Skip to main content
Log in

Circulating anti-heat-shock-protein antibodies in normal pregnancy and preeclampsia

  • Original Paper
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

It has been previously reported that circulating anti-heat-shock-protein (Hsp) antibody levels are elevated in cardiovascular disorders. The aim of the present study was to determine circulating antihuman Hsp60, antimycobacterial Hsp65, and antihuman Hsp70 antibody levels in healthy pregnant women and preeclamptic patients and to investigate their relationship to the clinical characteristics of the study subjects, as well as to the markers of inflammation (C-reactive protein (CRP)), endothelial activation (von Willebrand factor antigen), or endothelial injury (fibronectin), oxidative stress (malondialdehyde) and to serum Hsp70 levels. Ninety-three preeclamptic patients and 127 normotensive healthy pregnant women were involved in this case control study. Serum anti-Hsp60, anti-Hsp65, anti-Hsp70, and Hsp70 levels were measured with enzyme-linked immunosorbent assay (ELISA). Serum CRP levels were determined by an autoanalyzer using the manufacturer’s kit. Plasma von Willebrand factor antigen levels were quantified by ELISA, while plasma fibronectin concentration by nephelometry. Plasma malondialdehyde levels were measured by the thiobarbituric-acid-based colorimetric assay. For statistical analyses, nonparametric methods were applied. Anti-Hsp60, anti-Hsp65, and anti-Hsp70 antibodies were detected in all of our serum samples. There were no significant differences in serum anti-Hsp60, anti-Hsp65, and anti-Hsp70 antibody levels between the control and preeclamptic groups. Serum levels of Hsp70 and CRP, as well as plasma levels of VWF antigen, fibronectin, and malondialdehyde, were significantly higher in preeclamptic patients than in normotensive healthy pregnant women. Serum anti-Hsp60 antibody levels showed significant correlations with serum anti-Hsp65 antibody levels both in the control and the preeclamptic groups (Spearman R = 0.55 and 0.59; p < 0.001, respectively). However, no other relationship was found between clinical features (maternal age, smoking status, parity, body mass index, gestational age at blood draw, systolic and diastolic blood pressure, gestational age at delivery, and fetal birth weight) and measured laboratory parameters of the study subjects and serum anti-Hsp antibody levels in either study group. In conclusion, anti-Hsp60 and anti-Hsp70 antibodies as naturally occurring autoantibodies are present in the peripheral circulation of healthy pregnant women. Nevertheless, humoral immunity against heat shock proteins was not associated with preeclampsia. Further studies are warranted to explore the role of heat shock proteins and immune reactivity to them in the immunobiology of normal pregnancy and preeclampsia.

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.

Similar content being viewed by others

Abbreviations

ANCOVA:

analysis of covariance

AU:

arbitrary unit

BMI:

body mass index

CRP:

C-reactive protein

EDTA:

ethylenediamine tetraacetic acid

ELISA:

enzyme-linked immunosorbent assay

HELLP:

hemolysis, elevated liver enzymes, and low platelet count

HRP:

horseradish peroxidase

Hsp:

heat shock protein

Ig:

immunoglobulin

IL:

interleukin

OPD:

o-phenylene-diamine

PBS:

phosphate-buffered saline

Th :

T helper

VWF:Ag:

von Willebrand factor antigen

References

  • Birnie DH, Hood S, Holmes E, Hillis WS (1994) Anti-heat shock protein 65 titres in acute myocardial infarction. Lancet 344:1443. doi:10.1016/S0140-6736(94)90614-9

    Article  PubMed  CAS  Google Scholar 

  • Birnie DH, Holme ER, McKay IC, Hood S, McColl KE, Hillis WS (1998) Association between antibodies to heat shock protein 65 and coronary atherosclerosis. Possible mechanism of action of Helicobacter pylori and other bacterial infections in increasing cardiovascular risk. Eur Heart J 19:387–394. doi:10.1053/euhj.1997.0618

    Article  PubMed  CAS  Google Scholar 

  • Birnie DH, Vickers LE, Hillis WS, Norrie J, Cobbe SM (2005) Increased titres of anti-human heat shock protein 60 predict an adverse one year prognosis in patients with acute cardiac chest pain. Heart 91:1148–1153. doi:10.1136/hrt.2004.040485

    Article  PubMed  CAS  Google Scholar 

  • Burian K, Kis Z, Virok D et al (2001) Independent and joint effects of antibodies to human heat-shock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis. Circulation 103:1503–1508

    PubMed  CAS  Google Scholar 

  • Chan YC, Shukla N, Abdus-Samee M, Berwanger CS, Stanford J, Singh M, Mansfield AO, Stansby G (1999) Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur J Vasc Endovasc Surg 18:381–385. doi:10.1053/ejvs.1999.0885

    Article  PubMed  CAS  Google Scholar 

  • Child DF, Hudson PR, Hunter-Lavin C, Mukhergee S, China S, Williams CP, Williams JH (2006) Birth defects and anti-heat shock protein 70 antibodies in early pregnancy. Cell Stress Chaperones 11:101–105. doi:10.1379/CSC-130R1.1

    Article  PubMed  CAS  Google Scholar 

  • Duckitt K, Harrington D (2005) Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 330:565. doi:10.1136/bmj.38380.674340.E0

    Article  PubMed  Google Scholar 

  • Frostegard J, Lemne C, Andersson B, van der Zee R, Kiessling R, de Faire U (1997) Association of serum antibodies to heat-shock protein 65 with borderline hypertension. Hypertension 29:40–44

    PubMed  CAS  Google Scholar 

  • Gelber SE, Bongiovanni AM, Jean-Pierre C, Linhares IM, Skupski DW, Witkin SS (2007) Antibodies to the 70 kDa heat shock protein in midtrimester amniotic fluid and intraamniotic immunity. Am J Obstet Gynecol 197:278 e1–e4

    Google Scholar 

  • Gromadzka G, Zielinska J, Ryglewicz D, Fiszer U, Czlonkowska A (2001) Elevated levels of anti-heat shock protein antibodies in patients with cerebral ischemia. Cerebrovasc Dis 12:235–239. doi:10.1159/000047709

    Article  PubMed  CAS  Google Scholar 

  • Hightower LE (1991) Heat shock, stress proteins, chaperones, and proteotoxicity. Cell 66:191–197. doi:10.1016/0092-8674(91)90611-2

    Article  PubMed  CAS  Google Scholar 

  • Hoppichler F, Lechleitner M, Traweger C, Schett G, Dzien A, Sturm W, Xu Q (1996) Changes of serum antibodies to heat-shock protein 65 in coronary heart disease and acute myocardial infarction. Atherosclerosis 126:333–338. doi:10.1016/0021-9150(96)05931-X

    Article  PubMed  CAS  Google Scholar 

  • Horvath L, Cervenak L, Oroszlan M et al (2002) Antibodies against different epitopes of heat-shock protein 60 in children with type 1 diabetes mellitus. Immunol Lett 80:155–162. doi:10.1016/S0165-2478(01)00336-4

    Article  PubMed  CAS  Google Scholar 

  • Joubert K (2000) Standards of the body mass and body length of birth in Hungary on the basis of the 1990–1996 nation-wide live born data. Magy Noorv L 63:155–163

    Google Scholar 

  • Kligman I, Jeremias J, Rosenwaks Z, Witkin SS (1998) Cell-mediated immunity to human and Escherichia coli 60-kDa heat shock protein in women: association with a history of spontaneous abortion and endometriosis. Am J Reprod Immunol 40:32–36

    PubMed  CAS  Google Scholar 

  • Kocsis J, Veres A, Vatay A, Duba J, Karadi I, Fust G, Prohaszka Z (2002) Antibodies against the human heat shock protein hsp70 in patients with severe coronary artery disease. Immunol Invest 31:219–231. doi:10.1081/IMM-120016242

    Article  PubMed  CAS  Google Scholar 

  • Lamb JR, Bal V, Mendez-Samperio P et al (1989) Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol 1:191–196. doi:10.1093/intimm/1.2.191

    Article  PubMed  CAS  Google Scholar 

  • Lutz HU, Miescher S (2008) Natural antibodies in health and disease: an overview of the first international workshop on natural antibodies in health and disease. Autoimmun Rev 7:405–409. doi:10.1016/j.autrev.2008.03.005

    Article  PubMed  CAS  Google Scholar 

  • Madach K, Molvarec A, Rigo J Jr., Nagy B, Penzes I, Karadi I, Prohaszka Z (2008) Elevated serum 70 kDa heat shock protein level reflects tissue damage and disease severity in the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Eur J Obstet Gynecol Reprod Biol 139:133–138. doi:10.1016/j.ejogrb.2007.12.012

    Article  PubMed  CAS  Google Scholar 

  • Mandal K, Jahangiri M, Xu Q (2004) Autoimmunity to heat shock proteins in atherosclerosis. Autoimmun Rev 3:31–37. doi:10.1016/S1568-9972(03)00088-0

    Article  PubMed  CAS  Google Scholar 

  • Mayr M, Metzler B, Kiechl S, Willeit J, Schett G, Xu Q, Wick G (1999) Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis. Circulation 99:1560–1566

    PubMed  CAS  Google Scholar 

  • Molvarec A, Prohaszka Z, Nagy B, Szalay J, Fust G, Karadi I, Rigo J Jr. (2006) Association of elevated serum heat-shock protein 70 concentration with transient hypertension of pregnancy, preeclampsia and superimposed preeclampsia: a case-control study. J Hum Hypertens 20:780–786. doi:10.1038/sj.jhh.1002060

    Article  PubMed  CAS  Google Scholar 

  • Molvarec A, Prohaszka Z, Nagy B, Kalabay L, Szalay J, Fust G, Karadi I, Rigo J Jr. (2007a) Association of increased serum heat shock protein 70 and C-reactive protein concentrations and decreased serum alpha(2)-HS glycoprotein concentration with the syndrome of hemolysis, elevated liver enzymes, and low platelet count. J Reprod Immunol 73:172–179. doi:10.1016/j.jri.2006.07.002

    Article  PubMed  CAS  Google Scholar 

  • Molvarec A, Rigo J Jr., Nagy B, Walentin S, Szalay J, Fust G, Karadi I, Prohaszka Z (2007b) Serum heat shock protein 70 levels are decreased in normal human pregnancy. J Reprod Immunol 74:163–169. doi:10.1016/j.jri.2006.12.002

    Article  PubMed  CAS  Google Scholar 

  • Molvarec A, Rigo J Jr., Lazar L, Balogh K, Mako V, Cervenak L, Mezes M, Prohaszka Z (2008) Increased serum heat-shock protein 70 levels reflect systemic inflammation, oxidative stress and hepatocellular injury in preeclampsia. Cell Stress Chaperones doi:10.1007/s12192-008-0067-8

  • Pandey JP, Prohaszka Z, Veres A, Fust G, Hurme M (2004) Epistatic effects of genes encoding immunoglobulin GM allotypes and interleukin-6 on the production of autoantibodies to 60- and 65-kDa heat-shock proteins. Genes Immun 5:68–71. doi:10.1038/sj.gene.6364033

    Article  PubMed  CAS  Google Scholar 

  • Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 16:359–364. doi:10.1016/0003-2697(66)90167-9

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.3109/08820139809022710

    Article  PubMed  CAS  Google Scholar 

  • Pockley AG, Bulmer J, Hanks BM, Wright BH (1999) Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 4:29–35. doi:10.1379/1466-1268(1999)004<0029:IOHHSP>2.3.CO;2

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Pockley AG, De Faire U, Kiessling R, Lemne C, Thulin T, Frostegard J (2002) Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens 20:1815–1820. doi:10.1097/00004872-200209000-00027

    Article  PubMed  CAS  Google Scholar 

  • Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem Sci 33:71–79

    PubMed  CAS  Google Scholar 

  • Prohaszka Z, Duba J, Lakos G et al (1999) Antibodies against human heat-shock protein (hsp) 60 and mycobacterial hsp65 differ in their antigen specificity and complement-activating ability. Int Immunol 11:1363–1370. doi:10.1093/intimm/11.9.1363

    Article  PubMed  CAS  Google Scholar 

  • Prohaszka Z, Duba J, Horvath L et al (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. doi:10.1046/j.1365-2362.2001.00819.x

    Article  PubMed  CAS  Google Scholar 

  • Rea IM, McNerlan S, Pockley AG (2001) Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontol 36:341–352. doi:10.1016/S0531-5565(00)00215-1

    Article  PubMed  CAS  Google Scholar 

  • Redman CW, Sacks GP, Sargent IL (1999) Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 180:499–506. doi:10.1016/S0002-9378(99)70239-5

    Article  PubMed  CAS  Google Scholar 

  • Roberts JM, Gammill HS (2005a) Preeclampsia: recent insights. Hypertension 46:1243–1249. doi:10.1161/01.HYP.0000188408.49896.c5

    Article  PubMed  CAS  Google Scholar 

  • Roberts JM, Gammill H (2005b) Pre-eclampsia and cardiovascular disease in later life. Lancet 366:961–962. doi:10.1016/S0140-6736(05)67349-7

    Article  PubMed  Google Scholar 

  • Saito S, Sakai M (2003) Th1/Th2 balance in preeclampsia. J Reprod Immunol 59:161–173. doi:10.1016/S0165-0378(03)00045-7

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1172/JCI118320

    Article  PubMed  CAS  Google Scholar 

  • Veres A, Fust G, Smieja M et al (2002a) Relationship of anti-60 kDa heat shock protein and anti-cholesterol antibodies to cardiovascular events. Circulation 106:2775–2780. doi:10.1161/01.CIR.0000038890.39298.8D

    Article  PubMed  CAS  Google Scholar 

  • Veres A, Szamosi T, Ablonczy M et al (2002b) Complement activating antibodies against the human 60 kDa heat shock protein as a new independent family risk factor of coronary heart disease. Eur J Clin Invest 32:405–410. doi:10.1046/j.1365-2362.2002.01007.x

    Article  PubMed  CAS  Google Scholar 

  • Veres A, Prohaszka Z, Kilpinen S, Singh M, Fust G, Hurme M (2002c) The promoter polymorphism of the IL-6 gene is associated with levels of antibodies to 60-kDa heat-shock proteins. Immunogenetics 53:851–856. doi:10.1007/s00251-001-0405-9

    Article  PubMed  CAS  Google Scholar 

  • von Dadelszen P, Magee LA, Krajden M et al (2003) Levels of antibodies against cytomegalovirus and Chlamydophila pneumoniae are increased in early onset pre-eclampsia. BJOG 110:725–730

    Google Scholar 

  • Wilson R, Maclean MA, Jenkins C, Kinnane D, Mooney J, Walker JJ (2001) Abnormal immunoglobulin subclass patterns in women with a history of recurrent miscarriage. Fertil Steril 76:915–917. doi:10.1016/S0015-0282(01)02857-6

    Article  PubMed  CAS  Google Scholar 

  • Witkin SS, Sultan KM, Neal GS, Jeremias J, Grifo JA, Rosenwaks Z (1994) Unsuspected Chlamydia trachomatis infection and in vitro fertilization outcome. Am J Obstet Gynecol 171:1208–1214

    PubMed  CAS  Google Scholar 

  • Witkin SS, Jeremias J, Neuer A, David S, Kligman I, Toth M, Willner E, Witkin K (1996) Immune recognition of the 60 kD heat shock protein: implications for subsequent fertility. Infect Dis Obstet Gynecol 4:152–158

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1007/s003800070043

    Article  PubMed  CAS  Google Scholar 

  • Wu T, Tanguay RM (2006) Antibodies against heat shock proteins in environmental stresses and diseases: friend or foe? Cell Stress Chaperones 11:1–12. doi:10.1379/CSC-155R.1

    Article  PubMed  CAS  Google Scholar 

  • Xu Q, Willeit J, Marosi M et al (1993) Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet 341:255–259. doi:10.1016/0140-6736(93)92613-X

    Article  PubMed  CAS  Google Scholar 

  • Xu Q, Kiechl S, Mayr M, Metzler B, Egger G, Oberhollenzer F, Willeit J, Wick G (1999) Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis : clinical significance determined in a follow-up study. Circulation 100:1169–1174

    PubMed  CAS  Google Scholar 

  • Yuan J, Yang M, Yao H et al (2005) Plasma antibodies to heat shock protein 60 and heat shock protein 70 are associated with increased risk of electrocardiograph abnormalities in automobile workers exposed to noise. Cell Stress Chaperones 10:126–135. doi:10.1379/CSC-95R.1

    Article  PubMed  CAS  Google Scholar 

  • Zhu J, Quyyumi AA, Rott D, Csako G, Wu H, Halcox J, Epstein SE (2001) Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis. Circulation 103:1071–1075

    PubMed  CAS  Google Scholar 

  • Ziegert M, Witkin SS, Sziller I, Alexander H, Brylla E, Hartig W (1999) Heat shock proteins and heat shock protein-antibody complexes in placental tissues. Infect Dis Obstet Gynecol 7:180–185

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The skillful technical assistance of Szigeti Antalné and the support of Szilvia Walentin, Éva Imreh, and Mónika Kleiber (Central Laboratory, Kútvölgyi Clinical Center, Semmelweis University, Budapest, Hungary) are acknowledged with many thanks. This work was supported by research grants from the Hungarian Scientific Research Fund (NF 72689) and the Faculty of Medicine of the Semmelweis University.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Attila Molvarec.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molvarec, A., Derzsy, Z., Kocsis, J. et al. Circulating anti-heat-shock-protein antibodies in normal pregnancy and preeclampsia. Cell Stress and Chaperones 14, 491–498 (2009). https://doi.org/10.1007/s12192-009-0102-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-009-0102-4

Keywords

Navigation