Skip to main content

Advertisement

Log in

Immunopathology of lupus nephritis

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

Abstract

When patients with systemic lupus erythematosus (SLE) present with urinary abnormalities, a renal biopsy is usually needed to rule out or confirm lupus nephritis. Renal biopsy is also needed to define the type of renal manifestation as different entities are associated with different outcomes; hence, renal biopsy results shape lupus management. But why does lupus nephritis come in different shapes? Why do patients with SLE often show change over time in class of lupus nephritis or have mixed forms? How does autoimmunity in SLE evolve? Why does loss of tolerance against nuclear antigens preferentially affect the kidney? Why are immune complex deposits in different glomerular compartments associated with different outcomes? What determines crescent formation in lupus? In this review, we discuss these questions by linking the latest information on lupus pathogenesis into the context of the different classes of lupus nephritis. This should help the basic scientist, the pathologist, and the clinician to gain a more conceptual view on the immunopathology of lupus nephritis.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Liu Z, Davidson A (2012) Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat Med 18:871–882

    PubMed Central  PubMed  Google Scholar 

  2. Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365:2110–2121

    CAS  PubMed  Google Scholar 

  3. Manger K, Manger B, Repp R, Geisselbrecht M, Geiger A, Pfahlberg A, Harrer T, Kalden JR (2002) Definition of risk factors for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus. Ann Rheum Dis 61:1065–1070

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Hiepe F, Dorner T, Hauser AE, Hoyer BF, Mei H, Radbruch A (2011) Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 7:170–178

    CAS  PubMed  Google Scholar 

  5. Goodnow CC (2007) Multistep pathogenesis of autoimmune disease. Cell 130:25–35

    CAS  PubMed  Google Scholar 

  6. Saxena R, Mahajan T, Mohan C (2011) Lupus nephritis: current update. Arthritis Res Ther 13:240

    PubMed Central  PubMed  Google Scholar 

  7. Migliorini A, Anders HJ (2012) A novel pathogenetic concept-antiviral immunity in lupus nephritis. Nat Rev Nephrol 8:183–189

    CAS  PubMed  Google Scholar 

  8. Hakkim A, Furnrohr BG, Amann K, Laube B, Abu Abed U, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107:9813–9818

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Kaplan MJ, Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao WP, Olsen SH, Klinker M, Shealy D, Denny MF, Plumas J, Chaperot L, Kretzler M, Bruce AT (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552

    PubMed Central  PubMed  Google Scholar 

  10. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ, Banchereau J, Pascual V (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3:73ra20

    PubMed Central  PubMed  Google Scholar 

  11. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V, Bassett R, Amuro H, Fukuhara S, Ito T, Liu YJ, Gilliet M (2011) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 3:73ra19

    PubMed Central  PubMed  Google Scholar 

  12. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M, Shealy D, Denny MF, Plumas J, Chaperot L, Kretzler M, Bruce AT, Kaplan MJ (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Bosch X (2011) Systemic lupus erythematosus and the neutrophil. N Engl J Med 365:758–760

    CAS  PubMed  Google Scholar 

  14. Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M (2010) The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 6:280–289

    PubMed  Google Scholar 

  15. Kanta H, Mohan C (2009) Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation. Genes Immun 10(5):390–396

    CAS  PubMed  Google Scholar 

  16. 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 358:900–909

    CAS  PubMed  Google Scholar 

  17. Moser KL, Kelly JA, Lessard CJ, Harley JB (2009) Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun 10:373–379

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Cui Y, Sheng Y, Zhang X (2013) Genetic susceptibility to SLE: recent progress from GWAS. J Autoimmun 41:25–33

    CAS  PubMed  Google Scholar 

  19. Theofilopoulos AN, Baccala R, Beutler B, Kono DH (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23:307–336

    CAS  PubMed  Google Scholar 

  20. 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 171:5778–5786

    CAS  PubMed  Google Scholar 

  21. Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B (1988) Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol 140:2197–2200

    CAS  PubMed  Google Scholar 

  22. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665–1673

    CAS  PubMed  Google Scholar 

  23. Hughes GC (2012) Progesterone and autoimmune disease. Autoimmun Rev 11:A502–A514

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Kariko K, Ni H, Capodici J, Lamphier M, Weissman D (2004) mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 279:12542–12550

    CAS  PubMed  Google Scholar 

  25. Savarese E, Chae OW, Trowitzsch S, Weber G, Kastner B, Akira S, Wagner H, Schmid RM, Bauer S, Krug A (2006) U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107:3229–3234

    CAS  PubMed  Google Scholar 

  26. Teichmann LL, Ols ML, Kashgarian M, Reizis B, Kaplan DH, Shlomchik MJ (2010) Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33:967–978

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Savarese E, Steinberg C, Pawar RD, Reindl W, Akira S, Anders HJ, Krug A (2008) Requirement of Toll-like receptor 7 for pristane-induced production of autoantibodies and development of murine lupus nephritis. Arthritis Rheum 58:1107–1115

    CAS  PubMed  Google Scholar 

  28. 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 416:603–607

    CAS  PubMed  Google Scholar 

  29. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A (2005) RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202:1171–1177

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Lech M, Kulkarni OP, Pfeiffer S, Savarese E, Krug A, Garlanda C, Mantovani A, Anders HJ (2008) Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. J Exp Med 205:1879–1888

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Lech M, Skuginna V, Kulkarni OP, Gong J, Wei T, Stark RW, Garlanda C, Mantovani A, Anders HJ (2010) Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis. J Pathol 220:596–607

    CAS  PubMed  Google Scholar 

  32. Garlanda C, Anders HJ, Mantovani A (2009) TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends Immunol 30:439–446

    CAS  PubMed  Google Scholar 

  33. Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, Chan JH, Wright T, Punaro M, Bolland S, Soumelis V, Banchereau J, Coffman RL, Pascual V, Barrat FJ (2010) TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465:937–941

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Patole PS, Zecher D, Pawar RD, Grone HJ, Schlondorff D, Anders HJ (2005) G-rich DNA suppresses systemic lupus. J Am Soc Nephrol 16:3273–3280

    CAS  PubMed  Google Scholar 

  35. Pawar RD, Ramanjaneyulu A, Kulkarni OP, Lech M, Segerer S, Anders HJ (2007) Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J Am Soc Nephrol 18:1721–1731

    CAS  PubMed  Google Scholar 

  36. Anders HJ (2009) Pseudoviral immunity—a novel concept for lupus. Trends Mol Med 15:553–561

    CAS  PubMed  Google Scholar 

  37. 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 25:419–441

    CAS  PubMed  Google Scholar 

  38. 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 189:1639–1648

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Zikherman J, Parameswaran R, Weiss A (2012) Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489:160–164

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Allam R, Sayyed SG, Kulkarni O, Lichtnekert J, Anders HJ (2011) Murine double minute-2 drives systemic lupus erythematosus and lupus nephritis. J Am Soc Nephrol 22:2016–2027, in press

    Google Scholar 

  41. Liu Z, Davidson A (2011) BAFF and selection of autoreactive B cells. Trends Immunol 32:388–394

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Gayed M, Gordon C (2010) Novel treatments for systemic lupus erythematosus. Curr Opin Investig Drugs 11:1256–1264

    CAS  PubMed  Google Scholar 

  43. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15:241–250

    PubMed  Google Scholar 

  44. Mercadal L, Montcel ST, Nochy D, Queffeulou G, Piette JC, Isnard-Bagnis C, Martinez F (2002) Factors affecting outcome and prognosis in membranous lupus nephropathy. Nephrol Dial Transplant 17:1771–1778

    PubMed  Google Scholar 

  45. Schwartz MM, Korbet SM, Lewis EJ (2008) The prognosis and pathogenesis of severe lupus glomerulonephritis. Nephrol Dial Transplant 23:1298–1306

    PubMed  Google Scholar 

  46. Contreras G, Pardo V, Cely C, Borja E, Hurtado A, De La Cuesta C, Iqbal K, Lenz O, Asif A, Nahar N, Leclerq B, Leon C, Schulman I, Ramirez-Seijas F, Paredes A, Cepero A, Khan T, Pachon F, Tozman E, Barreto G, Hoffman D, Almeida Suarez M, Busse JC, Esquenazi M, Esquenazi A, Garcia Mayol L, Garcia Estrada H (2005) Factors associated with poor outcomes in patients with lupus nephritis. Lupus 14:890–895

    CAS  PubMed  Google Scholar 

  47. Hill GS, Delahousse M, Nochy D, Remy P, Mignon F, Mery JP, Bariety J (2001) Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int 59:304–316

    CAS  PubMed  Google Scholar 

  48. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang WK, Qu Z, Chen MH, Gao JJ, Li ZY, Zheng X, Ao J, Zhu SN, Wang SX, Zhao MH, Zou WZ, Liu G (2010) Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int 77:820–829

    PubMed  Google Scholar 

  49. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ (2009) M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361:11–21

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Dube GK, Markowitz GS, Radhakrishnan J, Appel GB, D'Agati VD (2002) Minimal change disease in systemic lupus erythematosus. Clin Nephrol 57:120–126

    CAS  PubMed  Google Scholar 

  51. Kraft SW, Schwartz MM, Korbet SM, Lewis EJ (2005) Glomerular podocytopathy in patients with systemic lupus erythematosus. J Am Soc Nephrol 16:175–179

    PubMed  Google Scholar 

  52. Han TS, Schwartz MM, Lewis EJ (2006) Association of glomerular podocytopathy and nephrotic proteinuria in mesangial lupus nephritis. Lupus 15:71–75

    CAS  PubMed  Google Scholar 

  53. Barber C, Herzenberg A, Aghdassi E, Su J, Lou W, Qian G, Yip J, Nasr SH, Thomas D, Scholey JW, Wither J, Urowitz M, Gladman D, Reich H, Fortin PR (2012) Evaluation of clinical outcomes and renal vascular pathology among patients with lupus. Clin J Am Soc Nephrol 7:757–764

    PubMed Central  PubMed  Google Scholar 

  54. Song D, Wu LH, Wang FM, Yang XW, Zhu D, Chen M, Yu F, Liu G, Zhao MH (2013) The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther 15:R12

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Park MH, D'Agati V, Appel GB, Pirani CL (1986) Tubulointerstitial disease in lupus nephritis: relationship to immune deposits, interstitial inflammation, glomerular changes, renal function, and prognosis. Nephron 44:309–319

    CAS  PubMed  Google Scholar 

  56. Nath KA (1992) Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20:1–17

    CAS  PubMed  Google Scholar 

  57. Hayakawa S, Nakabayashi K, Karube M, Arimura Y, Soejima A, Yamada A, Fujioka Y (2006) Tubulointerstitial immune complex nephritis in a patient with systemic lupus erythematosus: role of peritubular capillaritis with immune complex deposits in the pathogenesis of the tubulointerstitial nephritis. Clin Exp Nephrol 10:146–151

    PubMed  Google Scholar 

  58. Nowling TK, Gilkeson GS (2011) Mechanisms of tissue injury in lupus nephritis. Arthritis Res Ther 13:250

    PubMed Central  PubMed  Google Scholar 

  59. Yung S, Chan TM (2012) Autoantibodies and resident renal cells in the pathogenesis of lupus nephritis—getting to know the unknown. Clin Dev Immunol 2012:139365

    PubMed Central  PubMed  Google Scholar 

  60. Mortensen ES, Rekvig OP (2009) Nephritogenic potential of anti-DNA antibodies against necrotic nucleosomes. J Am Soc Nephrol 20:696–704

    CAS  PubMed  Google Scholar 

  61. Yung S, Cheung KF, Zhang Q, Chan TM (2010) Anti-dsDNA antibodies bind to mesangial annexin II in lupus nephritis. J Am Soc Nephrol 21:1912–1927

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Zhao Z, Deocharan B, Scherer PE, Ozelius LJ, Putterman C (2006) Differential binding of cross-reactive anti-DNA antibodies to mesangial cells: the role of alpha-actinin. J Immunol 176:7704–7714

    CAS  PubMed  Google Scholar 

  63. Mjelle JE, Rekvig OP, Van Der Vlag J, Fenton KA (2011) Nephritogenic antibodies bind in glomeruli through interaction with exposed chromatin fragments and not with renal cross-reactive antigens. Autoimmunity 44:373–383

    CAS  PubMed  Google Scholar 

  64. 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 43:179–188

    CAS  PubMed  Google Scholar 

  65. Niederer HA, Clatworthy MR, Willcocks LC, Smith KG (2010) FcgammaRIIB, FcgammaRIIIB, and systemic lupus erythematosus. Ann N Y Acad Sci 1183:69–88

    CAS  PubMed  Google Scholar 

  66. Sherer Y, Shoenfeld Y (2006) Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus. Autoimmun Rev 5:153–155

    CAS  PubMed  Google Scholar 

  67. Allam R, Lichtnekert J, Moll A, Taubitz A, Vielhauer V, Anders HJ (2009) Viral RNA and DNA sense common antiviral responses including type I interferons in mesangial cells. J Am Soc Nephrol 20:1986–1996, in press

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Fluer K, Allam R, Zecher D, Kulkarni O, Lichtnekert J, Schwarz M, Beutler B, Vielhauer V, Anders HJ (2009) Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via MDA5. Implications for viral infection-associated glomerulonephritis. Am J Pathol 175:2014–2022, in press

    Google Scholar 

  69. Hagele H, Allam R, Pawar RD, Anders HJ (2009) Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1. Nephrol Dial Transplant 24:3312–3318

    PubMed  Google Scholar 

  70. Hagele H, Allam R, Pawar RD, Reichel CA, Krombach F, Anders HJ (2009) Double-stranded DNA activates glomerular endothelial cells and enhances albumin permeability via a toll-like receptor-independent cytosolic DNA recognition pathway. Am J Pathol 175:1896–1904

    PubMed Central  PubMed  Google Scholar 

  71. Fairhurst AM, Xie C, Fu Y, Wang A, Boudreaux C, Zhou XJ, Cibotti R, Coyle A, Connolly JE, Wakeland EK, Mohan C (2009) Type I interferons produced by resident renal cells may promote end-organ disease in autoantibody-mediated glomerulonephritis. J Immunol 183:6831–6838

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Anders HJ, Lichtnekert J, Allam R (2010) Interferon-alpha and -beta in kidney inflammation. Kidney Int 77:848–854

    CAS  PubMed  Google Scholar 

  73. Triantafyllopoulou A, Franzke CW, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, van Rooijen N, Davidson A, Ivashkiv LB (2010) Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci U S A 107:3012–3017

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M, Perez de lema G, Strutz F, Bauer S, Rutz M, Wagner H, Grone HJ, Schlondorff D (2004) Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J 18:534–536

    CAS  PubMed  Google Scholar 

  75. Kanapathippillai P, Hedberg A, Fenton CG, Fenton KA (2013) Nucleosomes contribute to increase mesangial cell chemokine expression during the development of lupus nephritis. Cytokine 62:244–252

    CAS  PubMed  Google Scholar 

  76. Tojo T, Friou GJ (1968) Lupus nephritis: varying complement-fixing properties of immunoglobulin G antibodies to antigens of cell nuclei. Science 161:904–906

    CAS  PubMed  Google Scholar 

  77. Sekine H, Kinser TT, Qiao F, Martinez E, Paulling E, Ruiz P, Gilkeson GS, Tomlinson S (2011) The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. Arthritis Rheum 63:1076–1085

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Bao L, Haas M, Quigg RJ (2011) Complement factor H deficiency accelerates development of lupus nephritis. J Am Soc Nephrol 22:285–295

    PubMed Central  PubMed  Google Scholar 

  79. Hugo C, Shankland SJ, Bowen-Pope DF, Couser WG, Johnson RJ (1997) Extraglomerular origin of the mesangial cell after injury. A new role of the juxtaglomerular apparatus. J Clin Invest 100:786–794

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Migliorini A, Ebid R, Scherbaum CR, Anders HJ (2013) The danger control concept in kidney disease: mesangial cells. J Nephrol 26:437–449

    CAS  PubMed  Google Scholar 

  81. Hedberg A, Fismen S, Fenton KA, Fenton C, Osterud B, Mortensen ES, Rekvig OP (2011) Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes. Arthritis Rheum 63:1065–1075

    CAS  PubMed  Google Scholar 

  82. Rich SA (1981) Human lupus inclusions and interferon. Science 213:772–775

    CAS  PubMed  Google Scholar 

  83. Moreth K, Brodbeck R, Babelova A, Gretz N, Spieker T, Zeng-Brouwers J, Pfeilschifter J, Young MF, Schaefer RM, Schaefer L (2010) The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J Clin Invest 120:4251–4272

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, Fenton MJ, Tracey KJ, Yang H (2006) HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26:174–179

    CAS  PubMed  Google Scholar 

  85. Allam R, Scherbaum CR, Darisipudi MN, Mulay SR, Hagele H, Lichtnekert J, Hagemann JH, Rupanagudi KV, Ryu M, Schwarzenberger C, Hohenstein B, Hugo C, Uhl B, Reichel CA, Krombach F, Monestier M, Liapis H, Moreth K, Schaefer L, Anders HJ (2012) Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J Am Soc Nephrol 23:1375–1388

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Pawar RD, Castrezana-Lopez L, Allam R, Kulkarni OP, Segerer S, Radomska E, Meyer TN, Schwesinger CM, Akis N, Grone HJ, Anders HJ (2009) Bacterial lipopeptide triggers massive albuminuria in murine lupus nephritis by activating Toll-like receptor 2 at the glomerular filtration barrier. Immunology 128:e206–e221

    PubMed Central  PubMed  Google Scholar 

  87. Kulkarni O, Anders HJ (2008) Chemokines in lupus nephritis. Front Biosci 13:3312–3320

    CAS  PubMed  Google Scholar 

  88. Kulkarni O, Pawar RD, Purschke W, Eulberg D, Selve N, Buchner K, Ninichuk V, Segerer S, Vielhauer V, Klussmann S, Anders HJ (2007) Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. J Am Soc Nephrol 18:2350–2358

    CAS  PubMed  Google Scholar 

  89. Perez de Lema G, Maier H, Franz TJ, Escribese M, Chilla S, Segerer S, Camarasa N, Schmid H, Banas B, Kalaydjiev S, Busch DH, Pfeffer K, Mampaso F, Schlondorff D, Luckow B (2005) Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice. J Am Soc Nephrol 16:3592–3601

    CAS  PubMed  Google Scholar 

  90. Anders HJ, Belemezova E, Eis V, Segerer S, Vielhauer V, Perez de Lema G, Kretzler M, Cohen CD, Frink M, Horuk R, Hudkins KL, Alpers CE, Mampaso F, Schlondorff D (2004) Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J Am Soc Nephrol 15:1504–1513

    CAS  PubMed  Google Scholar 

  91. Bussolati B, Peri G, Salvidio G, Verzola D, Mantovani A, Camussi G (2003) The long pentraxin PTX3 is synthesized in IgA glomerulonephritis and activates mesangial cells. J Immunol 170:1466–1472

    CAS  PubMed  Google Scholar 

  92. Deban L, Russo RC, Sironi M, Moalli F, Scanziani M, Zambelli V, Cuccovillo I, Bastone A, Gobbi M, Valentino S, Doni A, Garlanda C, Danese S, Salvatori G, Sassano M, Evangelista V, Rossi B, Zenaro E, Constantin G, Laudanna C, Bottazzi B, Mantovani A (2010) Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 11:328–334

    CAS  PubMed  Google Scholar 

  93. Clark MR, Chang A, Henderson SG, Brandt D, Liu N, Guttikonda R, Hsieh C, Kaverina N, Utset TO, Meehan SM, Quigg RJ, Meffre E (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186:1849–1860

    PubMed Central  PubMed  Google Scholar 

  94. Lacotte S, Decossas M, Le Coz C, Brun S, Muller S, Dumortier H (2013) Early differentiated CD138(high) MHCII+ IgG+ plasma cells express CXCR3 and localize into inflamed kidneys of lupus mice. PLoS One 8:e58140

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Neusser MA, Lindenmeyer MT, Edenhofer I, Gaiser S, Kretzler M, Regele H, Segerer S, Cohen CD (2011) Intrarenal production of B-cell survival factors in human lupus nephritis. Mod Pathol 24:98–107

    CAS  PubMed  Google Scholar 

  96. Espeli M, Bokers S, Giannico G, Dickinson HA, Bardsley V, Fogo AB, Smith KG (2011) Local renal autoantibody production in lupus nephritis. J Am Soc Nephrol 22:296–305

    PubMed Central  PubMed  Google Scholar 

  97. Chang A, Henderson SG, Brandt D, Liu N, Guttikonda R, Hsieh C, Kaverina N, Utset TO, Meehan SM, Quigg RJ, Meffre E, Clark MR (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186:1849–1860

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Bekar KW, Owen T, Dunn R, Ichikawa T, Wang W, Wang R, Barnard J, Brady S, Nevarez S, Goldman BI, Kehry M, Anolik JH (2010) Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum 62:2443–2457

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Ramanujam M, Bethunaickan R, Huang W, Tao H, Madaio MP, Davidson A (2010) Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 mice. Arthritis Rheum 62:1457–1468

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Bethunaickan R, Berthier CC, Ramanujam M, Sahu R, Zhang W, Sun Y, Bottinger EP, Ivashkiv L, Kretzler M, Davidson A (2011) A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis. J Immunol 186:4994–5003

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Katsiari CG, Liossis SN, Sfikakis PP (2010) The pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus: a reappraisal. Semin Arthritis Rheum 39:491–503

    CAS  PubMed  Google Scholar 

  102. Apostolidis SA, Crispin JC, Tsokos GC (2011) IL-17-producing T cells in lupus nephritis. Lupus 20:120–124

    CAS  PubMed  Google Scholar 

  103. Steinmetz OM, Turner JE, Paust HJ, Lindner M, Peters A, Heiss K, Velden J, Hopfer H, Fehr S, Krieger T, Meyer-Schwesinger C, Meyer TN, Helmchen U, Mittrucker HW, Stahl RA, Panzer U (2009) CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis. J Immunol 183:4693–4704

    CAS  PubMed  Google Scholar 

  104. Moser K, Kalies K, Szyska M, Humrich JY, Amann K, Manz RA (2012) CXCR3 promotes the production of IgG1 autoantibodies but is not essential for the development of lupus nephritis in NZB/NZW mice. Arthritis Rheum 64:1237–1246

    CAS  PubMed  Google Scholar 

  105. Ryu M, Migliorini A, Miosge N, Gross O, Shankland S, Brinkkoetter PT, Hagmann H, Romagnani P, Liapis H, Anders HJ (2014) Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury. J Pathol. doi:10.1002/path.4046

    Google Scholar 

  106. Bollee G, Flamant M, Schordan S, Fligny C, Rumpel E, Milon M, Schordan E, Sabaa N, Vandermeersch S, Galaup A, Rodenas A, Casal I, Sunnarborg SW, Salant DJ, Kopp JB, Threadgill DW, Quaggin SE, Dussaule JC, Germain S, Mesnard L, Endlich K, Boucheix C, Belenfant X, Callard P, Endlich N, Tharaux PL (2011) Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med 17:1242–1250

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C, Mazzinghi B, Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J, Romagnani P (2009) Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 20:2593–2603

    PubMed Central  PubMed  Google Scholar 

  108. Smeets B, Uhlig S, Fuss A, Mooren F, Wetzels JF, Floege J, Moeller MJ (2009) Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells. J Am Soc Nephrol 20:2604–2615

    PubMed Central  PubMed  Google Scholar 

  109. Yu F, Tan Y, Liu G, Wang SX, Zou WZ, Zhao MH (2009) Clinicopathological characteristics and outcomes of patients with crescentic lupus nephritis. Kidney Int 76:307–317

    PubMed  Google Scholar 

  110. Bonsib SM (1984) Scanning electron microscopy of acellular glomeruli in human glomerulonephritis: application of a technique. Ultrastruct Pathol 7:215–217

    CAS  PubMed  Google Scholar 

  111. Pippin JW, Durvasula R, Petermann A, Hiromura K, Couser WG, Shankland SJ (2003) DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes. J Clin Invest 111:877–885

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Shankland SJ, Pippin JW, Couser WG (1999) Complement (C5b-9) induces glomerular epithelial cell DNA synthesis but not proliferation in vitro. Kidney Int 56:538–548

    CAS  PubMed  Google Scholar 

  113. Liapis H, Romagnani P, Anders HJ (2013) New insights into the pathology of podocyte loss: mitotic catastrophe. Am J Pathol 183(5):1364–1374

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Nangaku M, Shankland SJ, Couser WG (2005) Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 16:1195–1204

    CAS  PubMed  Google Scholar 

  115. Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC (2005) Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 16:2941–2952

    CAS  PubMed  Google Scholar 

  116. Ronconi E, Sagrinati C, Angelotti ML, Lazzeri E, Mazzinghi B, Ballerini L, Parente E, Becherucci F, Gacci M, Carini M, Maggi E, Serio M, Vannelli GB, Lasagni L, Romagnani S, Romagnani P (2009) Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol 20:322–332

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ (2009) Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 20:333–343

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Lasagni L, Romagnani P (2010) Glomerular epithelial stem cells: the good, the bad, and the ugly. J Am Soc Nephrol 21:1612–1619

    PubMed  Google Scholar 

  119. Peired A, Angelotti ML, Ronconi E, la Marca G, Mazzinghi B, Sisti A, Lombardi D, Giocaliere E, Della Bona M, Villanelli F, Parente E, Ballerini L, Sagrinati C, Wanner N, Huber TB, Liapis H, Lazzeri E, Lasagni L, Romagnani P (2013) Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J Am Soc Nephrol 24(11):1756–1768

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Ryu M, Mulay SR, Miosge N, Gross O, Anders HJ (2012) Tumour necrosis factor-alpha drives Alport glomerulosclerosis in mice by promoting podocyte apoptosis. J Pathol 226:120–131

    CAS  PubMed  Google Scholar 

  121. Migliorini A, Angelotti ML, Mulay SR, Kulkarni OO, Demleitner J, Dietrich A, Sagrinati C, Ballerini L, Peired A, Shankland SJ, Liapis H, Romagnani P, Anders HJ (2013) The antiviral cytokines IFN-alpha and IFN-beta modulate parietal epithelial cells and promote podocyte loss: implications for IFN toxicity, viral glomerulonephritis, and glomerular regeneration. Am J Pathol 183:431–440

    CAS  PubMed  Google Scholar 

  122. Smeets B, Kuppe C, Sicking EM, Fuss A, Jirak P, van Kuppevelt TH, Endlich K, Wetzels JF, Grone HJ, Floege J, Moeller MJ (2011) Parietal epithelial cells participate in the formation of sclerotic lesions in focal segmental glomerulosclerosis. J Am Soc Nephrol 22:1262–1274

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Anders HJ (2012) Four danger response programs determine glomerular and tubulointerstitial kidney pathology: clotting, inflammation, epithelial and mesenchymal healing. Organogenesis 8:29–40

    PubMed Central  PubMed  Google Scholar 

  124. Kriz W, Lemley KV (1999) The role of the podocyte in glomerulosclerosis. Curr Opin Nephrol Hypertens 8:489–497

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Deutsche Forschungsgemeinschaft AN372/11-1 and GRK 1202. The authors thank Jyaysi Desai for her help with Fig. 1.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hans-Joachim Anders.

Additional information

This article is a contribution to the special issue on Immunopathology of Glomerular Diseases - Guest Editors: P. Ronco and J. Floege

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anders, HJ., Fogo, A.B. Immunopathology of lupus nephritis. Semin Immunopathol 36, 443–459 (2014). https://doi.org/10.1007/s00281-013-0413-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-013-0413-5

Keywords

Navigation