Bechtel, Ulrike

Feucht, Helmut

Gruber, Rudolf

Kluth, Brigitte

Lederer, Stephan R.

Schiffl, Helmut

English

Stephan R. Lederer

Brigitte Kluth

Rudolf Gruber

Ulrike Bechtel

Helmut Feucht

Helmut Schiffl

Crossref

Heat-Shock Protein 65 and Atherosclerosis in Patients on Regular Hemodialysis

Universität München: Elektronischen Publikationen

Heat-shock protein 65 and atherosclerosis in patients on regular hemodialysis

Open Access LMU ( Ludwig-Maximilians-Univ. München)

nLetter to the EditorNephron 1998;79:355–356Heat-Shock Protein 65 andAtherosclerosis in Patients onRegular HemodialysisStephan R. LedereraBrigitte KluthbRudolf GruberbUlrike BechtelaHelmut Feucht aHelmut Schifflaa Medizinische Klinik, NephrologischeAbteilung, Klinikum Innenstadtder Universität München, undb Institut für Immunologie derUniversität München, DeutschlandDr. S.R. LedererMedizinische Klinik, Dialyseabteilung, Klinikum Innenstadt der LMUZiemssenstrasse 1D–80336 München (Germany)Tel. (089) 5160 2111, Fax (089) 5160 4924ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 1998 S. Karger AG, Basel0028–2766/98/0793–0355$15.00/0This article is also accessible online at:http://BioMedNet.com/kargerDear Sir,Atherosclerosis is one of the most significantyet unresolved problems in patients on regu-lar hemodialysis (HD) with major impact onmorbidity and mortality in patients withend-stage renal disease. A number of riskfactors associated with the development ofatherosclerosis in HD patients have beenidentified, such as hyperlipidemia, hyper-tension, diabetes, smoking and obesity [1].There is growing evidence that atherosclero-sis may – at least in part – result fromautoimmune processes, in which the familyof heat-shock proteins (HSP) may be in-volved [2]. HSPs are a family of about twodozen proteins which show highly homolo-gous sequences between bacterial and mam-malian species. They are induced duringchronic inflammation and other forms ofphysiological stress. Experimental evidencehas shown that expression of HSP 60 onendothelial cells triggers early inflammatoryatherosclerotic changes [3]. Furthermore,immunisation of normocholesterolemic rab-bits with a mycobacterial 65-kD HSP(mHSP 65) induced typical atheroscleroticlesions [2]. Crossreactivity of serum anti-bodies against mHSP 65 with the human 60-kD homologue present in high levels in ath-erosclerotic lesions was demonstrated byimmunoblotting and immunofluorescencetechniques [4]. In a series of 27 human sub-jects HSP 60 could be detected on endothe-lium, smooth muscle cells and/or mononu-clear cells of carotid and aortic specimenswith atherosclerotic lesions. No expressionof stress protein was detectable on controlspecimens with normal intima [5].In the present series we studied antibodytiters against mHSP 65 in patients on regularhemodialysis (HD) (table 1). In total, 77 pa-tients were included in the study (27 females,50 males; mean age 59 B 12 years). Themajor causes for end-stage renal disease werechronic glomerulonephritis, diabetic ne-phropathy and interstitial nephritis. Of the77 patients 29 (6 females, 23 males; meanage 61 B 12 years) showed typical manifes-tations of vascular disease as defined by car-diac ischemia and/or peripheral vascular dis-ease. All 29 patients had typical clinicalsymptoms and angiography was performedto confirm the diagnosis. The remaining 48patients (21 females, 27 males; mean age 57B 13 years) did not show symptoms of sig-nificant vascular disease. As a control, serawere obtained from healthy subjects (medi-cal students and laboratory staff, n = 90, 48females, 42 males, mean age 32 B 12 years).Purified recombinant (r)mHSP 65 has beenkindly provided by Dr. Jan van Embdenfrom the WHO IMMTUB/IMMLEP Bank.The microtiter plates were coated withmHSP 65 overnight at 4°C. After a washingstep, the wells were blocked with non-fattydry milk powder (Merck) in PBS and afterwashing incubated with diluted patient sera.After extensive washing the plates were incu-bated with peroxidase-conjugated rabbit an-tihuman IgG antiserum. The plates werewashed again and developed by addition ofsubstrate. The absorbance was measured inan ELISA reader at 405 nm. In each assayone positive serum was included as a posi-Table 1. Serum anti-HSP 65 antibody titers of indicated groups of patients on regularhemodialysis (OD ratio)HealthycontrolsAll HDpatientsHD patientswith ASHD patientswithout AS90 77 29 48Mean age, years 32B12 59B12 61B12 57B13Mean time on HD, months 58 42 68Means 0.0475 0.156 0.227 0.116+ SEM 0.004 0.137 0.144 0.116Significance1 p ! 0.05* p ! 0.01 p 1 0.05HD = Hemodialysis; AS = atherosclerosis.* Kruskal-Wallis test.1 Compared to healthy controls.356 Nephron 1998;79:355–356 Lederer/Kluth/Gruber/Bechtel/Feucht/Schiffltive control and 3 negative sera as negativecontrols. Arbitrary units were calculated foraccurate interassay comparison using theformula: OD ratio = OD sample/OD posi-tive control.In our study increased circulating anti-bodies to rmHSP 65 were detectable in only2 of 90 healthy donors. The titers of rmHSP65 antibodies of all HD patients were signifi-cantly elevated (OD ratio 0.156, p ! 0.05)(table 1). The analysis of the two subgroupsof HD patients with or without manifesta-tions of vascular disease as defined by thecriteria above, showed no significant differ-ence of rmHSP 65 antibody titers betweenhealthy controls and HD patients withoutvascular disease (OD ratio 0.116, p 1 0.05).On the other hand, HD patients with vascu-lar disease had clearly elevated antibody ti-ters to rmHSP 65 as compared to healthycontrols (OD ratio 0.227, p ! 0.01). Thecomparison of the two subgroups of HDpatients revealed the most striking differ-ence in antibody titers to rmHSP 65 (ODratio 0.227 vs. 0.116, p ! 0.001).The present study shows a correlationbetween serum anti-HSP 65 antibody titersand vascular events in end-stage renal dis-ease. As HD patients with no major underly-ing vascular disease do not differ from thenormal population in that respect, the inten-sity and duration of hemodialysis treatmentby itself does not seem to be responsible forincreased anti-HSP 65 antibodies. High se-rum antibodies to HSP 65 have been foundin patients with symptomatic carotid athero-sclerosis [1] or in patients with ischemic vas-culitis [6]. None of these patients sufferedend-stage renal disease. Whether or not se-rum antibodies increase with age or are themanifestations of atherosclerosis in elderlysubjects remains controversial. Canadian in-vestigators have attributed elevated serumanti-HSP 65 antibodies to age in patientswith thrombotic stroke or transient ischemicattacks, but not to the number of cerebrovas-cular events [7]. Looking at our data, we can-not support this observation in our patientgroup. Although the age-related increase ofserum anti-HSP 65 antibodies as well as ath-erosclerosis is well known [1], HD patientswith vascular disease were only slightly olderthan those without vascular damage. In con-clusion, our data provide further evidencefor the hypothesis of an autoimmune induc-tion of early inflammatory arterioscleroticchanges since HD patients with well-definedvascular lesions have high titers of anti-HSP65 antibodies independent of age and meth-odology. Further studies are necessary to de-termine whether antibodies to HSP 65 are ofdiagnostic and prognostic value in patientson chronic hemodialysis.OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOReferences1 Xu Q, Willeit J, Marosi M, Kleindienst R,Oberhollenzer F, Kiechl S, Stulnig T, Luef G,Wick G: Association of serum antibodies toheat-shock protein 65 with carotid atheroscle-rosis. Lancet 1993;341:255–259.2 Xu Q, Dietrich H, Steiner HJ, et al: Inductionof arteriosclerosis in normocholesterolaemicrabbits by immunization with heat shock pro-tein 65. Arterioscler Thromb 1992;12:789–799.3 Kleindienst R, Schett G, Amberger A, Seitz CS,Michaelis D, Metzler B, Dietrich H, Xu Q,Wick G: Atherosclerosis as an autoimmunecondition. Isr J Med Sci 1995;31:596–599.4 Xu Q, Luef G, Weimann S, Gupta RS, Wolf H,Wick G: Staining of endothelial cells and mac-rophages in atherosclerotic lesions with humanheat shock protein-reactive antisera. Arter-ioscler Thromb 1993;13:1763–1769.5 Kleindienst R, Xu Q, Willeit J, WaldenbergerFR, Weimann S, Wick G: Immunology of ath-erosclerosis: Demonstration of heat shock pro-tein 60 expression and T lymphocytes bearingalpha/beta or gamma/delta receptor in humanatherosclerotic lesions. Am J Pathol 1993;142:1927–1937.6 Gruber R, Lederer S, Bechtel U, Lob S, Rieth-müller G, Feucht HE: Increased antibody titersagainst mycobacterial heat-shock protein 65 inpatients with vasculitis and arteriosclerosis. IntArch Allergy Immunol 1996;110:95–98.7 Mantle R, Singh B, Hachinski V: Do serumantibodies to heat-shock protein 65 relate toage or stroke? Lancet 1995;346:1715.

Atherosclerosis as an autoimmune condition.

Do serum antibodies to heat-shock protein 65 relate to age or stroke? Lancet

et al: Induction of arteriosclerosis in normocholesterolaemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb

G: Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis.

G: Staining of endothelial cells and macrophages in atherosclerotic lesions with human heat shock protein-reactive antisera. Arterioscler Thromb

HE: Increased antibody titers against mycobacterial heat-shock protein 65 in patients with vasculitis and arteriosclerosis. Int Arch Allergy Immunol

Immunology of atherosclerosis: Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions.

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Heat-shock protein 65 and atherosclerosis in patients on regular hemodialysis

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