Advertisement

Evaluating the Role of Nucleic Acid Antigens in Murine Models of Systemic Lupus Erythematosus

  • Amanda A. Watkins
  • Ramon G. B. Bonegio
  • Ian R. Rifkin
Part of the Methods in Molecular Biology book series (MIMB, volume 1169)

Abstract

Impaired apoptotic cell clearance is thought to contribute to the pathogenesis of systemic autoimmune disease, in particular systemic lupus erythematosus (SLE). Endogenous RNA- and DNA-containing autoantigens released from dying cells can engage Toll-like receptors (TLR) 7/8 and TLR9, respectively in a number of immune cell types, thereby promoting innate and adaptive immune responses. Mouse models of lupus reliably phenocopy many of the characteristic features of SLE in humans and these models have proved invaluable in defining disease mechanisms. TLR7 signaling is essential for the development of autoantibodies to RNA and RNA-associated proteins like Sm and RNP, while TLR9 signaling is important for the development of antibodies to DNA and chromatin. TLR7 deficiency ameliorates end-organ disease, but, surprisingly, TLR9 deficiency exacerbates disease, possibly as a result of TLR7 overactivity in TLR9-deficient mice. Deficiency of interferon regulatory factor 5 (IRF5) inhibits autoantibody production and ameliorates disease likely due to its role in both TLR7 and TLR9 signaling. In this report we describe methods to analyze two commonly used mouse models of SLE in which TLRs and/or IRF5 have been shown to play a role in disease pathogenesis.

Key words

DNA autoantigens RNA autoantigens Anti-nuclear autoantibody assays Mouse models Glomerulonephritis Toll-like receptors Systemic lupus erythematosus 

Notes

Acknowledgements

This work was supported by a grant from the Alliance for Lupus Research (I.R.R) and the following grants from the National Institutes of Health: P01 AR050256 (I.R.R), RO1 DK090558 (R.G.B.B), and a Research Training in Immunology T32 Grant AI007309-23 (A.A.W).

References

  1. 1.
    Liu Z, Davidson A (2012) Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med 18:871–882PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Perry D, Sang A, Yin Y, Zheng YY, Morel L (2011) Murine models of systemic lupus erythematosus. J Biomed Biotechnol 2011:271694PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Cheung YH, Loh C, Pau E, Kim J, Wither J (2009) Insights into the genetic basis and immunopathogenesis of systemic lupus erythematosus from the study of mouse models. Semin Immunol 21:372–382PubMedCrossRefGoogle Scholar
  4. 4.
    Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277–285PubMedCrossRefGoogle Scholar
  5. 5.
    Andrews BS, Eisenberg RA, Theofilopoulos AN et al (1978) Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148:1198–1215PubMedCrossRefGoogle Scholar
  6. 6.
    Dixon FJ, Andrews BS, Eisenberg RA, McConahey PJ, Theofilopoulos AN, Wilson CB (1978) Etiology and pathogenesis of a spontaneous lupus-like syndrome in mice. Arthritis Rheum 21:S64–S67PubMedCrossRefGoogle Scholar
  7. 7.
    Kelley VE, Roths JB (1985) Interaction of mutant lpr gene with background strain influences renal disease. Clin Immunol Immunopathol 37:220–229PubMedCrossRefGoogle Scholar
  8. 8.
    Ghoreishi M, Dutz JP (2009) Murine models of cutaneous involvement in lupus erythematosus. Autoimmun Rev 8:484–487PubMedCrossRefGoogle Scholar
  9. 9.
    Marshak-Rothstein A, Rifkin IR (2007) Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol 25:419–441PubMedCrossRefGoogle Scholar
  10. 10.
    Hemmi H, Takeuchi O, Kawai T et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745PubMedCrossRefGoogle Scholar
  11. 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 25:417–428PubMedCrossRefGoogle Scholar
  12. 12.
    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 202:321–331PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531PubMedCrossRefGoogle Scholar
  14. 14.
    Heil F, Hemmi H, Hochrein H et al (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529PubMedCrossRefGoogle Scholar
  15. 15.
    Patole PS, Grone HJ, Segerer S et al (2005) Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J Am Soc Nephrol 16:1326–1338PubMedCrossRefGoogle Scholar
  16. 16.
    Pawar RD, Patole PS, Zecher D et al (2006) Toll-like receptor-7 modulates immune complex glomerulonephritis. J Am Soc Nephrol 17:141–149PubMedCrossRefGoogle Scholar
  17. 17.
    Drexler SK, Sacre SM, Foxwell BM (2006) Toll-like receptors: a new target in rheumatoid arthritis? Expert Rev Clin Immunol 2:585–599PubMedCrossRefGoogle Scholar
  18. 18.
    Roelofs MF, Joosten LA, Abdollahi-Roodsaz S et al (2005) The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum 52:2313–2322PubMedCrossRefGoogle Scholar
  19. 19.
    Miller LS, Modlin RL (2007) Toll-like receptors in the skin. Semin Immunopathol 29:15–26PubMedCrossRefGoogle Scholar
  20. 20.
    Anders HJ, Vielhauer V, Eis V et al (2004) Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J 18:534–536PubMedGoogle Scholar
  21. 21.
    Bolland S, Yim YS, Tus K, Wakeland EK, Ravetch JV (2002) Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(−/−) mice. J Exp Med 195:1167–1174PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Boross P, Arandhara VL, Martin-Ramirez J et al (2011) The inhibiting Fc receptor for IgG, FcgammaRIIB, is a modifier of autoimmune susceptibility. J Immunol 187:1304–1313PubMedCrossRefGoogle Scholar
  23. 23.
    Bolland S, Ravetch JV (1999) Inhibitory pathways triggered by ITIM-containing receptors. Adv Immunol 72:149–177PubMedCrossRefGoogle Scholar
  24. 24.
    Richez C, Yasuda K, Bonegio RG et al (2010) IFN regulatory factor 5 is required for disease development in the FcgammaRIIB−/−Yaa and FcgammaRIIB−/− mouse models of systemic lupus erythematosus. J Immunol 184:796–806PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Subramanian S, Tus K, Li QZ et al (2006) A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci U S A 103:9970–9975PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312:1669–1672PubMedCrossRefGoogle Scholar
  27. 27.
    Santiago-Raber ML, Kikuchi S, Borel P et al (2008) Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus. J Immunol 181:1556–1562PubMedCrossRefGoogle Scholar
  28. 28.
    Savitsky D, Tamura T, Yanai H, Taniguchi T (2010) Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother 59:489–510PubMedCrossRefGoogle Scholar
  29. 29.
    Ronnblom L (2011) The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups J Med Sci 116:227–237PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Paun A, Pitha PM (2007) The IRF family, revisited. Biochimie 89:744–753PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Deng Y, Tsao BP (2010) Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6:683–692PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Tada Y, Kondo S, Aoki S et al (2011) Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice. Arthritis Rheum 63:738–748PubMedCrossRefGoogle Scholar
  33. 33.
    Sato-Hayashizaki A, Ohtsuji M, Lin Q et al (2011) Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcgamma receptor type IIb-deficient C57BL/6 genetic background. Arthritis Rheum 63:2930–2938PubMedCrossRefGoogle Scholar
  34. 34.
    Purtha WE, Swiecki M, Colonna M, Diamond MS, Bhattacharya D (2012) Spontaneous mutation of the Dock2 gene in Irf5−/− mice complicates interpretation of type I interferon production and antibody responses. Proc Natl Acad Sci U S A 109:E898–E904PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Yasuda K, Nündel K, Watkins AA et al (2013) Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2. Int Immunol 25:295–306Google Scholar
  36. 36.
    Wiik AS, Hoier-Madsen M, Forslid J, Charles P, Meyrowitsch J (2010) Antinuclear antibodies: a contemporary nomenclature using HEp-2 cells. J Autoimmun 35:276–290PubMedCrossRefGoogle Scholar
  37. 37.
    Slater NG, Cameron JS, Lessof MH (1976) The Crithidia luciliae kinetoplast immunofluorescence test in systemic lupus erythematosus. Clin Exp Immunol 25:480–486PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, New York 2014

Authors and Affiliations

  • Amanda A. Watkins
    • 1
  • Ramon G. B. Bonegio
    • 1
  • Ian R. Rifkin
    • 1
  1. 1.Renal Section, Department of MedicineBoston University School of MedicineBostonUSA

Personalised recommendations