Abstract
In anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) genetic predisposition, ANCA autoantibodies, neutrophil extracellular traps (NETs), complement activation, and toll-like receptor signaling are implicated in AAV pathogenesis. Heat shock proteins (HSPs), a highly conserved group of small-sized molecular chaperones, take part in protein folding during cellular stress. Although HSPs were initially observed intracellularly, it has been shown that they can be secreted in the extracellular space and modulate the immune response in various autoimmune diseases including AAV. The scope of the present study is to investigate the role of heat shock protein 60 (HSP60) and 70 (HSP70) in the long renal effects in an ANCA vasculitis cohort. In this cohort of ANCA-associated vasculitis, 29 patients were followed up over 20 years. At diagnosis, immunohistochemistry was performed for HSP60 and HSP70 within the various nephron compartments. Higher renal HSP60 expression was associated with increased interstitial inflammatory infiltrates at diagnosis, while HSP70 expression was associated with a greater extent of interstitial fibrosis at diagnosis. Notably, intense tissue expression of HSP70 at the time of biopsy was associated with a worsened kidney survival. Renal HSP70 expression was associated with poor renal outcomes during long-term follow-up. This finding may indicate a role of HSPs in renal disease progression in ANCA vasculitis. Further validating studies are needed to verify a causative association between HSP70 expression and renal outcomes in ANCA-associated vasculitis.
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Alard JE, Dueymes M, Mageed RA, Saraux A, Youinou P, Jamin C (2009) Mitochondrial heat shock protein (HSP) 70 synergizes with HSP60 in transducing endothelial cell apoptosis induced by anti-HSP60 autoantibody. FASEB J 23:2772–2779. https://doi.org/10.1096/fj.08-128785
Alard JE, Dueymes M, Youinou P, Jamin C (2007) Modulation of endothelial cell damages by anti-Hsp60 autoantibodies in systemic autoimmune diseases. Autoimmun Rev 6:438–443. https://doi.org/10.1016/j.autrev.2007.01.012
Alard JE, Dueymes M, Youinou P, Jamin C (2008) HSP60 and anti-HSP60 antibodies in vasculitis: they are two of a kind. Clin Rev Allergy Immunol 35:66–71. https://doi.org/10.1007/s12016-007-8062-x
Alard JE, Hillion S, Guillevin L, Saraux A, Pers JO, Youinou P, Jamin C (2011) Autoantibodies to endothelial cell surface ATP synthase, the endogenous receptor for hsp60, might play a pathogenic role in vasculatides. PLoS One 6:e14654. https://doi.org/10.1371/journal.pone.0014654
Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175:2900–2912. https://doi.org/10.4049/jimmunol.175.5.2900
Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD, Waldherr R, Bruijn JA, Bajema IM (2010) Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 21:1628–1636. https://doi.org/10.1681/ASN.2010050477
Bonaguri C et al (2014) Cogan’s syndrome: anti-Hsp70 antibodies are a serological marker in the typical form. Isr Med Assoc J 16:285–288
Calderwood SK, Repasky EA, Neckers L, Hightower LE (2019) The IXth CSSI international symposium on heat shock proteins in biology and medicine: stress responses in health and disease: Alexandria Old Town, Alexandria, Virginia, November 10-13, 2018. Cell Stress Chaperones 24:1–6. https://doi.org/10.1007/s12192-018-00966-w
Chebotareva N, Bobkova I, Lysenko L, Neprinzeva N, Vinogradov A, Moiseev S (2018) Heat shock protein 70 and anti-heat shock protein 70 antibodies in patients with chronic glomerulonephritis. Cell Stress Chaperones 23:1229–1235. https://doi.org/10.1007/s12192-018-0928-8
Choi B, Choi M, Park C, Lee EK, Kang DH, Lee DJ, Yeom JY, Jung Y, Kim J, Lee S, Kang SW (2015) Cytosolic Hsp60 orchestrates the survival and inflammatory responses of vascular smooth muscle cells in injured aortic vessels. Cardiovasc Res 106:498–508. https://doi.org/10.1093/cvr/cvv130
Daniels GA, Sanchez-Perez L, Diaz RM, Kottke T, Thompson J, Lai M, Gough M, Karim M, Bushell A, Chong H, Melcher A, Harrington K, Vile RG (2004) A simple method to cure established tumors by inflammatory killing of normal cells. Nat Biotechnol 22:1125–1132. https://doi.org/10.1038/nbt1007
Dhillon V, Latchman D, Isenberg D (1991) Heat shock proteins and systemic lupus erythematosus. Lupus 1:3–8. https://doi.org/10.1177/096120339100100102
Georgopoulos C, McFarland H (1993) Heat shock proteins in multiple sclerosis and other autoimmune diseases. Immunol Today 14:373–375. https://doi.org/10.1016/0167-5699(93)90135-8
Gruden G, Bruno G, Chaturvedi N, Burt D, Pinach S, Schalkwijk C, Stehouwer CD, Witte DR, Fuller JH, Cavallo-Perin P, EURODIAB Prospective Complications Study Group (2009) ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/ macrovascular complications in type 1 diabetes: the EURODIAB Study. J Intern Med 266:527–536. https://doi.org/10.1111/j.1365-2796.2009.02129.x
Hauer HA, Bajema IM, van Houwelingen H, Ferrario F, Noël LH, Waldherr R, Jayne DR, Rasmussen N, Bruijn JA, Hagen EC, European Vasculitis Study Group (EUVAS) (2002) Renal histology in ANCA-associated vasculitis: differences between diagnostic and serologic subgroups. Kidney Int 61:80–89. https://doi.org/10.1046/j.1523-1755.2002.00089.x
Hernadez-Pando R et al (1995) Histological and subcellular distribution of 65 and 70 kD heat shock proteins in experimental nephrotoxic injury. Exp Toxicol Pathol 47:501–508
Imamura Y, Kurokawa MS, Yoshikawa H, Nara K, Takada E, Masuda C, Tsukikawa S, Ozaki S, Matsuda T, Suzuki N (2005) Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet’s disease. Clin Exp Immunol 139:371–378. https://doi.org/10.1111/j.1365-2249.2005.02695.x
Ioannidou DJ, Krasagakis K, Daphnis EK, Perakis KE, Sotsiou F, Tosca AD (2002) Cutaneous small vessel vasculitis: an entity with frequent renal involvement. Arch Dermatol 138:412–414. https://doi.org/10.1001/archderm.138.3.412
Jamin C, Dugué C, Alard JÉ, Jousse S, Saraux A, Guillevin L, Piette JC, Youinou P (2005) Induction of endothelial cell apoptosis by the binding of anti-endothelial cell antibodies to Hsp60 in vasculitis-associated systemic autoimmune diseases. Arthritis Rheum 52:4028–4038. https://doi.org/10.1002/art.21401
Jennette JC (2013) Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol 17:603–606. https://doi.org/10.1007/s10157-013-0869-6
Jindal S, Dudani AK, Singh B, Harley CB, Gupta RS (1989) Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Mol Cell Biol 9:2279–2283. https://doi.org/10.1128/mcb.9.5.2279
Jorgensen C, Gedon E, Jaquet C, Sany J (1998) Gastric administration of recombinant 65 kDa heat shock protein delays the severity of type II collagen induced arthritis in mice. J Rheumatol 25:763–767
Kim EY, Durai M, Mia Y, Kim HR, Moudgil KD (2016) Modulation of adjuvant arthritis by cellular and humoral immunity to Hsp65. Front Immunol 7:203. https://doi.org/10.3389/fimmu.2016.00203
Komiya I, Arimura Y, Nakabayashi K, Yamada A, Osaki T, Yamaguchi H, Kamiya S (2011) Increased concentrations of antibody against heat shock protein in patients with myeloperoxidase anti-neutrophil cytoplasmic autoantibody positive microscopic polyangiitis. Microbiol Immunol 55:531–538. https://doi.org/10.1111/j.1348-0421.2011.00351.x
Lang A, Benke D, Eitner F, Engel D, Ehrlich S, Breloer M, Hamilton-Williams E, Specht S, Hoerauf A, Floege J, von Bonin A, Kurts C (2005) Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal. J Am Soc Nephrol 16:383–391. https://doi.org/10.1681/ASN.2004040276
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130:461–470. https://doi.org/10.7326/0003-4819-130-6-199903160-00002
Li Z, Srivastava P (2004) Heat-shock proteins. Curr Protoc Immunol Appendix 1:Appendix 1T doi:https://doi.org/10.1002/0471142735.ima01ts58
Lu W, Cheng P, Chen S (1998) HSP60, HSP70 in the pathogenesis of Kawasaki disease: implication and action. J Tongji Med Univ 18:145–148. https://doi.org/10.1007/BF02888523
Mahr A, Katsahian S, Varet H, Guillevin L, Hagen EC, Höglund P, Merkel PA, Pagnoux C, Rasmussen N, Westman K, Jayne DRW, for the French Vasculitis Study Group (FVSG) and the European Vasculitis Society (EUVAS) (2013) Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis. Ann Rheum Dis 72:1003–1010. https://doi.org/10.1136/annrheumdis-2012-201750
Ntatsaki E, Watts RA, Scott DG (2010) Epidemiology of ANCA-associated vasculitis. Rheum Dis Clin North Am 36:447–461. https://doi.org/10.1016/j.rdc.2010.04.002
O'Neill S, Harrison EM, Ross JA, Wigmore SJ, Hughes J (2014) Heat-shock proteins and acute ischaemic kidney injury. Nephron Exp Nephrol 126:167–174. https://doi.org/10.1159/000363323
Panagiotakis SH, Perysinakis GS, Kritikos H, Vassilopoulos D, Vrentzos G, Linardakis M, Bertsias G, Glaser K, Daphnis E, Boumpas DT (2009) The epidemiology of primary systemic vasculitides involving small vessels in Crete (southern Greece): a comparison of older versus younger adult patients. Clin Exp Rheumatol 27:409–415
Pockley AG, Shepherd J, Corton JM (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 27:367–377. https://doi.org/10.3109/08820139809022710
Pockley AG, Wu R, Lemne C, Kiessling R, de Faire U, Frostegard J (2000) Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension 36:303–307. https://doi.org/10.1161/01.hyp.36.2.303
Prohaszka Z, Duba J, Horvath L, Csaszar A, Karadi I, Szebeni A, Singh M, Fekete B, Romics L, Fust G (2001) Comparative study on antibodies to human and bacterial 60 kDa heat shock proteins in a large cohort of patients with coronary heart disease and healthy subjects. Eur J Clin Invest 31:285–292. https://doi.org/10.1046/j.1365-2362.2001.00819.x
Rowaiye OO, Kusztal M, Klinger M (2015) The kidneys and ANCA-associated vasculitis: from pathogenesis to diagnosis. Clin Kidney J 8:343–350. https://doi.org/10.1093/ckj/sfv020
Schett G, Xu Q, Amberger A, Van der Zee R, Recheis H, Willeit J, Wick G (1995) Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest 96:2569–2577. https://doi.org/10.1172/JCI118320
Slot MC, Theunissen R, van Paassen P, Damoiseaux JG, Tervaert JW (2006) Evaluation of antibodies against human HSP60 in patients with MPO-ANCA associated glomerulonephritis: a cohort study. J Autoimmune Dis 3:4. https://doi.org/10.1186/1740-2557-3-4
Tsen F, Bhatia A, O'Brien K, Cheng CF, Chen M, Hay N, Stiles B, Woodley DT, Li W (2013) Extracellular heat shock protein 90 signals through subdomain II and the NPVY motif of LRP-1 receptor to Akt1 and Akt2: a circuit essential for promoting skin cell migration in vitro and wound healing in vivo. Mol Cell Biol 33:4947–4959. https://doi.org/10.1128/MCB.00559-13
Tsuji T, Kato A, Yasuda H, Miyaji T, Luo J, Sakao Y, Ito H, Fujigaki Y, Hishida A (2009) The dimethylthiourea-induced attenuation of cisplatin nephrotoxicity is associated with the augmented induction of heat shock proteins. Toxicol Appl Pharmacol 234:202–208. https://doi.org/10.1016/j.taap.2008.09.031
Vabulas RM, Wagner H, Schild H (2002) Heat shock proteins as ligands of toll-like receptors. Curr Top Microbiol Immunol 270:169–184. https://doi.org/10.1007/978-3-642-59430-4_11
Venkataseshan VS, Marquet E (1996) Heat shock protein 72/73 in normal and diseased kidneys. Nephron 73:442–449. https://doi.org/10.1159/000189108
Wright BH, Corton JM, El-Nahas AM, Wood RF, Pockley AG (2000) Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels 15:18–22. https://doi.org/10.1007/s003800070043
Yin Ji X, Kang MR, Choi JS, Jeon HS, Han HS, Kim JY, Son BR, Lee YM, Hahn YS (2007) Levels of intra- and extracellular heat shock protein 60 in Kawasaki disease patients treated with intravenous immunoglobulin. Clin Immunol 124:304–310. https://doi.org/10.1016/j.clim.2007.05.006
Zuo D, Subjeck J, Wang XY (2016) Unfolding the role of large heat shock proteins: new insights and therapeutic implications. Front Immunol 7:75. https://doi.org/10.3389/fimmu.2016.00075
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The contribution of Dr. F. Sotsiou and Prof. D. Emmanouil to this work was invaluable.
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This study is supported by ELKE Research Committee, University of Crete (Research Program Nr. 2976).
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I.P.: data analysis, statistical analysis, and manuscript review. A.A.: manuscript preparation, manuscript review, and data analysis. S.S.: data analysis and manuscript review). E.D. and K.S.: manuscript review and conceptual planning.
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Petrakis, I., Androvitsanea, A., Stratakis, S. et al. Intense immunostaining of heat shock protein 70 within renal interstitium associates with long-term renal survival in an ANCA-associated vasculitis cohort. Cell Stress and Chaperones 26, 51–65 (2021). https://doi.org/10.1007/s12192-020-01151-8
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DOI: https://doi.org/10.1007/s12192-020-01151-8