270–279. doi:10.1038/gene.2010.73

    PubMed  CAS  PubMed Central  Google Scholar 

  99. Bhoj VG, Chen ZJ (2008) Linking retroelements to autoimmunity. Cell 134(4):569–571. doi:10.1016/j.cell.2008.08.010

    PubMed  CAS  Google Scholar 

  100. 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(2):640–649. doi:10.1002/art.20034

    PubMed  CAS  Google Scholar 

  101. Korb LC, Ahearn JM (1997) C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol 158(10):4525–4528

    PubMed  CAS  Google Scholar 

  102. Sellar GC, Cockburn D, Reid KB (1992) Localization of the gene cluster encoding the A, B, and C chains of human C1q to 1p34.1-1p36.3. Immunogenetics 35(3):214–216

    PubMed  CAS  Google Scholar 

  103. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T (2000) Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 25(2):177–181

    PubMed  CAS  Google Scholar 

  104. Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL, Earp HS, Matsushima GK (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411(6834):207–211

    PubMed  CAS  Google Scholar 

  105. 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(7):1241–1250. doi:10.1002/1529-0131(199807)41:7<1241::AID-ART15>3.0.CO;2-H

    PubMed  CAS  Google Scholar 

  106. 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(1):191–201. doi:10.1002/1529-0131(200201)46:1<191::AID-ART10027>3.0.CO;2-K

    PubMed  Google Scholar 

  107. Russell PJ, Steinberg AD (1983) Studies of peritoneal macrophage function in mice with systemic lupus erythematosus: depressed phagocytosis of opsonized sheep erythrocytes in vitro. Clin Immunol Immunopathol 27(3):387–402

    PubMed  CAS  Google Scholar 

  108. Russell PJ, Cameron FH (1986) Studies of macrophage function in murine systemic lupus erythematosus. 3. The nature, anatomical location, and reversibility of the phagocytic defect. J Leukoc Biol 39(1):49–62

    PubMed  CAS  Google Scholar 

  109. Fournie GJ, Izui S, Lambert PH, Conte JJ (1976) Genesis and pathogenicity of anti-DNA antibodies. Adv Nephrol Necker Hosp 6:47–61

    PubMed  CAS  Google Scholar 

  110. Izui S, Kobayakawa T, Zryd MJ, Louis J, Lambert PH (1977) Mechanism for induction of anti-DNA antibodies by bacterial lipopolysaccharides in mice; II. Correlation between anti-DNA induction and polyclonal antibody formation by various polyclonal B lymphocyte activators. J Immunol 119(6):2157–2162

    PubMed  CAS  Google Scholar 

  111. Izui S, Lambert PH, Fournie GJ, Turler H, Miescher PA (1977) Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identification of circulating DNA and renal localization of DNA-anti-DNA complexes. J Exp Med 145(5):1115–1130

    PubMed  CAS  Google Scholar 

  112. 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(6):1733–1742. doi:10.1002/art.24535

    PubMed  CAS  Google Scholar 

  113. Rhodes B, Furnrohr BG, Roberts AL, Tzircotis G, Schett G, Spector TD, Vyse TJ (2012) The rs1143679 (R77H) lupus associated variant of ITGAM (CD11b) impairs complement receptor 3 mediated functions in human monocytes. Ann Rheum Dis 71(12):2028–2034. doi:10.1136/annrheumdis-2012-201390

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Fossati-Jimack L, Ling GS, Cortini A, Szajna M, Malik TH, McDonald JU, Pickering MC, Cook HT, Taylor PR, Botto M (2013) Phagocytosis is the main CR3-mediated function affected by the lupus-associated variant of CD11b in human myeloid cells. PLoS ONE 8(2):e57082. doi:10.1371/journal.pone.0057082

    PubMed  CAS  PubMed Central  Google Scholar 

  115. Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13(2):277–285

    PubMed  CAS  Google Scholar 

  116. Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons JL, Schwartzberg PL, Cook MC, Walters GD, Vinuesa CG (2009) Follicular helper T cells are required for systemic autoimmunity. J Exp Med 206(3):561–576. doi:10.1084/jem.20081886

    PubMed  CAS  PubMed Central  Google Scholar 

  117. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, Yu D, Domaschenz H, Whittle B, Lambe T, Roberts IS, Copley RR, Bell JI, Cornall RJ, Goodnow CC (2005) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435(7041):452–458

    PubMed  CAS  Google Scholar 

  118. Chan VW, Meng F, Soriano P, DeFranco AL, Lowell CA (1997) Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. Immunity 7(1):69–81

    PubMed  CAS  Google Scholar 

  119. Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA, Dunn AR (1995) Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83(2):301–311

    PubMed  CAS  Google Scholar 

  120. Nishizumi H, Taniuchi I, Yamanashi Y, Kitamura D, Ilic D, Mori S, Watanabe T, Yamamoto T (1995) Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 3(5):549–560

    PubMed  CAS  Google Scholar 

  121. Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC (1998) Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8(4):497–508

    PubMed  CAS  Google Scholar 

  122. O'Keefe TL, Williams GT, Batista FD, Neuberger MS (1999) Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med 189(8):1307–1313

    PubMed  PubMed Central  Google Scholar 

  123. Portanova JP, Claman HN, Kotzin BL (1985) Autoimmunization in murine graft-vs-host disease. I. Selective production of antibodies to histones and DNA. J Immunol 135(6):3850–3856

    PubMed  CAS  Google Scholar 

  124. Gleichmann E, Van Elven EH, Van der Veen JP (1982) A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol 12(2):152–159. doi:10.1002/eji.1830120210

    PubMed  CAS  Google Scholar 

  125. Morris SC, Cheek RL, Cohen PL, Eisenberg RA (1990) Autoantibodies in chronic graft versus host result from cognate T-B interactions. J Exp Med 171(2):503–517

    PubMed  CAS  Google Scholar 

  126. Satoh M, Reeves WH (1994) Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med 180(6):2341–2346

    PubMed  CAS  Google Scholar 

  127. Lee PY, Weinstein JS, Nacionales DC, Scumpia PO, Li Y, Butfiloski E, van Rooijen N, Moldawer L, Satoh M, Reeves WH (2008) A novel type I IFN-producing cell subset in murine lupus. J Immunol 180(7):5101–5108

    PubMed  CAS  PubMed Central  Google Scholar 

  128. Desai DD, Marion TN (2000) Induction of anti-DNA antibody with DNA-peptide complexes. Int Immunol 12(11):1569–1578

    PubMed  CAS  Google Scholar 

  129. Desai DD, Krishnan MR, Swindle JT, Marion TN (1993) Antigen-specific induction of antibodies against native mammalian DNA in nonautoimmune mice. J Immunol 151(3):1614–1626

    PubMed  CAS  Google Scholar 

  130. Eilat D, Wabl M (2012) B cell tolerance and positive selection in lupus. J Immunol 189(2):503–509. doi:10.4049/jimmunol.1200848

    PubMed  CAS  PubMed Central  Google Scholar 

  131. Beck-Engeser GB, Eilat D, Harrer T, Jack HM, Wabl M (2009) Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir. Proc Natl Acad Sci U S A 106(49):20865–20870. doi:10.1073/pnas.0908074106

    PubMed  CAS  PubMed Central  Google Scholar 

  132. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416(6881):603–607

    PubMed  CAS  Google Scholar 

  133. Webb R, Wren JD, Jeffries M, Kelly JA, Kaufman KM, Tang Y, Frank MB, Merrill J, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Reveille JD, Alarcon GS, Vila LM, Alarcon-Riquelme ME, James JA, Vyse TJ, Moser KL, Gaffney PM, Gilkeson GS, Harley JB, Sawalha AH (2009) Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus. Arthritis Rheum 60(4):1076–1084. doi:10.1002/art.24360

    PubMed  CAS  PubMed Central  Google Scholar 

  134. Goodnow CC (1996) Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. Proc Natl Acad Sci U S A 93(6):2264–2271

    PubMed  CAS  PubMed Central  Google Scholar 

  135. Krishnan MR, Marion TN (1998) Comparison of the frequencies of arginines in heavy chain CDR3 of antibodies expressed in the primary B-cell repertoires of autoimmune-prone and normal mice. Scand J Immunol 48(3):223–232

    PubMed  CAS  Google Scholar 

  136. Christensen SR, Shlomchik MJ (2007) Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin Immunol 19(1):11–23

    PubMed  CAS  PubMed Central  Google Scholar 

  137. Lam GK, Petri M (2005) Assessment of systemic lupus erythematosus. Clin Exp Rheumatol 23(5 Suppl 39):S120–S132

    PubMed  CAS  Google Scholar 

  138. Rahman A, Isenberg DA (2008) Systemic lupus erythematosus. N Engl J Med 358(9):929–939. doi:10.1056/NEJMra071297

    PubMed  CAS  Google Scholar 

  139. Hasselaar P, Derksen RH, Blokzijl L, de Groot PG (1990) Crossreactivity of antibodies directed against cardiolipin, DNA, endothelial cells and blood platelets. Thromb Haemost 63(2):169–173

    PubMed  CAS  Google Scholar 

  140. Lafer EM, Rauch J, Andrzejewski C Jr, Mudd D, Furie B, Furie B, Schwartz RS, Stollar BD (1981) Polyspecific monoclonal lupus autoantibodies reactive with both polynucleotides and phospholipids. J Exp Med 153(4):897–909

    PubMed  CAS  Google Scholar 

  141. Manson JJ, Ma A, Rogers P, Mason LJ, Berden JH, van der Vlag J, D'Cruz DP, Isenberg DA, Rahman A (2009) Relationship between anti-dsDNA, anti-nucleosome and anti-alpha-actinin antibodies and markers of renal disease in patients with lupus nephritis: a prospective longitudinal study. Arthritis Res Ther 11(5):R154. doi:10.1186/ar2831

    PubMed  PubMed Central  Google Scholar 

  142. Koffler D, Schur PH, Kunkel HG (1967) Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126(4):607–624

    PubMed  CAS  PubMed Central  Google Scholar 

  143. Isenberg DA (1997) Autoantibodies: markers of disease or pathogenic? Ann N Y Acad Sci 823:256–262

    PubMed  CAS  Google Scholar 

  144. Krishnan MR, Wang C, Marion TN (2012) Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice. Kidney Int 82(2):184–192. doi:10.1038/ki.2011.484

    PubMed  CAS  PubMed Central  Google Scholar 

  145. Marion TN, Krishnan MR, Steeves MA, Desai DD (2003) Affinity maturation and autoimmunity to DNA. Curr Dir Autoimmun 6:123–153

    PubMed  Google Scholar 

  146. Crow MK (2007) Type I interferon in systemic lupus erythematosus. Curr Top Microbiol Immunol 316:359–386

    PubMed  CAS  Google Scholar 

  147. Banchereau J, Pascual V (2006) Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25(3):383–392. doi:10.1016/j.immuni.2006.08.010

    PubMed  CAS  Google Scholar 

  148. Pascual V, Banchereau J, Palucka AK (2003) The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol 15(5):548–556

    PubMed  CAS  Google Scholar 

  149. Wofsy D, Seaman WE (1985) Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med 161(2):378–391

    PubMed  CAS  Google Scholar 

  150. Vinuesa CG, Linterman MA, Goodnow CC, Randall KL (2010) T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol Rev 237(1):72–89. doi:10.1111/j.1600-065X.2010.00937.x

    PubMed  CAS  Google Scholar 

  151. Patakas A, Benson RA, Withers DR, Conigliaro P, McInnes IB, Brewer JM, Garside P (2012) Th17 effector cells support B cell responses outside of germinal centres. PLoS ONE 7(11):e49715. doi:10.1371/journal.pone.0049715

    PubMed  CAS  PubMed Central  Google Scholar 

  152. Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL, Le TV, Lorenz RG, Xu H, Kolls JK, Carter RH, Chaplin DD, Williams RW, Mountz JD (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9(2):166–175. doi:10.1038/ni1552

    PubMed  CAS  Google Scholar 

  153. Hochberg MC, Petri M (1993) Clinical features of systemic lupus erythematosus. Curr Opin Rheumatol 5(5):575–586

    PubMed  CAS  Google Scholar 

  154. 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(7):1052–1056. doi:10.1093/rheumatology/kem112

    CAS  Google Scholar 

  155. Papadimitraki ED, Isenberg DA (2009) Childhood- and adult-onset lupus: an update of similarities and differences. Expert Rev Clin Immunol 5(4):391–403. doi:10.1586/eci.09.29

    PubMed  Google Scholar 

  156. Mellors RC, Ortega LG, Holman HR (1957) Role of gamma globulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction. J Exp Med 106(2):191–202

    PubMed  CAS  PubMed Central  Google Scholar 

  157. Freedman P, Markowitz AS (1962) Isolation of antibody-like gamma-globulin from lupus glomeruli. Br Med J 1(5286):1175–1178

    PubMed  CAS  PubMed Central  Google Scholar 

  158. Krishnan C, Kaplan MH (1967) Immunopathologic studies of systemic lupus erythematosus. II. Antinuclear reaction of gamma-globulin eluted from homogenates and isolated glomeruli of kidneys from patients with lupus nephritis. J Clin Invest 46(4):569–579. doi:10.1172/JCI105558

    PubMed  CAS  PubMed Central  Google Scholar 

  159. Aarons I (1964) Renal immunofluorescence in Nzb-Nzw mice. Nature 203:1080–1081. doi:10.1038/2031080a0

    PubMed  CAS  Google Scholar 

  160. Channing AA, Kasuga T, Horowitz RE, Dubois EL, Demopoulos HB (1965) An ultrastructural study of spontaneous lupus nephritis in the NZB-BL-NZW mouse. Am J Pathol 47(4):677–694

    PubMed  CAS  PubMed Central  Google Scholar 

  161. Farquhar MG, Vernier RL, Good RA (1957) An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus. J Exp Med 106(5):649–660

    PubMed  CAS  PubMed Central  Google Scholar 

  162. Kalaaji M, Mortensen E, Jorgensen L, Olsen R, Rekvig OP (2006) Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells. Am J Pathol 168(6):1779–1792. doi:10.2353/ajpath.2006.051329

    PubMed  CAS  PubMed Central  Google Scholar 

  163. Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ (1999) A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 189(10):1639–1648

    PubMed  CAS  PubMed Central  Google Scholar 

  164. Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D (1994) The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 180(4):1295–1306

    PubMed  CAS  Google Scholar 

  165. Takai T, Li M, Sylvestre D, Clynes R, Ravetch JV (1994) FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell 76(3):519–529

    PubMed  CAS  Google Scholar 

  166. Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV (2005) FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity 23(1):41–51. doi:10.1016/j.immuni.2005.05.010

    PubMed  CAS  Google Scholar 

  167. Clynes R, Dumitru C, Ravetch JV (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279(5353):1052–1054. doi:10.1126/science.279.5353.1052

    PubMed  CAS  Google Scholar 

  168. Godau J, Heller T, Hawlisch H, Trappe M, Howells E, Best J, Zwirner J, Verbeek JS, Hogarth PM, Gerard C, Van Rooijen N, Klos A, Gessner JE, Kohl J (2004) C5a initiates the inflammatory cascade in immune complex peritonitis. J Immunol 173(5):3437–3445

    PubMed  CAS  Google Scholar 

  169. Wang Y, Hu Q, Madri JA, Rollins SA, Chodera A, Matis LA (1996) Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc Natl Acad Sci U S A 93(16):8563–8568

    PubMed  CAS  PubMed Central  Google Scholar 

  170. Shushakova N, Skokowa J, Schulman J, Baumann U, Zwirner J, Schmidt RE, Gessner JE (2002) C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. J Clin Invest 110(12):1823–1830. doi:10.1172/JCI16577

    PubMed  CAS  PubMed Central  Google Scholar 

  171. Skokowa J, Ali SR, Felda O, Kumar V, Konrad S, Shushakova N, Schmidt RE, Piekorz RP, Nurnberg B, Spicher K, Birnbaumer L, Zwirner J, Claassens JW, Verbeek JS, van Rooijen N, Kohl J, Gessner JE (2005) Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation. J Immunol 174(5):3041–3050

    PubMed  CAS  Google Scholar 

  172. Walport MJ (2000) Lupus, DNase and defective disposal of cellular debris. Nat Genet 25(2):135–136. doi:10.1038/75963

    PubMed  CAS  Google Scholar 

  173. Uciechowski P, Schwarz M, Gessner JE, Schmidt RE, Resch K, Radeke HH (1998) IFN-gamma induces the high-affinity Fc receptor I for IgG (CD64) on human glomerular mesangial cells. Eur J Immunol 28(9):2928–2935

    PubMed  CAS  Google Scholar 

  174. Morcos M, Hansch GM, Schonermark M, Ellwanger S, Harle M, Heckl-Ostreicher B (1994) Human glomerular mesangial cells express CD16 and may be stimulated via this receptor. Kidney Int 46(6):1627–1634

    PubMed  CAS  Google Scholar 

  175. Lopez-Armada MJ, Gomez-Guerrero C, Egido J (1996) Receptors for immune complexes activate gene expression and synthesis of matrix proteins in cultured rat and human mesangial cells: role of TGF-beta. J Immunol 157(5):2136–2142

    PubMed  CAS  Google Scholar 

  176. Kanapathippillai P, Hedberg A, Fenton CG, Fenton KA (2013) Nucleosomes contribute to increase mesangial cell chemokine expression during the development of lupus nephritis. Cytokine 62(2):244–252. doi:10.1016/j.cyto.2013.03.016

    PubMed  CAS  Google Scholar 

  177. Qing X, Zavadil J, Crosby MB, Hogarth MP, Hahn BH, Mohan C, Gilkeson GS, Bottinger EP, Putterman C (2006) Nephritogenic anti-DNA antibodies regulate gene expression in MRL/lpr mouse glomerular mesangial cells. Arthritis Rheum 54(7):2198–2210. doi:10.1002/art.21934

    PubMed  CAS  Google Scholar 

  178. Radeke HH, Janssen-Graalfs I, Sowa EN, Chouchakova N, Skokowa J, Loscher F, Schmidt RE, Heeringa P, Gessner JE (2002) Opposite regulation of type II and III receptors for immunoglobulin G in mouse glomerular mesangial cells and in the induction of anti-glomerular basement membrane (GBM) nephritis. J Biol Chem 277(30):27535–27544. doi:10.1074/jbc.M200419200

    PubMed  CAS  Google Scholar 

  179. Patole PS, Pawar RD, Lech M, Zecher D, Schmidt H, Segerer S, Ellwart A, Henger A, Kretzler M, Anders HJ (2006) Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice. Nephrol Dial Transplant 21(11):3062–3073. doi:10.1093/ndt/gfl336

    PubMed  CAS  Google Scholar 

  180. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408(6813):740–745

    PubMed  CAS  Google Scholar 

  181. Bergtold A, Gavhane A, D'Agati V, Madaio M, Clynes R (2006) FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J Immunol 177(10):7287–7295

    PubMed  CAS  Google Scholar 

  182. Calvani N, Richards HB, Tucci M, Pannarale G, Silvestris F (2004) Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol 138(1):171–178. doi:10.1111/j.1365-2249.2004.02588.x

    PubMed  CAS  PubMed Central  Google Scholar 

  183. Jacob CO, van der Meide PH, McDevitt HO (1987) In vivo treatment of (NZB X NZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon. J Exp Med 166(3):798–803

    PubMed  CAS  Google Scholar 

  184. Bagavant H, Deshmukh US, Wang H, Ly T, Fu SM (2006) Role for nephritogenic T cells in lupus glomerulonephritis: progression to renal failure is accompanied by T cell activation and expansion in regional lymph nodes. J Immunol 177(11):8258–8265

    PubMed  CAS  Google Scholar 

  185. Harrington LE, Mangan PR, Weaver CT (2006) Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18(3):349–356. doi:10.1016/j.coi.2006.03.017

    PubMed  CAS  Google Scholar 

  186. Nalbandian A, Crispin JC, Tsokos GC (2009) Interleukin-17 and systemic lupus erythematosus: current concepts. Clin Exp Immunol 157(2):209–215. doi:10.1111/j.1365-2249.2009.03944.x

    PubMed  CAS  PubMed Central  Google Scholar 

  187. Pisitkun P, Ha HL, Wang H, Claudio E, Tivy CC, Zhou H, Mayadas TN, Illei GG, Siebenlist U (2012) Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis. Immunity 37(6):1104–1115. doi:10.1016/j.immuni.2012.08.014

    PubMed  CAS  PubMed Central  Google Scholar 

  188. Ebling F, Hahn BH (1980) Restricted subpopulations of DNA antibodies in kidneys of mice with systemic lupus. Comparison of antibodies in serum and renal eluates. Arthritis Rheum 23(4):392–403

    PubMed  CAS  Google Scholar 

  189. Gladman DD, Urowitz MB, Keystone EC (1979) Serologically active clinically quiescent systemic lupus erythematosus: a discordance between clinical and serological features. Am J Med 66:210–215

    PubMed  CAS  Google Scholar 

  190. Madaio MP (1999) The role of autoantibodies in the pathogenesis of lupus nephritis. Semin Nephrol 19(1):48–56

    PubMed  CAS  Google Scholar 

  191. Ng KP, Manson JJ, Rahman A, Isenberg DA (2006) Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus. Arthritis Rheum 55(6):900–904. doi:10.1002/art.22356

    PubMed  CAS  Google Scholar 

  192. Swaak AJ, Aarden LA, Statius van Eps LW, Feltkamp TE (1979) Anti-dsDNA and complement profiles as prognostic guides in systemic lupus erythematosus. Arthritis Rheum 22(3):226–235

    PubMed  CAS  Google Scholar 

  193. Steeves MA, Marion TN (2004) Tolerance to DNA in (NZB x NZW)F1 mice that inherit an anti-DNA V(H) as a conventional micro H chain transgene but not as a V(H) knock-in transgene. J Immunol 172(11):6568–6577

    PubMed  CAS  Google Scholar 

  194. Friedmann D, Yachimovich N, Mostoslavsky G, Pewzner-Jung Y, Ben-Yehuda A, Rajewsky K, Eilat D (1999) Production of high affinity autoantibodies in autoimmune New Zealand Black/New Zealand white F1 mice targeted with an anti-DNA heavy chain. J Immunol 162(8):4406–4416

    PubMed  CAS  Google Scholar 

  195. Wellmann U, Letz M, Schneider A, Amann K, Winkler TH (2001) An Ig mu-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice. Int Immunol 13(12):1461–1469

    PubMed  CAS  Google Scholar 

  196. Gilkeson GS, Bernstein K, Pippen AM, Clarke SH, Marion T, Pisetsky DS, Ruiz P, Lefkowith JB (1995) The influence of variable-region somatic mutations on the specificity and pathogenicity of murine monoclonal anti-DNA antibodies. Clin Immunol Immunopathol 76(1 Pt 1):59–67. doi:10.1006/clin.1995.1088

    PubMed  CAS  Google Scholar 

  197. Madaio MP, Carlson J, Cataldo J, Ucci A, Migliorini P, Pankewycz O (1987) Murine monoclonal anti-DNA antibodies bind directly to glomerular antigens and form immune deposits. J Immunol 138(9):2883–2889

    PubMed  CAS  Google Scholar 

  198. Pankewycz OG, Migliorini P, Madaio MP (1987) Polyreactive autoantibodies are nephritogenic in murine lupus nephritis. J Immunol 139(10):3287–3294

    PubMed  CAS  Google Scholar 

  199. Sabbaga J, Line SR, Potocnjak P, Madaio MP (1989) A murine nephritogenic monoclonal anti-DNA autoantibody binds directly to mouse laminin, the major non-collagenous protein component of the glomerular basement membrane. Eur J Immunol 19(1):137–143. doi:10.1002/eji.1830190122

    PubMed  CAS  Google Scholar 

  200. 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(9):3076–3082

    PubMed  CAS  Google Scholar 

  201. Kalaaji M, Fenton KA, Mortensen ES, Olsen R, Sturfelt G, Alm P, Rekvig OP (2007) Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis. Kidney Int 71(7):664–672. doi:10.1038/sj.ki.5002133

    PubMed  CAS  Google Scholar 

  202. Fenton KA, Tommeras B, Marion TN, Rekvig OP (2010) Pure anti-dsDNA mAbs need chromatin structures to promote glomerular mesangial deposits in BALB/c mice. Autoimmunity 43(2):179–188. doi:10.3109/08916930903305633

    PubMed  CAS  Google Scholar 

  203. 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(2):568–577. doi:10.1172/JCI117371

    PubMed  CAS  PubMed Central  Google Scholar 

  204. Izui S, Lambert PH, Miescher PA (1976) In vitro demonstration of a particular affinity of glomerular basement membrane and collagen for DNA. A possible basis for a local formation of DNA-anti-DNA complexes in systemic lupus erythematosus. J Exp Med 144(2):428–443

    PubMed  CAS  Google Scholar 

  205. Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389(6648):251–260. doi:10.1038/38444

    PubMed  CAS  Google Scholar 

  206. Schalch T, Duda S, Sargent DF, Richmond TJ (2005) X-ray structure of a tetranucleosome and its implications for the chromatin fibre. Nature 436(7047):138–141. doi:10.1038/nature03686

    PubMed  CAS  Google Scholar 

  207. Materese CK, Savelyev A, Papoian GA (2009) Counterion atmosphere and hydration patterns near a nucleosome core particle. J Am Chem Soc 131(41):15005–15013. doi:10.1021/ja905376q

    PubMed  CAS  Google Scholar 

  208. Caulfield JP, Farquhar MG (1976) Distribution of annionic sites in glomerular basement membranes: their possible role in filtration and attachment. Proc Natl Acad Sci U S A 73(5):1646–1650

    PubMed  CAS  PubMed Central  Google Scholar 

  209. Kanwar YS, Farquhar MG (1979) Anionic sites in the glomerular basement membrane. In vivo and in vitro localization to the laminae rarae by cationic probes. J Cell Biol 81(1):137–153

    PubMed  CAS  Google Scholar 

  210. Mjelle JE, Rekvig OP, Fenton KA (2007) Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis. Ann Rheum Dis 66(12):1661–1668. doi:10.1136/ard.2007.070482

    PubMed  CAS  PubMed Central  Google Scholar 

  211. Rumore P, Muralidhar B, Lin M, Lai C, Steinman CR (1992) Haemodialysis as a model for studying endogenous plasma DNA: oligonucleosome-like structure and clearance. Clin Exp Immunol 90(1):56–62

    PubMed  CAS  PubMed Central  Google Scholar 

  212. Gauthier VJ, Tyler LN, Mannik M (1996) Blood clearance kinetics and liver uptake of mononucleosomes in mice. J Immunol 156(3):1151–1156

    PubMed  CAS  Google Scholar 

  213. Radic M, Marion TN (2013) Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity. Semin Immunopathol 35(4):465–480. doi:10.1007/s00281-013-0376-6

    PubMed  CAS  Google Scholar 

  214. Agodoa LY, Gauthier VJ, Mannik M (1985) Antibody localization in the glomerular basement membrane may precede in situ immune deposit formation in rat glomeruli. J Immunol 134(2):880–884

    PubMed  CAS  Google Scholar 

  215. Campbell AM, Kashgarian M, Shlomchik MJ (2012) NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci Transl Med 4(157):157ra141. doi:10.1126/scitranslmed.3004801

    PubMed  PubMed Central  Google Scholar 

  216. Morshed M, Hlushchuk R, Simon D, Walls AF, Obata-Ninomiya K, Karasuyama H, Djonov V, Eggel A, Kaufmann T, Simon HU, Yousefi S (2014) NADPH oxidase-independent formation of extracellular DNA traps by basophils. J Immunol. doi:10.4049/jimmunol.1303418

    PubMed  Google Scholar 

  217. Cline AM, Radic MZ (2004) Murine lupus autoantibodies identify distinct subsets of apoptotic bodies. Autoimmunity 37(2):85–93

    PubMed  CAS  Google Scholar 

  218. Ullal AJ, Pisetsky DS (2013) The role of microparticles in the generation of immune complexes in murine lupus. Clin Immunol 146(1):1–9. doi:10.1016/j.clim.2012.10.004

    PubMed  CAS  PubMed Central  Google Scholar 

  219. Gauthier VJ, Mannik M, Striker GE (1982) Effect of cationized antibodies in performed immune complexes on deposition and persistence in renal glomeruli. J Exp Med 156(3):766–777

    PubMed  CAS  Google Scholar 

  220. Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H, Madaio MP, Bottinger EP, Davidson A (2008) Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol 180(3):1938–1947

    PubMed  CAS  PubMed Central  Google Scholar 

  221. Hansen CB, Dahle KW (2012) Cutaneous lupus erythematosus. Dermatol Ther 25(2):99–111. doi:10.1111/j.1529-8019.2012.01508.x

    PubMed  Google Scholar 

  222. Oke V, Wahren-Herlenius M (2013) Cutaneous lupus erythematosus: clinical aspects and molecular pathogenesis. J Intern Med 273(6):544–554. doi:10.1111/joim.12057

    PubMed  CAS  Google Scholar 

  223. Flier J, Boorsma DM, van Beek PJ, Nieboer C, Stoof TJ, Willemze R, Tensen CP (2001) Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol 194(4):398–405

    PubMed  CAS  Google Scholar 

  224. Wenzel J, Zahn S, Mikus S, Wiechert A, Bieber T, Tuting T (2007) The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets. Br J Dermatol 157(4):752–757. doi:10.1111/j.1365-2133.2007.08137.x

    PubMed  CAS  Google Scholar 

  225. Hofmann SC, Bosma A, Bruckner-Tuderman L, Vukmanovic-Stejic M, Jury EC, Isenberg DA, Mauri C (2013) Invariant natural killer T cells are enriched at the site of cutaneous inflammation in lupus erythematosus. J Dermatol Sci 71(1):22–28. doi:10.1016/j.jdermsci.2013.04.012

    PubMed  CAS  Google Scholar 

  226. 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(11):3639–3645. doi:10.1002/art.21398

    PubMed  CAS  Google Scholar 

  227. Wittmann M, Macdonald A, Renne J (2009) IL-18 and skin inflammation. Autoimmun Rev 9(1):45–48. doi:10.1016/j.autrev.2009.03.003

    PubMed  CAS  Google Scholar 

  228. Tanasescu C, Balanescu E, Balanescu P, Olteanu R, Badea C, Grancea C, Vagu C, Bleotu C, Ardeleanu C, Georgescu A (2010) IL-17 in cutaneous lupus erythematosus. Eur J Intern Med 21(3):202–207. doi:10.1016/j.ejim.2010.03.004

    PubMed  CAS  Google Scholar 

  229. Zahn S, Rehkamper C, Kummerer BM, Ferring-Schmidt S, Bieber T, Tuting T, Wenzel J (2011) Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFN-lambda) in cutaneous lupus erythematosus. J Invest Dermatol 131(1):133–140. doi:10.1038/jid.2010.244

    PubMed  CAS  Google Scholar 

  230. Maverakis E, Miyamura Y, Bowen MP, Correa G, Ono Y, Goodarzi H (2010) Light, including ultraviolet. J Autoimmun 34(3):J247–J257. doi:10.1016/j.jaut.2009.11.011

    PubMed  CAS  PubMed Central  Google Scholar 

  231. Bennion SD, Norris DA (1997) Ultraviolet light modulation of autoantigens, epidermal cytokines and adhesion molecules as contributing factors of the pathogenesis of cutaneous LE. Lupus 6(2):181–192

    PubMed  CAS  Google Scholar 

  232. Reefman E, Kuiper H, Limburg PC, Kallenberg CG, Bijl M (2008) Type I interferons are involved in the development of ultraviolet B-induced inflammatory skin lesions in systemic lupus erythaematosus patients. Ann Rheum Dis 67(1):11–18. doi:10.1136/ard.2007.070359

    PubMed  CAS  Google Scholar 

  233. Oh SH, Roh HJ, Kwon JE, Lee SH, Kim JY, Choi HJ, Lim BJ (2011) Expression of interleukin-17 is correlated with interferon-alpha expression in cutaneous lesions of lupus erythematosus. Clin Exp Dermatol 36(5):512–520. doi:10.1111/j.1365-2230.2010.03996.x

    PubMed  CAS  Google Scholar 

  234. Uehara T, Xi Peng X, Bennett B, Satoh Y, Friedman G, Currin R, Brenner DA, Lemasters J (2004) c-Jun N-terminal kinase mediates hepatic injury after rat liver transplantation. Transplantation 78(3):324–332

    PubMed  CAS  Google Scholar 

  235. Uehara T, Bennett B, Sakata ST, Satoh Y, Bilter GK, Westwick JK, Brenner DA (2005) JNK mediates hepatic ischemia reperfusion injury. J Hepatol 42(6):850–859. doi:10.1016/j.jhep.2005.01.030

    PubMed  CAS  Google Scholar 

  236. Caricchio R, McPhie L, Cohen PL (2003) Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol 171(11):5778–5786

    PubMed  CAS  Google Scholar 

  237. Korhonen R, Linker K, Pautz A, Forstermann U, Moilanen E, Kleinert H (2007) Post-transcriptional regulation of human inducible nitric-oxide synthase expression by the Jun N-terminal kinase. Mol Pharmacol 71(5):1427–1434. doi:10.1124/mol.106.033449

    PubMed  CAS  Google Scholar 

  238. Suschek CV, Krischel V, Bruch-Gerharz D, Berendji D, Krutmann J, Kroncke KD, Kolb-Bachofen V (1999) Nitric oxide fully protects against UVA-induced apoptosis in tight correlation with Bcl-2 up-regulation. J Biol Chem 274(10):6130–6137

    PubMed  CAS  Google Scholar 

  239. Kuhn A, Fehsel K, Lehmann P, Krutmann J, Ruzicka T, Kolb-Bachofen V (1998) Aberrant timing in epidermal expression of inducible nitric oxide synthase after UV irradiation in cutaneous lupus erythematosus. J Invest Dermatol 111(1):149–153. doi:10.1046/j.1523-1747.1998.00253.x

    PubMed  CAS  Google Scholar 

  240. Belmont HM, Levartovsky D, Goel A, Amin A, Giorno R, Rediske J, Skovron ML, Abramson SB (1997) Increased nitric oxide production accompanied by the up-regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus. Arthritis Rheum 40(10):1810–1816. doi:10.1002/1529-0131(199710)40:10<1810::AID-ART13>3.0.CO;2-D

    PubMed  CAS  Google Scholar 

  241. Yokogawa M, Takaishi M, Nakajima K, Kamijima R, Fujimoto C, Kataoka S, Terada Y, Sano S (2014) Epicutaneous application of toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: a new model of systemic lupus erythematosus. Arthritis & Rheumatol 66(3):694–706. doi:10.1002/art.38298

    CAS  Google Scholar 

  242. Zamora MR, Warner ML, Tuder R, Schwarz MI (1997) Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome. Medicine (Baltimore) 76(3):192–202

    CAS  Google Scholar 

  243. Hunninghake GW, Fauci AS (1979) Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 119(3):471–503

    PubMed  CAS  Google Scholar 

  244. Emlen W (1993) Systemic lupus erythematosus and mixed connective tissue disease. Immunol Allergy Clin N Am 13(2):291–311

    Google Scholar 

  245. Santiago-Casas Y, Vila LM (2009) Pulmonary hemorrhage in patients with systemic lupus erythematosus. Curr Respir Med Rev 5(1):49–54. doi:10.2174/157339809787354065

    CAS  Google Scholar 

  246. Kamen DL, Strange C (2010) Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med 31(3):479–488. doi:10.1016/j.ccm.2010.05.001

    PubMed  Google Scholar 

  247. Virdi RP, Bashir A, Shahzad G, Iqbal J, Mejia JO (2012) Diffuse alveolar hemorrhage: a rare life-threatening condition in systemic lupus erythematosus. Case Rep Pulmonol 2012:836017. doi:10.1155/2012/836017

    PubMed  PubMed Central  Google Scholar 

  248. Santos-Ocampo AS, Mandell BF, Fessler BJ (2000) Alveolar hemorrhage in systemic lupus erythematosus: presentation and management. Chest 118(4):1083–1090

    PubMed  CAS  Google Scholar 

  249. Marino CT, Pertschuk LP (1981) Pulmonary hemorrhage in systemic lupus erythematosus. Arch Intern Med 141(2):201–203

    PubMed  CAS  Google Scholar 

  250. Travis WD, Colby TV, Lombard C, Carpenter HA (1990) A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 14(12):1112–1125

    PubMed  CAS  Google Scholar 

  251. Hughson MD, He Z, Henegar J, McMurray R (2001) Alveolar hemorrhage and renal microangiopathy in systemic lupus erythematosus. Arch Pathol Lab Med 125(4):475–483. doi:10.1043/0003-9985(2001)125<0475:aharmi>2.0.co;2

    PubMed  CAS  Google Scholar 

  252. Leatherman JW (1987) Immune alveolar hemorrhage. Chest 91(6):891–897

    PubMed  CAS  Google Scholar 

  253. Myers JL, Katzenstein AA (1986) Microangiitis in lupus-induced pulmonary hemorrhage. Am J Clin Pathol 85(5):552–556

    PubMed  CAS  Google Scholar 

  254. Schwab EP, Schumacher HR Jr, Freundlich B, Callegari PE (1993) Pulmonary alveolar hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 23(1):8–15

    PubMed  CAS  Google Scholar 

  255. Nellessen CM, Poge U, Brensing KA, Sauerbruch T, Klehr HU, Rabe C (2008) Diffuse alveolar haemorrhage in a systemic lupus erythematosus patient successfully treated with rituximab: a case report. Nephrol Dial Transplant 23(1):385–386. doi:10.1093/ndt/gfm701

    PubMed  Google Scholar 

  256. Badsha H, Teh CL, Kong KO, Lian TY, Chng HH (2004) Pulmonary hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 33(6):414–421

    PubMed  Google Scholar 

  257. Esmaeilbeigi F, Juvet S, Hwang D, Mittoo S (2012) Desquamative interstitial pneumonitis in a patient with systemic lupus erythematosus. Can Respir J : J Can Thoracic Soc 19(1):50–52

    Google Scholar 

  258. Haupt HM, Moore GW, Hutchins GM (1981) The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients. Am J Med 71(5):791–798

    PubMed  CAS  Google Scholar 

  259. Matthay RA, Schwarz MI, Petty TL, Stanford RE, Gupta RC, Sahn SA, Steigerwald JC (1975) Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore) 54(5):397–409

    CAS  Google Scholar 

  260. Cervera R, Font J, Pare C, Azqueta M, Perez-Villa F, Lopez-Soto A, Ingelmo M (1992) Cardiac disease in systemic lupus erythematosus: prospective study of 70 patients. Ann Rheum Dis 51(2):156–159

    PubMed  CAS  PubMed Central  Google Scholar 

  261. Law WG, Thong BY, Lian TY, Kong KO, Chng HH (2005) Acute lupus myocarditis: clinical features and outcome of an oriental case series. Lupus 14(10):827–831

    PubMed  CAS  Google Scholar 

  262. Nihoyannopoulos P, Gomez PM, Joshi J, Loizou S, Walport MJ, Oakley CM (1990) Cardiac abnormalities in systemic lupus erythematosus. Association with raised anticardiolipin antibodies. Circulation 82(2):369–375

    PubMed  CAS  Google Scholar 

  263. Crozier IG, Li E, Milne MJ, Nicholls MG (1990) Cardiac involvement in systemic lupus erythematosus detected by echocardiography. Am J Cardiol 65(16):1145–1148

    PubMed  CAS  Google Scholar 

  264. Sturfelt G, Eskilsson J, Nived O, Truedsson L, Valind S (1992) Cardiovascular disease in systemic lupus erythematosus. A study of 75 patients form a defined population. Medicine (Baltimore) 71(4):216–223

    CAS  Google Scholar 

  265. Wolkove N, Frank H (1974) Lupus pericarditis. Can Med Assoc J 111(12):1331–1333

    PubMed  CAS  PubMed Central  Google Scholar 

  266. Castier MB, Albuquerque EM, Menezes ME, Klumb E, Albanesi Filho FM (2000) Cardiac tamponade in systemic lupus erythematosus. Report of four cases. Arq Bras Cardiol 75(5):446–448

    PubMed  CAS  Google Scholar 

  267. Goldenber D (1973) Pericardial-fluid complement. Ann Intern Med 78(5):786

    PubMed  CAS  Google Scholar 

  268. Doherty NE, Siegel RJ (1985) Cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 110(6):1257–1265

    PubMed  CAS  Google Scholar 

  269. Harvey AM, Shulman LE, Tumulty PA, Conley CL, Schoenrich EH (1954) Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine (Baltimore) 33(4):291–437

    CAS  Google Scholar 

  270. Badui E, Garcia-Rubi D, Robles E, Jimenez J, Juan L, Deleze M, Diaz A, Mintz G (1985) Cardiovascular manifestations in systemic lupus erythematosus. Prospective study of 100 patients. Angiology 36(7):431–441

    PubMed  CAS  Google Scholar 

  271. Estes D, Christian CL (1971) The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 50(2):85–95

    CAS  Google Scholar 

  272. Bulkley BH, Roberts WC (1975) The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med 58(2):243–264

    PubMed  CAS  Google Scholar 

  273. Esscher E, Scott JS (1979) Congenital heart block and maternal systemic lupus erythematosus. Br Med J 1(6173):1235–1238

    PubMed  CAS  PubMed Central  Google Scholar 

  274. Buyon JP, Ben-Chetrit E, Karp S, Roubey RA, Pompeo L, Reeves WH, Tan EM, Winchester R (1989) Acquired congenital heart block. Pattern of maternal antibody response to biochemically defined antigens of the SSA/Ro-SSB/La system in neonatal lupus. J Clin Invest 84(2):627–634. doi:10.1172/JCI114208

    PubMed  CAS  PubMed Central  Google Scholar 

  275. Derksen RH, Meilof JF (1992) Anti-Ro/SS-A and anti-La/SS-B autoantibody levels in relation to systemic lupus erythematosus disease activity and congenital heart block. A longitudinal study comprising two consecutive pregnancies in a patient with systemic lupus erythematosus. Arthritis Rheum 35(8):953–959

    PubMed  CAS  Google Scholar 

  276. Fritsch C, Hoebeke J, Dali H, Ricchiuti V, Isenberg DA, Meyer O, Muller S (2006) 52-kDa Ro/SSA epitopes preferentially recognized by antibodies from mothers of children with neonatal lupus and congenital heart block. Arthritis Res & Ther 8(1):R4. doi:10.1186/ar1848

    Google Scholar 

  277. Reed BR, Lee LA, Harmon C, Wolfe R, Wiggins J, Peebles C, Weston WL (1983) Autoantibodies to SS-A/Ro in infants with congenital heart block. J Pediatr 103(6):889–891

    PubMed  CAS  Google Scholar 

  278. Eftekhari P, Salle L, Lezoualc'h F, Mialet J, Gastineau M, Briand JP, Isenberg DA, Fournie GJ, Argibay J, Fischmeister R, Muller S, Hoebeke J (2000) Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. Eur J Immunol 30(10):2782–2790. doi:10.1002/1521-4141(200010)30:10<2782::AID-IMMU2782>3.0.CO;2-9

    PubMed  CAS  Google Scholar 

  279. Roldan CA, Shively BK, Crawford MH (1996) An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med 335(19):1424–1430. doi:10.1056/NEJM199611073351903

    PubMed  CAS  Google Scholar 

  280. Libman E, Sacks B (1924) A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med 33(8):701–737. doi:10.1001/archinte.1924.00110300044002

    Google Scholar 

  281. D'Alton JG, Preston DN, Bormanis J, Green MS, Kraag GR (1985) Multiple transient ischemic attacks, lupus anticoagulant and verrucous endocarditis. Stroke 16(3):512–514

    PubMed  Google Scholar 

  282. Bidani AK, Roberts JL, Schwartz MM, Lewis EJ (1980) Immunopathology of cardiac lesions in fatal systemic lupus erythematosus. Am J Med 69(6):849–858

    PubMed  CAS  Google Scholar 

  283. Ziporen L, Goldberg I, Arad M, Hojnik M, Ordi-Ros J, Afek A, Blank M, Sandbank Y, Vilardell-Tarres M, de Torres I, Weinberger A, Asherson RA, Kopolovic Y, Shoenfeld Y (1996) Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic findings in deformed heart valves. Lupus 5(3):196–205

    PubMed  CAS  Google Scholar 

  284. Skaggs BJ, Hahn BH, McMahon M (2012) Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol 8(4):214–223. doi:10.1038/nrrheum.2012.14

    PubMed  CAS  PubMed Central  Google Scholar 

  285. Fesmire J, Wolfson-Reichlin M, Reichlin M (2010) Effects of autoimmune antibodies anti-lipoprotein lipase, anti-low density lipoprotein, and anti-oxidized low density lipoprotein on lipid metabolism and atherosclerosis in systemic lupus erythematosus. Rev Bras Reumatol 50(5):539–551

    PubMed  PubMed Central  Google Scholar 

  286. O'Neill SG, Giles I, Lambrianides A, Manson J, D'Cruz D, Schrieber L, March LM, Latchman DS, Isenberg DA, Rahman A (2010) Antibodies to apolipoprotein A-I, high-density lipoprotein, and C-reactive protein are associated with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 62(3):845–854. doi:10.1002/art.27286

    PubMed  Google Scholar 

  287. Cieslik P, Hrycek A, Klucinski P (2008) Vasculopathy and vasculitis in systemic lupus erythematosus. Pol Arch Med Wewn 118(1–2):57–63

    PubMed  Google Scholar 

  288. Calamia KT, Balabanova M (2004) Vasculitis in systemic lupus erythematosis. Clin Dermatol 22(2):148–156. doi:10.1016/j.clindermatol.2003.12.022

    PubMed  Google Scholar 

  289. Ramos-Casals M, Nardi N, Lagrutta M, Brito-Zeron P, Bove A, Delgado G, Cervera R, Ingelmo M, Font J (2006) Vasculitis in systemic lupus erythematosus: prevalence and clinical characteristics in 670 patients. Medicine (Baltimore) 85(2):95–104. doi:10.1097/01.md.0000216817.35937.70

    Google Scholar 

  290. Kumar N, Choudhary N, Agarwal G, Rizvi Y, Kaul B, Ahlawat R (2007) Extensive medium-vessel vasculitis with SLE: an unusual association. J Clin Rheumatol 13(3):140–142. doi:10.1097/RHU.0b013e318064e779

    PubMed  Google Scholar 

  291. Matsumoto T, Kobayashi S, Shimizu H, Nakajima M, Watanabe S, Kitami N, Sato N, Abe H, Aoki Y, Hoshi T, Hashimoto H (2000) The liver in collagen diseases: pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver. Liver 20(5):366–373

    PubMed  CAS  Google Scholar 

  292. Swanepoel CR, Floyd A, Allison H, Learmonth GM, Cassidy MJ, Pascoe MD (1983) Acute acalculous cholecystitis complicating systemic lupus erythematosus: case report and review. Br Med J (Clin Res Ed) 286(6361):251–252

    CAS  Google Scholar 

  293. Yuan S, Ye Y, Chen D, Qiu Q, Zhan Z, Lian F, Li H, Liang L, Xu H, Yang X (2013) Lupus mesenteric vasculitis: clinical features and associated factors for the recurrence and prognosis of disease. Semin Arthritis Rheum. doi:10.1016/j.semarthrit.2013.11.005

    PubMed  Google Scholar 

  294. Ashouri JF, Davis JL, Farkas A, Durack JC, Ramachandran R, Dall'Era M (2012) A young woman with systemic lupus erythematosus and extensive mesenteric vasculitis involving small and medium vessels. Arthritis Care Res (Hoboken) 64(12):1928–1933. doi:10.1002/acr.21833

    Google Scholar 

  295. Weisman MH, McDanald EC, Wilson CB (1981) Studies of the pathogenesis of interstitial cystitis, obstructive uropathy, and intestinal malabsorption in a patient with systemic lupus erythematosus. Am J Med 70(4):875–881

    PubMed  CAS  Google Scholar 

  296. Geri G, Saadoun D, Guillevin R, Crozier S, Lubetzki C, Mokhtari K, Amoura Z, Wechsler B, Le Boutin D, Costedoat-Chalumeau N, Samson Y, Cacoub P (2014) Central nervous system angiitis: a series of 31 patients. Clin Rheumatol 33(1):105–110. doi:10.1007/s10067-013-2403-3

    PubMed  Google Scholar 

  297. Sun W, Jiao Y, Cui B, Gao X, Xia Y, Zhao Y (2013) Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis. Lab Invest 93(6):626–638. doi:10.1038/labinvest.2013.61

    PubMed  CAS  Google Scholar 

  298. Sciascia S, Bertolaccini ML, Baldovino S, Roccatello D, Khamashta MA, Sanna G (2013) Central nervous system involvement in systemic lupus erythematosus: overview on classification criteria. Autoimmun Rev 12(3):426–429. doi:10.1016/j.autrev.2012.08.014

    PubMed  Google Scholar 

  299. Borowoy AM, Pope JE, Silverman E, Fortin PR, Pineau C, Smith CD, Arbillaga H, Gladman D, Urowitz M, Zummer M, Hudson M, Tucker L, Peschken C (2012) Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 faces of lupus cohort. Semin Arthritis Rheum 42(2):179–185. doi:10.1016/j.semarthrit.2012.03.011

    PubMed  Google Scholar 

  300. Levy DM, Ardoin SP, Schanberg LE (2009) Neurocognitive impairment in children and adolescents with systemic lupus erythematosus. Nat Clin Pract Rheumatol 5(2):106–114. doi:10.1038/ncprheum0988

    PubMed  PubMed Central  Google Scholar 

  301. Bosma GP, Middelkoop HA, Rood MJ, Bollen EL, Huizinga TW, van Buchem MA (2002) Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 46(10):2665–2672. doi:10.1002/art.10574

    PubMed  Google Scholar 

  302. Appenzeller S, Bonilha L, Rio PA, Min Li L, Costallat LT, Cendes F (2007) Longitudinal analysis of gray and white matter loss in patients with systemic lupus erythematosus. Neuroimage 34(2):694–701. doi:10.1016/j.neuroimage.2006.09.029

    PubMed  Google Scholar 

  303. Sibbitt WL Jr, Brooks WM, Kornfeld M, Hart BL, Bankhurst AD, Roldan CA (2010) Magnetic resonance imaging and brain histopathology in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum 40(1):32–52. doi:10.1016/j.semarthrit.2009.08.005

    PubMed  PubMed Central  Google Scholar 

  304. Sibbitt WL Jr, Sibbitt RR, Brooks WM (1999) Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 42(10):2026–2038. doi:10.1002/1529-0131(199910)42:10<2026::aid-anr2>3.0.co;2-j

    PubMed  Google Scholar 

  305. Luyendijk J, Steens SC, Ouwendijk WJ, Steup-Beekman GM, Bollen EL, van der Grond J, Huizinga TW, Emmer BJ, van Buchem MA (2011) Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging. Arthritis Rheum 63(3):722–732. doi:10.1002/art.30157

    PubMed  CAS  Google Scholar 

  306. Nobili F, Mignone A, Rossi E, Morbelli S, Piccardo A, Puppo F, Indiveri F, Sambuceti G, Rodriguez G (2006) Migraine during systemic lupus erythematosus: findings from brain single photon emission computed tomography. J Rheumatol 33(11):2184–2191

    PubMed  Google Scholar 

  307. Zhang X, Zhu Z, Zhang F, Shu H, Li F, Dong Y (2005) Diagnostic value of single-photon-emission computed tomography in severe central nervous system involvement of systemic lupus erythematosus: a case–control study. Arthritis Rheum 53(6):845–849. doi:10.1002/art.21591

    PubMed  Google Scholar 

  308. Appenzeller S, Amorim BJ, Ramos CD, Rio PA, de Etchebehere EC, Camargo EE, Cendes F, Costallat LT (2007) Voxel-based morphometry of brain SPECT can detect the presence of active central nervous system involvement in systemic lupus erythematosus. Rheumatology (Oxford) 46(3):467–472. doi:10.1093/rheumatology/kel255

    CAS  Google Scholar 

  309. Kapadia M, Sakic B (2011) Autoimmune and inflammatory mechanisms of CNS damage. Prog Neurobiol 95(3):301–333. doi:10.1016/j.pneurobio.2011.08.008

    PubMed  CAS  Google Scholar 

  310. Axford JS, Howe FA, Heron C, Griffiths JR (2001) Sensitivity of quantitative (1)H magnetic resonance spectroscopy of the brain in detecting early neuronal damage in systemic lupus erythematosus. Ann Rheum Dis 60(2):106–111

    PubMed  CAS  PubMed Central  Google Scholar 

  311. Trysberg E, Nylen K, Rosengren LE, Tarkowski A (2003) Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthritis Rheum 48(10):2881–2887. doi:10.1002/art.11279

    PubMed  Google Scholar 

  312. Kwiecinski J, Klak M, Trysberg E, Blennow K, Tarkowski A, Jin T (2009) Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 60(7):2094–2101. doi:10.1002/art.24603

    PubMed  CAS  Google Scholar 

  313. Gono T, Kawaguchi Y, Kaneko H, Nishimura K, Hanaoka M, Kataoka S, Okamoto Y, Katsumata Y, Yamanaka H (2011) Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 50(9):1578–1585. doi:10.1093/rheumatology/keq408

    CAS  Google Scholar 

  314. Lefranc D, Launay D, Dubucquoi S, de Seze J, Dussart P, Vermersch M, Hachulla E, Hatron PY, Vermersch P, Mouthon L, Prin L (2007) Characterization of discriminant human brain antigenic targets in neuropsychiatric systemic lupus erythematosus using an immunoproteomic approach. Arthritis Rheum 56(10):3420–3432. doi:10.1002/art.22863

    PubMed  CAS  Google Scholar 

  315. Ndhlovu M, Preuss BE, Dengjel J, Stevanovic S, Weiner SM, Klein R (2011) Identification of alpha-tubulin as an autoantigen recognized by sera from patients with neuropsychiatric systemic lupus erythematosus. Brain Behav Immun 25(2):279–285. doi:10.1016/j.bbi.2010.09.019

    PubMed  CAS  Google Scholar 

  316. Galeazzi M, Annunziata P, Sebastiani GD, Bellisai F, Campanella V, Ferrara GB, Font J, Houssiau F, Passiu G, De Ramon GE, Fernandez-Nebro A, Bracci L, Scorza R, Puddu P, Jedryka-Goral A, Smolen J, Tincani A, Carcassi C, Morozzi G, Marcolongo R (2000) Anti-ganglioside antibodies in a large cohort of European patients with systemic lupus erythematosus: clinical, serological, and HLA class II gene associations. European Concerted Action on the Immunogenetics of SLE The Journal of rheumatology 27(1):135–141

    CAS  Google Scholar 

  317. Sanna G, Piga M, Terryberry JW, Peltz MT, Giagheddu S, Satta L, Ahmed A, Cauli A, Montaldo C, Passiu G, Peter JB, Shoenfeld Y, Mathieu A (2000) Central nervous system involvement in systemic lupus erythematosus: cerebral imaging and serological profile in patients with and without overt neuropsychiatric manifestations. Lupus 9(8):573–583

    PubMed  CAS  Google Scholar 

  318. Afeltra A, Garzia P, Mitterhofer AP, Vadacca M, Galluzzo S, Del Porto F, Finamore L, Pascucci S, Gasparini M, Lagana B, Caccavo D, Ferri GM, Amoroso A, Francia A (2003) Neuropsychiatric lupus syndromes: relationship with antiphospholipid antibodies. Neurology 61(1):108–110

    PubMed  Google Scholar 

  319. Hanly JG, Urowitz MB, Siannis F, Farewell V, Gordon C, Bae SC, Isenberg D, Dooley MA, Clarke A, Bernatsky S, Gladman D, Fortin PR, Manzi S, Steinsson K, Bruce IN, Ginzler E, Aranow C, Wallace DJ, Ramsey-Goldman R, van Vollenhoven R, Sturfelt G, Nived O, Sanchez-Guerrero J, Alarcon GS, Petri M, Khamashta M, Zoma A, Font J, Kalunian K, Douglas J, Qi Q, Thompson K, Merrill JT (2008) Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study. Arthritis Rheum 58(3):843–853. doi:10.1002/art.23218

    PubMed  CAS  Google Scholar 

  320. Meroni PL, Tincani A, Sepp N, Raschi E, Testoni C, Corsini E, Cavazzana I, Pellegrini S, Salmaggi A (2003) Endothelium and the brain in CNS lupus. Lupus 12(12):919–928

    PubMed  CAS  Google Scholar 

  321. Lu XY, Chen XX, Huang LD, Zhu CQ, Gu YY, Ye S (2010) Anti-alpha-internexin autoantibody from neuropsychiatric lupus induce cognitive damage via inhibiting axonal elongation and promote neuron apoptosis. PLoS ONE 5(6):e11124. doi:10.1371/journal.pone.0011124

    PubMed  PubMed Central  Google Scholar 

  322. Sasajima T, Watanabe H, Sato S, Sato Y, Ohira H (2006) Anti-triosephosphate isomerase antibodies in cerebrospinal fluid are associated with neuropsychiatric lupus. J Neuroimmunol 181(1–2):150–156. doi:10.1016/j.jneuroim.2006.09.003

    PubMed  CAS  Google Scholar 

  323. Jurencak R, Fritzler M, Tyrrell P, Hiraki L, Benseler S, Silverman E (2009) Autoantibodies in pediatric systemic lupus erythematosus: ethnic grouping, cluster analysis, and clinical correlations. J Rheumatol 36(2):416–421. doi:10.3899/jrheum.080588

    PubMed  Google Scholar 

  324. Sun XY, Shi J, Han L, Su Y, Li ZG (2008) Anti-histones antibodies in systemic lupus erythematosus: prevalence and frequency in neuropsychiatric lupus. J Clin Lab Anal 22(4):271–277. doi:10.1002/jcla.20248

    PubMed  Google Scholar 

  325. Kowal C, Degiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT, Diamond B (2006) Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci U S A 103(52):19854–19859. doi:10.1073/pnas.0608397104

    PubMed  CAS  PubMed Central  Google Scholar 

  326. Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B (2006) Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci U S A 103(3):678–683. doi:10.1073/pnas.0510055103

    PubMed  CAS  PubMed Central  Google Scholar 

  327. Kowal C, DeGiorgio LA, Nakaoka T, Hetherington H, Huerta PT, Diamond B, Volpe BT (2004) Cognition and immunity; antibody impairs memory. Immunity 21(2):179–188. doi:10.1016/j.immuni.2004.07.011

    PubMed  CAS  Google Scholar 

  328. Baraczka K, Nekam K, Pozsonyi T, Jakab L, Szongoth M, Sesztak M (2001) Concentration of soluble adhesion molecules (sVCAM-1, sICAM-1 and sL-selectin) in the cerebrospinal fluid and serum of patients with multiple sclerosis and systemic lupus erythematosus with central nervous involvement. Neuroimmunomodulation 9(1):49–54

    PubMed  CAS  Google Scholar 

  329. Baraczka K, Nekam K, Pozsonyi T, Szuts I, Ormos G (2004) Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus. Eur J Neurol 11(1):37–42

    PubMed  CAS  Google Scholar 

  330. Katsumata Y, Harigai M, Kawaguchi Y, Fukasawa C, Soejima M, Takagi K, Tanaka M, Ichida H, Tochimoto A, Kanno T, Nishimura K, Kamatani N, Hara M (2007) Diagnostic reliability of cerebral spinal fluid tests for acute confusional state (delirium) in patients with systemic lupus erythematosus: interleukin 6 (IL-6), IL-8, interferon-alpha, IgG index, and Q-albumin. J Rheumatol 34(10):2010–2017

    PubMed  CAS  Google Scholar 

  331. Trysberg E, Carlsten H, Tarkowski A (2000) Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 9(7):498–503

    PubMed  CAS  Google Scholar 

  332. Fragoso-Loyo H, Richaud-Patin Y, Orozco-Narvaez A, Davila-Maldonado L, Atisha-Fregoso Y, Llorente L, Sanchez-Guerrero J (2007) Interleukin-6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus. Arthritis Rheum 56(4):1242–1250. doi:10.1002/art.22451

    PubMed  CAS  Google Scholar 

  333. Svenungsson E, Andersson M, Brundin L, van Vollenhoven R, Khademi M, Tarkowski A, Greitz D, Dahlstrom M, Lundberg I, Klareskog L, Olsson T (2001) Increased levels of proinflammatory cytokines and nitric oxide metabolites in neuropsychiatric lupus erythematosus. Ann Rheum Dis 60(4):372–379

    PubMed  CAS  PubMed Central  Google Scholar 

  334. Trysberg E, Tarkowski A (2004) Cerebral inflammation and degeneration in systemic lupus erythematosus. Curr Opin Rheumatol 16(5):527–533

    PubMed  Google Scholar 

  335. Tomita M, Holman BJ, Williams LS, Pang KC, Santoro TJ (2001) Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus. J Neurosci Res 64(1):26–33

    PubMed  CAS  Google Scholar 

  336. Mondal TK, Saha SK, Miller VM, Seegal RF, Lawrence DA (2008) Autoantibody-mediated neuroinflammation: pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model. Brain Behav Immun 22(6):949–959. doi:10.1016/j.bbi.2008.01.013

    PubMed  CAS  Google Scholar 

  337. Walport MJ (2002) Complement and systemic lupus erythematosus. Arthritis Res 4(Suppl 3):S279–S293

    PubMed  PubMed Central  Google Scholar 

  338. Jacob A, Hack B, Chiang E, Garcia JG, Quigg RJ, Alexander JJ (2010) C5a alters blood–brain barrier integrity in experimental lupus. FASEB J 24(6):1682–1688. doi:10.1096/fj.09-138834

    PubMed  CAS  PubMed Central  Google Scholar 

  339. Jacob A, Bao L, Brorson J, Quigg RJ, Alexander JJ (2010) C3aR inhibition reduces neurodegeneration in experimental lupus. Lupus 19(1):73–82. doi:10.1177/0961203309348978

    PubMed  CAS  PubMed Central  Google Scholar 

  340. Jacob A, Hack B, Bai T, Brorson JR, Quigg RJ, Alexander JJ (2010) Inhibition of C5a receptor alleviates experimental CNS lupus. J Neuroimmunol 221(1–2):46–52. doi:10.1016/j.jneuroim.2010.02.011

    PubMed  CAS  PubMed Central  Google Scholar 

  341. Alexander JJ, Jacob A, Bao L, Macdonald RL, Quigg RJ (2005) Complement-dependent apoptosis and inflammatory gene changes in murine lupus cerebritis. J Immunol 175(12):8312–8319

    PubMed  CAS  Google Scholar 

  342. Alexander JJ, Bao L, Jacob A, Kraus DM, Holers VM, Quigg RJ (2003) Administration of the soluble complement inhibitor, Crry-Ig, reduces inflammation and aquaporin 4 expression in lupus cerebritis. Biochim Biophys Acta 1639(3):169–176

    PubMed  CAS  Google Scholar 

  343. Alexander JJ, Jacob A, Vezina P, Sekine H, Gilkeson GS, Quigg RJ (2007) Absence of functional alternative complement pathway alleviates lupus cerebritis. Eur J Immunol 37(6):1691–1701. doi:10.1002/eji.200636638

    PubMed  CAS  Google Scholar 

  344. Ainiala H, Hietaharju A, Dastidar P, Loukkola J, Lehtimaki T, Peltola J, Korpela M, Heinonen T, Nikkari ST (2004) Increased serum matrix metalloproteinase 9 levels in systemic lupus erythematosus patients with neuropsychiatric manifestations and brain magnetic resonance imaging abnormalities. Arthritis Rheum 50(3):858–865. doi:10.1002/art.20045

    PubMed  CAS  Google Scholar 

  345. Voulgarelis M, Kokori SI, Ioannidis JP, Tzioufas AG, Kyriaki D, Moutsopoulos HM (2000) Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin. Ann Rheum Dis 59(3):217–222

    PubMed  CAS  PubMed Central  Google Scholar 

  346. Schett G, Firbas U, Fureder W, Hiesberger H, Winkler S, Wachauer D, Koller M, Kapiotis S, Smolen J (2001) Decreased serum erythropoietin and its relation to anti-erythropoietin antibodies in anaemia of systemic lupus erythematosus. Rheumatology (Oxford) 40(4):424–431

    CAS  Google Scholar 

  347. Garcia-Valladares I, Atisha-Fregoso Y, Richaud-Patin Y, Jakez-Ocampo J, Soto-Vega E, Elias-Lopez D, Carrillo-Maravilla E, Cabiedes J, Ruiz-Arguelles A, Llorente L (2006) Diminished expression of complement regulatory proteins (CD55 and CD59) in lymphocytes from systemic lupus erythematosus patients with lymphopenia. Lupus 15(9):600–605

    PubMed  CAS  Google Scholar 

  348. Ruiz-Arguelles A, Llorente L (2007) The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias. Autoimmun Rev 6(3):155–161. doi:10.1016/j.autrev.2006.09.008

    PubMed  CAS  Google Scholar 

  349. Midgley A, McLaren Z, Moots RJ, Edwards SW, Beresford MW (2009) The role of neutrophil apoptosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 60(8):2390–2401. doi:10.1002/art.24634

    PubMed  CAS  Google Scholar 

  350. Hepburn AL, Narat S, Mason JC (2010) The management of peripheral blood cytopenias in systemic lupus erythematosus. Rheumatology (Oxford) 49(12):2243–2254. doi:10.1093/rheumatology/keq269

    CAS  Google Scholar 

  351. Enami T, Suzuki T, Ito S, Yoshimi A, Sugihara M, Mamura M, Hayashi T, Goto D, Matsumoto I, Tsutsumi A, Sumida T (2007) Successful treatment of refractory thrombotic thrombocytopenic purpura with cyclosporine and corticosteroids in a patient with systemic lupus erythematosus and antibodies to ADAMTS13. Intern Med 46(13):1033–1037

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge research support from the National Institutes of Heath grants AI26833 and RR301812 and the University of Tennessee Health Science Center (UTHSC) of Excellence for Diseases of Connective Tissues (TNM) and the Goodman Chair of Excellence in Medicine, the Division of Connective Tissue Diseases, Department of Medicine, UTHSC, and the Department of Veterans Affairs Medical Center, Memphis, TN (AEP). The authors thank and acknowledge Ms. Virginia Woo-Rasberry and Ms. Carol Farmer for their assistance in preparing the manuscript. The authors also acknowledge and thank Marko Radic for review and comments.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tony N. Marion.

Additional information

This article is a contribution to the special issue on Mechanisms of Tissue Injury in Autoimmune Diseases - Guest Editor: Dan Eilat

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marion, T.N., Postlethwaite, A.E. Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus. Semin Immunopathol 36, 495–517 (2014). https://doi.org/10.1007/s00281-014-0440-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-014-0440-x

Keywords

Navigation