Immunologic Research

, Volume 63, Issue 1–3, pp 187–196 | Cite as

Molecular studies of lupus nephritis kidneys

  • Anne Davidson
  • Ramalingam Bethunaickan
  • Celine Berthier
  • Ranjit Sahu
  • Weijia Zhang
  • Matthias Kretzler
AUTOIMMUNITY/IMMUNOREGULATION/INFLAMMATION

Abstract

Lupus nephritis is a devastating complication of systemic lupus erythematosus (SLE) for which current therapies are insufficiently effective. Histologic evaluation of renal biopsies is a poor predictor of therapeutic response or outcome. Integrated immunologic, genomic and proteomic approaches may yield new insights into disease pathogenesis and thereby improve therapeutic strategies for lupus nephritis. Given the lack of sequential biopsies from humans, it also remains essential to study informative animal models of disease. Cross-species analyses can identify cells or pathways that are relevant to human disease and can be further studied in mouse models. Using a systems biology approach in which we compare molecular data from kidneys of three different mouse models of lupus nephritis with data from human lupus biopsies, we have found that inflammatory events escalate rapidly around the time of proteinuria onset. This is followed by hypoxia and metabolic stress, and by tubular and endothelial dysfunction. The failure of complete reversal of these abnormalities may increase the sensitivity of the kidney to further insult. We further found that renal macrophages and dendritic cells are key players in lupus nephritis both in mouse models and humans and that macrophages display a hybrid molecular profile that reflects incomplete resolution of inflammation and excessive tissue remodeling. Finally, our studies have suggested several new biomarkers for disease stage that can now be tested longitudinally in human SLE patients.

Keywords

Lupus Nephritis Macrophages Inflammation Biomarkers 

References

  1. 1.
    Sidiropoulos PI, Kritikos HD, Boumpas DT. Lupus nephritis flares. Lupus. 2005;14(1):49–52.PubMedCrossRefGoogle Scholar
  2. 2.
    Mok CC, Ying KY, Tang S, Leung CY, Lee KW, Ng WL, et al. Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum. 2004;50(8):2559–68.PubMedCrossRefGoogle Scholar
  3. 3.
    Wiesendanger M, Stanevsky A, Kovsky S, Diamond B. Novel therapeutics for systemic lupus erythematosus. Curr Opin Rheumatol. 2006;18(3):227–35.PubMedCrossRefGoogle Scholar
  4. 4.
    Davidson A, Aranow C. Pathogenesis and treatment of systemic lupus erythematosus nephritis. Curr Opin Rheumatol. 2006;18(5):468–75.PubMedGoogle Scholar
  5. 5.
    Chan TM. Preventing renal failure in patients with severe lupus nephritis. Kidney Int Suppl. 2005;94:S116–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’Nan P, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004;350(10):971–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Contreras G, Tozman E, Nahar N, Metz D. Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide. Lupus. 2005;14(Suppl 1):s33–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Costenbader KH, Solomon DH, Winkelmayer W, Brookhart MA. Incidence of end-stage renal disease due to Lupus Nephritis in the US, 1995–2004 Arthritis and Rheumatism. 2008(Supplementary):Abstract 1927.Google Scholar
  9. 9.
    Lefkowith JB, Kiehl M, Rubenstein J, DiValerio R, Bernstein K, Kahl L, et al. Heterogeneity and clinical significance of glomerular-binding antibodies in systemic lupus erythematosus. J Clin Invest. 1996;98(6):1373–80.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Li QZ, Xie C, Wu T, Mackay M, Aranow C, Putterman C, et al. Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J Clin Invest. 2005;115(12):3428–39.PubMedCrossRefGoogle Scholar
  11. 11.
    Bagavant H, Fu SM. Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol. 2009;21(5):489–94.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hedberg A, Mortensen ES, Rekvig OP. Chromatin as a target antigen in human and murine lupus nephritis. Arthritis Res Ther. 2011;13(2):214.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Turnberg D, Cook HT. Complement and glomerulonephritis: new insights. Curr Opin Nephrol Hypertens. 2005;14(3):223–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Clynes R, Dumitru C, Ravetch JV. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science. 1998;279(5353):1052–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Davidson A, Berthier C, Kretzler M. Pathogenetic mechanisms in lupus nephritis. In: Hahn B, Wallace D, editors. Dubois SLE, 8 ed. Amsterdam: Elsevier; 2012.Google Scholar
  16. 16.
    Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Rovin BH, Parikh SV, Alvarado A. The kidney biopsy in lupus nephritis: is it still relevant? Rheum Dis Clin North Am. 2014;40(3):537–52, ix.Google Scholar
  18. 18.
    Vandepapeliere J, Aydin S, Cosyns JP, Depresseux G, Jadoul M, Houssiau FA. Prognosis of proliferative lupus nephritis subsets in the Louvain Lupus Nephritis inception Cohort. Lupus. 2014;23(2):159–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Kono DH, Theofilopoulos AN. Genetics of systemic autoimmunity in mouse models of lupus. Int Rev Immunol. 2000;19(4–5):367–87.PubMedCrossRefGoogle Scholar
  20. 20.
    Morel L. Genetics of SLE: evidence from mouse models. Nat Rev Rheumatol. 2010;6(6):348–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol. 1985;37(1):269–390.PubMedCrossRefGoogle Scholar
  22. 22.
    Perry D, Sang A, Yin Y, Zheng YY, Morel L. Murine models of systemic lupus erythematosus. J Biomed Biotechnol. 2011;2011:271694.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bethunaickan R, Berthier CC, Ramanujam M, Sahu R, Zhang W, Sun Y, et al. A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis. J Immunol. 2011;186(8):4994–5003.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Schiffer L, Sinha J, Wang X, Huang W, von Gersdorff G, Schiffer M, et al. Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J Immunol. 2003;171(1):489–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Ramanujam M, Wang X, Huang W, Liu Z, Schiffer L, Tao H, et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest. 2006;116(3):724–34.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, et al. Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol. 2003;170(9):4818–25.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Ramanujam M, Bethunaickan R, Huang W, Tao H, Madaio MP, Davidson A. Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 mice. Arthritis Rheum. 2010;62(5):1457–68.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 2006;312(5780):1669–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Subramanian S, Tus K, Li QZ, Wang A, Tian XH, Zhou J, et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA. 2006;103(26):9970–5.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Akkerman A, Huang W, Wang X, Ramanujam M, Schiffer L, Madaio M, et al. CTLA4Ig prevents initiation but not evolution of anti-phospholipid syndrome in NZW/BXSB mice. Autoimmunity. 2004;37(6–7):445–51.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Hang LM, Izui S, Dixon FJ. (NZW x BXSB)F1 hybrid. A model of acute lupus and coronary vascular disease with myocardial infarction. J Exp Med. 1981;154(1):216–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Kahn P, Ramanujam M, Bethunaickan R, Huang W, Tao H, Madaio MP, et al. Prevention of murine antiphospholipid syndrome by BAFF blockade. Arthritis Rheum. 2008;58(9):2824–34.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Berthier CC, Bethunaickan R, Gonzalez-Rivera T, Nair V, Ramanujam M, Zhang W, et al. Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis. J Immunol. 2012;189(2):988–1001.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bethunaickan R, Berthier CC, Zhang W, Kretzler M, Davidson A. Comparative transcriptional profiling of 3 murine models of SLE nephritis reveals both unique and shared regulatory networks. PLoS ONE. 2013;8(10):e77489.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Bethunaickan R, Berthier CC, Zhang W, Eksi R, Li HD, Guan Y, et al. Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB x NZW)F1 and NZM2410 mice. Arthritis Rheumatol. 2014;66(8):2246–58.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H, et al. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol. 2008;180(3):1938–47.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hill GS, Delahousse M, Nochy D, Mandet C, Bariety J. Proteinuria and tubulointerstitial lesions in lupus nephritis. Kidney Int. 2001;60(5):1893–903.PubMedCrossRefGoogle Scholar
  38. 38.
    Hill GS, Delahousse M, Nochy D, Remy P, Mignon F, Mery JP, et al. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 2001;59(1):304–16.PubMedCrossRefGoogle Scholar
  39. 39.
    Yang N, Isbel NM, Nikolic-Paterson DJ, Li Y, Ye R, Atkins RC, et al. Local macrophage proliferation in human glomerulonephritis. Kidney Int. 1998;54(1):143–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Lindenmeyer M, Noessner E, Nelson PJ, Segerer S. Dendritic cells in experimental renal inflammation—part I. Nephron Exp Nephrol. 2011;119(4):e83–90.PubMedCrossRefGoogle Scholar
  41. 41.
    Noessner E, Lindenmeyer M, Nelson PJ, Segerer S. Dendritic cells in human renal inflammation—part II. Nephron Exp Nephrol. 2011;119(4):e91–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Woltman AM, de Fijter JW, Zuidwijk K, Vlug AG, Bajema IM, van der Kooij SW, et al. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions. Kidney Int. 2007;71(10):1001–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Holdsworth SR, Tipping PG. Leukocytes in glomerular injury. Semin Immunopathol. 2007;29(4):355–74.PubMedCrossRefGoogle Scholar
  44. 44.
    Timoshanko JR, Sedgwick JD, Holdsworth SR, Tipping PG. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J Am Soc Nephrol. 2003;14(7):1785–93.PubMedCrossRefGoogle Scholar
  45. 45.
    Heymann F, Meyer-Schwesinger C, Hamilton-Williams EE, Hammerich L, Panzer U, Kaden S, et al. Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury. J Clin Invest. 2009;119(5):1286–97.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Sahu R, Bethunaickan R, Singh S, Davidson A. Structure and function of renal macrophages and dendritic cells from lupus-prone mice. Arthritis Rheumatol. 2014;66(6):1596–607.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    John R, Nelson PJ. Dendritic cells in the kidney. J Am Soc Nephrol. 2007;18(10):2628–35.PubMedCrossRefGoogle Scholar
  48. 48.
    Soos TJ, Sims TN, Barisoni L, Lin K, Littman DR, Dustin ML, et al. CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int. 2006;70(3):591–6.PubMedGoogle Scholar
  49. 49.
    Kawakami T, Lichtnekert J, Thompson LJ, Karna P, Bouabe H, Hohl TM, et al. Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions. J Immunol. 2013;191(6):3358–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014;159(6):1312–26.PubMedCrossRefGoogle Scholar
  52. 52.
    Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity. 2014;40(5):642–56.PubMedCrossRefGoogle Scholar
  53. 53.
    Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656–61.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13(11):1118–28.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317(5838):666–70.PubMedCrossRefGoogle Scholar
  56. 56.
    Hume DA. Differentiation and heterogeneity in the mononuclear phagocyte system. Mucosal Immunol. 2008;1(6):432–41.PubMedCrossRefGoogle Scholar
  57. 57.
    Anders HJ, Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int. 2011;80(9):915–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, et al. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol. 2008;86(5):398–408.PubMedCrossRefGoogle Scholar
  59. 59.
    Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40(2):274–88.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Guo S, Wietecha TA, Hudkins KL, Kida Y, Spencer MW, Pichaiwong W, et al. Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis. Kidney Int. 2011;80(9):946–58.PubMedCrossRefGoogle Scholar
  61. 61.
    Lin SL, Castano AP, Nowlin BT, Lupher ML Jr, Duffield JS. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol. 2009;183(10):6733–43.PubMedCrossRefGoogle Scholar
  62. 62.
    Li L, Huang L, Sung SS, Vergis AL, Rosin DL, Rose CE Jr, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 2008;74(12):1526–37.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, et al. Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low)IL-10(high) regulatory phenotype in macrophages. J Immunol. 2010;185(4):2044–50.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol. 2011;22(2):317–26.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Liu K, Nussenzweig MC. Development and homeostasis of dendritic cells. Eur J Immunol. 2010;40(8):2099–102.PubMedCrossRefGoogle Scholar
  66. 66.
    Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, Hashimoto D, et al. The origin and development of nonlymphoid tissue CD103+ DCs. J Exp Med. 2009;206(13):3115–30.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Liu K, Waskow C, Liu X, Yao K, Hoh J, Nussenzweig M. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol. 2007;8(6):578–83.PubMedCrossRefGoogle Scholar
  68. 68.
    Kassianos AJ, Wang X, Sampangi S, Muczynski K, Healy H, Wilkinson R. Increased tubulointerstitial recruitment of human CD141(hi) CLEC9A(+) and CD1c(+) myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease. Am J Physiol Renal Physiol. 2013;305(10):F1391–401.PubMedCrossRefGoogle Scholar
  69. 69.
    Brunner HI, Bennett MR, Mina R, Suzuki M, Petri M, Kiani AN, et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum. 2012;64(8):2687–97.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Rovin BH, Song H, Birmingham DJ, Hebert LA, Yu CY, Nagaraja HN. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J Am Soc Nephrol. 2005;16(2):467–73.PubMedCrossRefGoogle Scholar
  71. 71.
    Tian S, Li J, Wang L, Liu T, Liu H, Cheng G, et al. Urinary levels of RANTES and M-CSF are predictors of lupus nephritis flare. Inflamm Res. 2007;56(7):304–10.PubMedCrossRefGoogle Scholar
  72. 72.
    Sasaki S, Nagai Y, Yanagibashi T, Watanabe Y, Ikutani M, Kariyone A, et al. Serum soluble MD-1 levels increase with disease progression in autoimmune prone MRL(lpr/lpr) mice. Mol Immunol. 2012;49(4):611–20.PubMedCrossRefGoogle Scholar
  73. 73.
    Reyes-Thomas J, Blanco I, Putterman C. Urinary biomarkers in lupus nephritis. Clin Rev Allergy Immunol. 2011;40(3):138–50.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010;2010:638413.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Anne Davidson
    • 1
  • Ramalingam Bethunaickan
    • 1
  • Celine Berthier
    • 3
  • Ranjit Sahu
    • 1
  • Weijia Zhang
    • 2
  • Matthias Kretzler
    • 3
  1. 1.Center for Autoimmunity and Musculoskeletal DiseasesFeinstein Institute for Medical ResearchNew YorkUSA
  2. 2.Department of MedicineMount Sinai Medical CenterNew YorkUSA
  3. 3.Department of Internal Medicine, NephrologyUniversity of MichiganAnn ArborUSA

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