Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Cellular and Molecular Immunology

Volumn 9, Issue 3, 2012, Pages 255-266

  Shimp III, Samuel K ^a   Chafin, Cristen B ^b   Regna, Nicole L ^b   Hammond, Sarah E ^b   Read, Molly A ^a   Caudell, David L ^b   Rylander, Marissa Nichole ^a   Reilly, Christopher M ^b,c  

^a VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY   (United States)

^b VIRGINIA MARYLAND REGIONAL COLLEGE OF VETERINARY MEDICINE   (United States)

^c EDWARD VIA COLLEGE OF OSTEOPATHIC MEDICINE   (United States)

Author keywords

17 DMAG; Geldanamycin; heat shock protein 90; MRL lpr; systemic lupus erythematosus

Indexed keywords

ALVESPIMYCIN; COMPLEMENT COMPONENT C3; DOUBLE STRANDED DNA ANTIBODY; GELDANAMYCIN; HEAT SHOCK PROTEIN 90; IMMUNOGLOBULIN G; INTERLEUKIN 12; INTERLEUKIN 6; NITRIC OXIDE; TRANSCRIPTION FACTOR FOXP3;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBODY PRODUCTION; ANTIINFLAMMATORY ACTIVITY; ARTICLE; B LYMPHOCYTE; C57BL 6 MOUSE; CD4 CD8 RATIO; CD8+ T LYMPHOCYTE; COMPLEMENT DEPOSITION; CONTROLLED STUDY; GLOMERULONEPHRITIS; IMMUNOGLOBULIN DEPOSITION; IN VITRO STUDY; IN VIVO STUDY; KIDNEY; MESANGIUM CELL; MOUSE; MURPHY ROTHS LARGE LYMPHOPROLIFERATIVE MOUSE; NONHUMAN; PROTEIN EXPRESSION; PROTEINURIA; SPLEEN CELL; SPLENOMEGALY; SYSTEMIC LUPUS ERYTHEMATOSUS;

ANIMALS; ANTIBODIES, ANTINUCLEAR; BENZOQUINONES; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; DISEASE MODELS, ANIMAL; HSP90 HEAT-SHOCK PROTEINS; HUMANS; INTERLEUKIN-12; INTERLEUKIN-6; LACTAMS, MACROCYCLIC; LUPUS ERYTHEMATOSUS, SYSTEMIC; LYMPHOCYTE ACTIVATION; MESANGIAL CELLS; MICE; MICE, INBRED C57BL; MICE, INBRED MRL LPR; NITRIC OXIDE;

MUS;

EID: 84860861107     PISSN: 16727681     EISSN: None     Source Type: Journal    
DOI: 10.1038/cmi.2012.5     Document Type: Article

References (100)

1. Bandholtz L, Guo Y, Palmberg C, Mattsson K, Ohlsson B, High A et al. Hsp90 binds CpG oligonucleotides directly: implications for hsp90 as a missing link in CpG signaling and recognition. Cell Mol Life Sci 2003; 60: 422-429. (Pubitemid 36343920)
2. De Nardo D, Masendycz P, Ho S, Cross M, Fleetwood AJ, Reynolds EC et al. A central role for the Hsp90?Cdc37 molecular chaperone module in interleukin-1 receptorassociated- kinase-dependent signaling by Toll-like receptors. J Biol Chem 2005; 280: 9813-9822. (Pubitemid 40395827)
3. Dello Russo C, Polak PE, Mercado PR, Spagnolo A, Sharp A, Murphy P et al. The heatshock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. J Neurochem 2006; 99: 1351-1362. (Pubitemid 44733930)
4. Dhillon VB, McCallum S, Norton P, Twomey BM, Erkeller-Yuksel F, Lydyard P et al. Differential heat shock protein overexpression and its clinical relevance in systemic lupus erythematosus. Ann Rheum Dis 1993; 52: 436-442. (Pubitemid 23209600)
5. Dhillon VB, McCallum S, Latchman DS, Isenberg DA. Elevation of the 90 kDa heat-shock protein in specific subsets of systemic lupus erythematosus. QJMed1994; 87: 215-222.
6. Latchman DS, Isenberg DA. The role of hsp90 in SLE. Autoimmunity 1994; 19: 211-218.
7. Faulds G, Conroy S, MadaioM, Isenberg D, Latchman D. Increased levels of antibodies to heat shock proteins with increasing age in Mrl/Mp-lpr/lpr mice. Br J Rheumatol 1995; 34: 610-615.
8. Ripley BJ, Isenberg DA, Latchman DS. Elevated levels of the 90 kDa heat shock protein (hsp90) in SLE correlate with levels of IL-6 and autoantibodies to hsp90. J Autoimmun 2001; 17: 341-346. (Pubitemid 34098418)
9. Kenderov A, Minkova V, Mihailova D, Giltiay N, Kyurkchiev S, Kehayov I et al. Lupusspecific kidney deposits of HSP90 are associated with altered IgG idiotypic interactions of anti-HSP90 autoantibodies. Clin Exp Immunol 2002; 129: 169-176.
10. Liu B, Dai J, Zheng H, Stoilova D, Sun S, Li Z. Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci USA 2003; 100: 15824-15829. (Pubitemid 38021074)
11. Han JM, Kwon NH, Lee JY, Jeong SJ, Jung HJ, KimHRet al. Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLoSONE2010; 5: e9792.
12. Taldone T, Gozman A, Maharaj R, Chiosis G. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr Opin Pharmacol 2008; 8: 370-374.
13. Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L et al. Update on Hsp90 Inhibitors in Clinical Trial. Curr Top Med Chem 2009; 9: 1479-1492.
14. Sõ ti C, Nagy E, Giricz Z, Vígh L, Csermely P, Ferdinandy P. Heat shock proteins as emerging therapeutic targets. Br J Pharmacol 2005; 146: 769-780. (Pubitemid 41622243)
15. Garnier C, Lafitte D, Tsvetkov PO, Barbier P, Leclerc-Devin J,Millot J-M, et al. Binding of ATP to Heat Shock Protein 90. J Biol Chem 2002; 277: 12208-12214.
16. Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 1995; 36: 305-315.
17. Blagg BS, Kerr TD. Hsp90 inhibitors: small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation. Med Res Rev 2006; 26: 310-338.
18. Egorin M, Lagattuta T, Hamburger D, Covey J, White K,Musser S et al. Pharmacokinetics, tissue distribution, and metabolism of 17- (dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 2002; 49: 7-19.
19. Egorin MJ, Zuhowski EG, Rosen DM, Sentz DL, Covey JM, Eiseman JL. Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17- demethoxygeldanamycin (NSC 330507) in CD2F1 mice1. Cancer Chemother Pharmacol 2001; 47: 291-302. (Pubitemid 32640768)
20. Chatterjee A, Dimitropoulou C, Drakopanayiotakis F, Antonova G, Snead C, Cannon J et al. Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis. Am J Respir Crit Care Med 2007; 176: 667-675. (Pubitemid 47503074)
21. Rice JW, Veal JM, Fadden RP, Barabasz AF, Partridge JM, Barta TE et al. Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis Rheum 2008; 58: 3765-3775.
22. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005; 5: 761-762.
23. Zhang H, Burrows F. Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med (Berl) 2004; 82: 488-499. (Pubitemid 39149859)
24. Donnelly A, Blagg BS. Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem 2008; 15: 2702-2717.
25. Yun TJ, Harning EK, Giza K, Rabah D, Li P, Arndt JW et al. EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity. J Immunol 2011; 186: 563-575.
26. Suzuka H, Yoshifusa H, Nakamura Y,Miyawaki S, Shibata Y. Morphological analysis of autoimmune disease in MRL-lpr,Yaa male mice with rapidly progressive systemic lupus erythematosus. Autoimmunity 1993; 14: 275-282. (Pubitemid 23214052)
27. Ka SM, Cheng CW, Shui HA,WuWM, Chang DM, Lin YC et al. Mesangial cells of lupusprone mice are sensitive to chemokine production. Arthritis Res Ther 2007; 9: R67.
28. Theofilopoulos AN, Koundouris S, Kono DH, Lawson BR. The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity. Arthritis Res 2001; 3: 136-141. (Pubitemid 32303429)
29. Aringer M, Smolen JS. Cytokine expression in lupus kidneys. Lupus 2005; 14: 13-18. (Pubitemid 40216062)
30. Reilly CM, Oates JC, Sudian J, Crosby MB, Halushka PV, Gilkeson GS. Prostaglandin J2 inhibition of mesangial cell iNOS expression. Clin Immunol 2001; 98: 337-345.
31. Kikawada E, Lenda DM, Kelley VR. IL-12 deficiency in MRL-Faslpr mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. J Immunol 2003; 170: 3915-3925. (Pubitemid 36359263)
32. Santiago-Raber ML, Laporte C, Reininger L, Izui S. Genetic basis of murine lupus. Autoimmun Rev 2004; 3: 33-39. (Pubitemid 38197968)
33. Theofilopoulos AN, Kono DH. Mechanisms and genetics of autoimmunity. Ann NY Acad Sci 1998; 841: 225-235. (Pubitemid 28362852)
34. Singh AK. Lupus in the Fas lane? J R Coll Physicians Lond 1995; 29: 475-478.
35. Deng G-M, Liu L, Tsokos GC. Targeted tumor necrosis factor receptor I preligand assembly domain improves skin lesions in MRL/lpr mice. Arthritis Rheum 2010; 62: 2424-2431.
36. Ichinose K, Juang YT, Crispín JC, Kis-Toth K, Tsokos GC. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/ calmodulin-dependent protein kinase type IV. Arthritis Rheum 2011; 63: 523-529.
37. Xie C, Patel R, Wu T, Zhu J, Henry T, Bhaskarabhatla M et al. PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr. Int Immunol 2007; 19: 509-522. (Pubitemid 46523398)
38. Sekine H, Reilly CM, Molano ID, Garnier G, Circolo A, Ruiz P et al. Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice. J Immunol 2001; 166: 6444-6451. (Pubitemid 32440780)
39. Xie C, Sharma R, Wang H, Zhou XJ, Mohan C. Strain distribution pattern of susceptibility to immune-mediated nephritis. J Immunol 2004; 172: 5047-5055. (Pubitemid 38456432)
40. Xie C, Zhou XJ, Liu X, Mohan C. Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strain. Arthritis Rheum 2003; 48: 1080-1092. (Pubitemid 36418251)
41. Du Y, Fu Y, Mohan C. Experimental anti-GBM nephritis as an analytical tool for studying spontaneous lupus nephritis. Arch Immunol Ther Exp (Warsz) 2008; 56: 31-40.
42. Divekar AA, Dubey S, Gangalum PR, Singh RR. Dicer insufficiency and microRNA- 155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu. J Immunol 2011; 186: 924-930.
43. Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum 2009; 60: 1472-1483.
44. Wieten L, Broere F, van der Zee R, Koerkamp EK, Wagenaar J, van Eden W. Cell stress induced HSP are targets of regulatory T cells: a role for HSP inducing compounds as anti-inflammatory immuno-modulators? FEBS Lett 2007; 581: 3716-3722. (Pubitemid 47081007)
45. Giannini A, Bijlmakers MJ. Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Mol Cell Biol 2004; 24: 5667-5676. (Pubitemid 38787953)
46. Gilkeson G, Cannon C, Oates J, Reilly C, Goldman D, Petri M. Correlation of serum measures of nitric oxide production with lupus disease activity. J Rheumatol 1999; 26: 318-324. (Pubitemid 29066735)
47. Hertlein E, Wagner AJ, Jones J, Lin TS, Maddocks KJ, TownsWH3rd et al. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood 2010; 116: 45-53.
48. Gilkeson GS, Pippen AM, Pisetsky DS. Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA. J Clin Invest 1995; 95: 1398-1402.
49. Schwarz M, Wahl M, Resch K, Radeke HH. IFNc induces functional chemokine receptor expression in human mesangial cells. Clin Exp Immunol 2002; 128: 285-294. (Pubitemid 34534042)
50. Teramoto K, Negoro N, Kitamoto K, Iwai T, Iwao H, Okamura M et al. Microarray analysis of glomerular gene expression in murine lupus nephritis. J Pharmacol Sci 2008; 106: 56-67. (Pubitemid 351159069)
51. Jeon YK, Park CH, Kim KY, Li YC, Kim J, Kim YA et al. The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation. J Pathol 2007; 213: 170-179. (Pubitemid 47612239)
52. Dey A, Cederbaum AI. Geldanamycin, an inhibitor of Hsp90, potentiates cytochrome P4502E1-mediated toxicity in HepG2 cells. J Pharmacol Exp Ther 2006; 317: 1391-1399. (Pubitemid 43764146)
53. Eiseman JL, Lan J, Lagattuta TF, Hamburger DR, Joseph E, Covey JM et al. Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2- dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol 2005; 55: 21-32. (Pubitemid 40064492)
54. Ramanathan RK, Egorin MJ, Erlichman C, Remick SC, Ramalingam SS, Naret C et al. Phase I pharmacokinetic and pharmacodynamic study of 17- dimethylaminoethylamino- 17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. J Clin Oncol 2010; 28: 1520-1526.
55. Hollingshead M, Alley M, Burger AM, Borgel S, Pacula-Cox C, Fiebig HH et al. In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17- demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol 2005; 56: 115-125. (Pubitemid 40884267)
56. Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. 17-AAG and 17-DMAGinduced inhibition of cell proliferation through B-Raf downregulation in WTB-Rafexpressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci 2008; 49: 2348-2356.
57. Bishop SC, Burlison JA, Blagg BS. Hsp90: a novel target for the disruption of multiple signaling cascades. Curr Cancer Drug Targets 2007; 7: 369-388. (Pubitemid 46849241)
58. Vidal S, Kono DH, Theofilopoulos AN. Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6-Faslpr mice. J Clin Invest 1998; 101: 696-702. (Pubitemid 28084255)
59. Reilly CM, Mishra N, Miller JM, Joshi D, Ruiz P, Richon VM et al. Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. J Immunol 2004; 173: 4171-4178. (Pubitemid 39280783)
60. Crispin JC, Kyttaris VC, Terhorst C, Tsokos GC. T cells as therapeutic targets in SLE. Nat Rev Rheumatol 2010; 6: 317-325.
61. Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol 2010; 6: 326-337.
62. La Cava A. The busy life of regulatory T cells in systemic lupus erythematosus. Discov Med 2009; 8: 13-17.
63. Staub HL, Dal Ben ERR, Bisi MC, Keiserman MW. Revisiting anti-hsp90 antibodies in systemic lupus erythematosus. Clin Exp Rheumatol 2010; 28: 928.
64. Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci 2007; 32: 517-530. (Pubitemid 46708702)
65. Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 2002; 8: S55-S61. (Pubitemid 34297080)
66. Karkoulis PK, Stravopodis DJ, Margaritis LH, Voutsinas GE. 17-Allylamino-17- demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC Cancer 2010; 10: 481.
67. Broemer M, Krappmann D, Scheidereit C. Requirement of Hsp90 activity for IkB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-kB activation. Oncogene 2004; 23: 5378-5386. (Pubitemid 39005813)
68. Liu B, Yang Y, Qiu Z, Staron M, Hong F, Li Y et al. Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun 2010; 1: 79.
69. Patel RK, Mohan C. PI3K/AKT signaling and systemic autoimmunity. Immunol Res 2005; 31: 47-55. (Pubitemid 40065424)
70. Wu T, Mohan C. The AKT axis as a therapeutic target in autoimmune diseases. Endocr Metab Immune Disord Drug Targets 2009; 9: 145-150.
71. Fernandez D, Perl A. mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discov Med 2010; 9: 173-178.
72. Liu J, Beller DI. Distinct pathways for NF-kappa B regulation are associated with aberrant macrophage IL-12 production in lupus- and diabetes-prone mouse strains. J Immunol 2003; 170: 4489-4496. (Pubitemid 36519954)
73. Finck BK, Chan B, Wofsy D. Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest 1994; 94: 585-991.
74. Mihara M, Takagi N, Takeda Y, Ohsugi Y. IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 1998; 112: 397-402. (Pubitemid 28267419)
75. Tsai CY, Wu TH, Yu CL, Lu JY, Tsai YY. Increased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. Nephron 2000; 85: 207-214.
76. Wax S, Piecyk M, Maritim B, Anderson P. Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts. Arthritis Rheum 2003; 48: 541-550. (Pubitemid 36278024)
77. Antonova G, Lichtenbeld H, Xia T, Chatterjee A, Dimitropoulou C, Catravas JD. Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc 2007; 37: 19-35. (Pubitemid 47015830)
78. Yoshida M, Xia Y. Heat shock protein 90 as an endogenous protein enhancer of inducible nitric-oxide synthase. J Biol Chem 2003; 278: 36953-36958. (Pubitemid 37140030)
79. Bae J, Mitsiades C, Tai YT, Bertheau R, Shammas M, Batchu RB et al. Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell. J Immunol 2007; 178: 7730-7737. (Pubitemid 46898044)
80. ShimpIIISK, Parson CB, Regna NL, Thomas A, Chafin CB, Reilly CM et al. HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and NF-kB pathways. Inflamm Res 2012; in press
81. Madrigal-Matute J, Lopez-Franco O, Blanco-Colio LM, Munoz-Garcia B, Ramos-Mozo P, Ortega L et al.Heat shock protein90 inhibitors attenuate inflammatory responses in atherosclerosis. Cardiovasc Res 2010; 86: 330-337.
82. Dasu MR, Devaraj S, Park S, Jialal I. Increased Toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 2010; 33: 861-868.
83. Pockley AG, Calderwood SK, Multhoff G. The atheroprotective properties of Hsp70: a role for Hsp70-endothelial interactions? Cell Stress Chaperones 2009; 14: 545-553.
84. de Jong PR, Schadenberg AW, Jansen NJ, Prakken BJ. Hsp70 and cardiac surgery: molecular chaperone and inflammatory regulator with compartmentalized effects. Cell Stress Chaperones 2009; 14: 117-131.
85. Chen H, Wu Y, Zhang Y, Jin L, Luo L, Xue B et al. Hsp70 inhibits lipopolysaccharideinduced NF-kappaB activation by interacting with TRAF6 and inhibiting its ubiquitination. FEBS Lett 2006; 580: 3145-3152. (Pubitemid 43729683)
86. Julkunen H, Ekblom-Kullberg S, Miettinen A. Nonrenal and renal activity of systemic lupus erythematosus: a comparison of two anti-C1q and five anti-dsDNA assays and complement C3 and C4. Rheumatology Int 2011; 1-7
87. Clynes R, Dumitru C, Ravetch JV. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 1998; 279: 1052-1054. (Pubitemid 28113310)
88. Sekine H, Kinser TT, Qiao F, Martinez E, Paulling E, Ruiz P et al. The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. Arthritis Rheum 2011; 63: 1076-1085.
89. Sun L, Zhou L, Chen M, Zhong R, Liu J. Amelioration of systemic lupus erythematosus by withangulatin A in MRL/lpr mice. J Cell Biochem 2011; 112: 2376-2382.
90. Wenderfer SE, Wang H, Ke B, Wetsel RA, Braun MC. C3a receptor deficiency accelerates the onset of renal injury in the MRL/lpr mouse. Mol Immunol 2009; 46: 1397-1404.
91. Kasperkiewicz M, Muller R, Manz R, Magens M, Hammers CM, Somlai C et al. Heatshock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets. Blood 2011; 117: 6135-6142.
92. Sobel ES, Morel L, Baert R, Mohan C, Schiffenbauer J, Wakeland EK. Genetic dissection of systemic lupus erythematosus pathogenesis: evidence for functional expression of Sle3/5 by non-T cells. J Immunol 2002; 169: 4025-4032.
93. Zhu J, Liu X, Xie C, Yan M, Yu Y, Sobel ES et al. T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. J Clin Invest 2005; 115: 1869-1878. (Pubitemid 40979726)
94. Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, Klinenberg JR. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 1991; 147: 117-123.
95. Wan S, Xia C, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD41CD251 T cell regulatory functions. J Immunol 2007; 178: 271-279. (Pubitemid 46033610)
96. de Zoeten EF, Wang L, Butler K, Beier UH, Akimova T, Sai H et al.Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp31 T-regulatory cells. Mol Cell Biol 2011; 31: 2066-2078.
97. Madaio MP. B cells and autoantibodies in the pathogenesis of lupus nephritis. Immunol Res 1998; 17: 123-132. (Pubitemid 28072401)
98. Chan OT, Madaio MP, ShlomchikMJ. The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 1999; 169: 107-121. (Pubitemid 29338727)
99. Theofilopoulos AN, Singer PA, Kofler R, Kono DH, Duchosal MA, Balderas RS. B and T cell antigen receptor repertoires in lupus/arthritis murine models. Springer Semin Immunopathol 1989; 11: 335-368. (Pubitemid 20015943)
100. Grimaldi CM. Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol 2006; 18: 456-461. (Pubitemid 44200327)