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Heat shock proteins in the diagnosis and prognosis of reproductive disorders in women

HEALTH OF WOMAN. 2018.7(133):77–83; doi 10.15574/HW.2018.133.77

Yakovenko L. F., Romashchenko O. V., Kroupskaya I. V.                          
Institute of Molecular Biology and Genetics of the National Academy of Sciences of Ukraine, Kyiv
Institute of Urology, National Academy of Medical Sciences of Ukraine, Kyiv

Heat shock proteins are structurally highly conserved and abundantly expressed by prokaryotic and eukaryotic cells under stressful conditions. HSPs are immunodominant antigens for many microbes. They are overexpressed at sites of acute and chronic inflammation and involved in the patogenesis of various diseases.

Clinical studies and results of own investigations provided evidence that HSPs and anti-HSPs antibodies can be biomarkers for the diagnosis and prognosis of reproductive disorders in women. The involvement of HSPs and anti-HSPs antibodies in pathogenesis of tubal infertility, ovarian failure, pregnancy loss is discussed.

Key words: heat shock proteins, antibodies against heat shock proteins, infertility, pregnancy loss, in vitro fertilisation.

REFERENCES

1. Vorobyova GМ, Tkachenko YV, Yakovenko LF et al. (2014). Antibodies to Hsp60 in newborn babies, to whom during the intervention for clinical inborn heart failure, autologous cord blood was transfused, in early and late postoperative period. Klinicheskaia hirurgiia 12: 38-45.

2. Makarenko M, Hovsyeyev D, Sydoryk L. (2016). Chaperonin as the normal controls and pathological antistress response in the human reproductive system. Health of woman 5: 126-129.

3. Makarenko M, Hovsyeyev D, Vorona R. (2016). Identification and characterization of antibodies against human Hsp60 at pregnancy. Health of woman 8:75-78.

4. Yakovenko LF, Romaschеnko OV, Sidorik LL. (2009). Antibodies to chlamydial heat shock protein 60 are “marker” infertility in women with pelvic inflammatory disease chlamydial etiology? PAG. 6:78-87.

5. Yakovenko LF, Romaschеnko OV, Rudenko AV et al. (2011). Antibodies to GroEl E.coli (homolog of human Hsp60) in women with pelvic inflammatory disease. PAG. 1: 91-95.

6. Arno G, Yuan Y, Cleary R et al. (1995). Serologic responses of infertile women to the 60-kD chlamydial heat shock protein (hsp60). Fertil.Steril. 64:730-735. https://doi.org/10.1016/S0015-0282(16)57847-9

7. Belhia FGremlich SMuller-Brochut A et al. (2010). Anti-60-kDa heat shock protein antibodies in fetal serum: a biomarker for unexplained small for gestational age fetuses. Gynecol Obstet Invest. 70(4):299-305. https://doi.org/10.1159/000314021; PMid:21051851

8. Budrys NGong SRodgers A et al. (2012). Chlamydia trachomatis antigens recognized in women with tubal factor infertility, normal fertility, and acute infection. Obstet Gynecol. 119(5):1009-1016. https://doi.org/10.1097/AOG.0b013e3182519326; PMid:22525912 PMCid:PMC4608258

9. Bulut Y, Faure E, Thomas L et al. (2002). Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol. 168:1435-1440. https://doi.org/10.4049/jimmunol.168.3.1435; PMid:11801686

10. Campanella C, Gammazza A, Mularoni L et al. (2009). A comparative analysis of the products of GROEL-1 gene from Chlamydia trachomatis serovar D and the HSP60 var1 transcript from Homo sapiens suggests a possible autoimmune response. Int J Immunogenet. 36:73-8. https://doi.org/10.1111/j.1744-313X.2008.00819.x; PMid:19207939

11. Cappello F, de Conway M, Di Felice V et al. (2009). Chlamydia trachomatis infection and anti-Hsp60 immunity: the two sides of the coin. PLoS Pathog. 5(8):1-9. https://doi.org/10.1371/journal.ppat.1000552; PMid:19714222 PMCid:PMC2726942

12. Child D, Hudson P, Hunter-Lavin C et al. (2006). Birth defects and anti-heat shock protein 70 antibodies in early pregnancy. Cell Stress and Chaperones. 11(1):101-105. https://doi.org/10.1379/CSC-130R1.1; PMid:16572734 PMCid:PMC1400609

13. Choudhury AKhole V. (2015). Immune-mediated destruction of ovarian follicles associated with the presence of HSP90 antibodies. Mol Reprod Dev. 82(2):81-89. https://doi.org/10.1002/mrd.22428; PMid:25653208

14. Daponte APournaras SDeligeoroglou E et al. (2012). Serum interleukin-1β, interleukin-8 and anti-heat shock 60 Chlamydia trachomatis antibodies as markers of ectopic pregnancy. J Reprod Immunol. 93(2):102-108. https://doi.org/10.1016/j.jri.2012.01.003; PMid:22386127

15. Dieudé M, Senécal J-L, Raymond Y. (2004). Induction of endothelial cell apoptosis by heat-shock protein 60–reactive antibodies from anti–endothelial cell autoantibody–positive systemic lupus erythematosus patients. Arthritis Rheum. 50(10):3221-3231. https://doi.org/10.1002/art.20564; PMid:15476243

16. Dieude M, Gillis M, Theoret J et al. (2009). Autoantibodies to heat shock protein 60 promote thrombus formation in a murine model of arterial thrombosis. J.Tromb.Hatmost. 7(4):710-719. https://doi.org/10.1111/j.1538-7836.2009.03305.x

17. Dutta R, Jha R, Salhan S et al. (2008). Chlamydya trachomatis-specific heat shock protein 60 antibodies can serve as prognostic marker in secondary infertile women. Infection. 36(4):374-378. https://doi.org/10.1007/s15010-008-7129-9; PMid:18642113

18. Equils O, Lu D, Gatter M et al. (2006). Chlamydya Heat Shock Protein 60 Induces Trophoblast Apoptosis through TLR4. J. Immunol. 177:1257-1263. https://doi.org/10.4049/jimmunol.177.2.1257; https://doi.org/10.4049/jimmunol.177.5.3493; PMid:16818785

19. Gao HMeng JXu M et al. (2013). Serum Heat Shock Protein 70 Concentration in Relation to Polycystic Ovary Syndrome in a Non-Obese Chinese Population. PLoS One. 8;6; 1-18 https://doi.org/10.1371/journal.pone.0067727

20. Graspeuntner SBohlmann MGillmann K et al. (2018). Microbiota-based analysis reveals specific bacterial traits and a novel strategy for the diagnosis of infectious infertility. PLoS One. 1:1-15. https://doi.org/10.1371/journal.pone.0191047

21. Hjelholt AChristiansen GJohannesson T et al. (2011). Tubal factor infertility is associated with antibodies against Chlamydia trachomatis heat shock protein 60 (HSP60) but not human HSP60. Hum Reprod. 26(8):2069-2076. https://doi.org/10.1093/humrep/der167; PMid:21642639

22. Higgins D, Hemsley S, Canfield P. (2005). Association of Uterine and Salpingeal Fibrosis with Clamydial Hsp60 and Hsp10 Antigen-Specific Antibodies in Chlamydya-Infected Koals. Clin. and Diagnost. Labor. Immunol. 12(5):632-639. PMid:15879024 PMCid:PMC1112079

23. Jaiswal M, Agrawal V, Jaiswal Y. (2013). Lipopolysaccharide drives alternation of heat shock proteins and induces failure of blastocyst implantation in mouse. Biol Reprod.  88;6:1-12. https://doi.org/10.1095/biolreprod.113.108068; PMid:23677983

24. Jakus S, Neuer A, Dieterle S et al. (2008). Antibody to the Chlamydia trachomatis 60kDa heat shock protein in follicular fluid and in vitro fertilization outcome. American Journal of Reproductive Immunology. 59(2):85–89. https://doi.org/10.1111/j.1600-0897.2007.00539.x; PMid:18076634

25. Jauniaux E, Hempstock J, Greenwold N et al. (2003). Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol. 162:115-125. https://doi.org/10.1016/S0002-9440(10)63803-5

26. Johnson B, Le T, Dobbin C et al. (2005). Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem. 280:4037-4047. https://doi.org/10.1074/jbc.M411569200; PMid:15546885

27. Kampinga H, Hageman J, Vos M et al. (2009). Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones. 14:105–111. https://doi.org/10.1007/s12192-008-0068-7; PMid:18663603 PMCid:PMC2673902

28. Kinnunen A, Surcel H, Halttunen M et al. (2003). Chlamydia trachomatis heat shock protein-60 induced interferon-gamma and interleukin-10 production in infertile women. Clin Exp Immunol. 131:299-303. https://doi.org/10.1046/j.1365-2249.2003.02048.x; PMid:12562392 PMCid:PMC1808640

29. Kligman IJeremias JRosenwaks Z et al. (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(1):32-36. https://doi.org/10.1111/j.1600-0897.1998.tb00385.x; PMid:9689358

30. La Verda D, Albanese L, Ruther P et al. (2000). Seroreactivity to Chlamydya trachomatis HSP10 correlates with severity of human genital track disease. Infect Immun. 68:303-309. https://doi.org/10.1128/IAI.68.1.303-309.2000

31. Lamb J, Bal V, Nendez-Sampererio A et al. (1989). Stress proteins may provide a link between the immune response to infection and autoimmunity. Int. Immunol. 1:191-196. https://doi.org/10.1093/intimm/1.2.191; PMid:2484883

32. Lichtenwalner A, Patton D, Voorhis W et al. (2004). Heat Shock Protein 60 is the major antigen which stimulates delayed-type hypersensity reaction in the macaque model of Chlamydya trachomatis salpingitis. Infect. Immun. 72(2):1159-1161. https://doi.org/10.1128/IAI.72.2.1159-1161.2004; PMid:14742566 PMCid:PMC321634

33. Linhares I, Witkin S. (2010). Immunopathogenic consequences of Chlamydya trachomatis 60 kDa heat shock protein expression in the femal reproductive tract. Cell Stress Chaperons. 15:467-473. https://doi.org/10.1007/s12192-010-0171-4; PMid:20182835 PMCid:PMC3006632

34. Liu H, Hou F, Liang H et al. (2013). Effects of diagnostic ultrasound on HSP70 expression in chorionic villi in rats during early pregnancy and the role of HSP70 in apoptosis in chorionic villi. Int J Mol Med. 32:1085-1092. https://doi.org/10.3892/ijmm.2013.1489; PMid:24026294

35. Leng X, Wang X, Pang W et al. (2013). Evidence of a role for both anti-Hsp70 antibody and endothelial surface membrane Hsp70 in atherosclerosis. Cell Stress Chaperones. 18:483-493. https://doi.org/10.1007/s12192-013-0404-4; PMid:23334859 PMCid:PMC3682019

36. Matsuda M, Sasaki A, Shimizu K et al. (2017). Increased Anti-HSP60 and Anti-HSP70 Antibodies in Women with Unexplained Recurrent Pregnancy Loss. Acta Med Okayama. 71(3):201-208. PMid:28655939

37. Mayr M, Metzler B, Kiechl S et al. (2017). 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  71;3:201-208.

38. Molvarec A, Rigó J, Nagy B et al. (2007). Serum heat shock protein 70 levels are decreased in normal human pregnancy. J Reprod Immunol. 74(1-2):163-169. https://doi.org/10.1016/j.jri.2006.12.002; PMid:17296233

39. Molvarec A, Derzsy Z, Kocsis J et al. (2009). Circulating anti-heat-shock-protein antibodies in normal pregnancy and preeclampsia. Cell Stress Chaperones. 14(5):491-498. https://doi.org/10.1007/s12192-009-0102-4; PMid:19205928 PMCid:PMC2728282

40. Morrison R, Belland R, Lyng K et al. (1989). The 57-kD Chlamydyal hypersensitivity antigen is a stress response protein. J. Exp. Med. 170:1271-1283. https://doi.org/10.1084/jem.170.4.1271; PMid:2571668

41. Muralidharan S, Mandrekar P. (2013). Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol. 94(6):1167-1184. https://doi.org/10.1189/jlb.0313153; PMid:23990626 PMCid:PMC3828604

42. Nip M, Miller D, Taylor P et al. (1994). Expression of heat shock protein 70 kDa in human endometrium of normal and infertile women. Hum Reprod. 9(7): 1253-1256. https://doi.org/10.1093/oxfordjournals.humrep.a138689; PMid:7962428

43. Neuer A, Lam K-N, Tiller F-W et al. (1997). Humoral immune response to membrane components of Chlamydya trachomatis and expression of human 60 kDa heat shock protein in follicular fluid of in-vitro fertilization patients. Hum Reprod. 12:925-929. https://doi.org/10.1093/humrep/12.5.925; PMid:9194641

44. Neuer A, Mele C, Liu H et al. (1998). Monoclonal antibodies to mammalian heat shock proteins impairs mouse embryo development in vitro. Hum Reprod. 13:987-990. https://doi.org/10.1093/humrep/13.4.987; PMid:9619559

45. Neuer A, Spandorfer S, Giraldo P et al. (1999). Heat shock protein expression during gametogenesis and embryogenesis. Review. Infect Dis Obstet Gynecol. 7:10-16. https://doi.org/10.1155/S1064744999000034; https://doi.org/10.1002/(SICI)1098-0997(1999)7:1/2<10::AID-IDOG3>3.0.CO;2-7

46. Neuer A, Spandorfer S, Giraldo P et al. (2000). The role of heat shock proteins in reproduction. Hum Reprod Update. 6:149-159. https://doi.org/10.1093/humupd/6.2.149; PMid:10782573

47. Ozyurek EKaracan TOzdalgicoglu C et al. (2018). Seropositivity for the human heat shock protein (Hsp)60 accompanying seropositivity for Chlamydia trachomatis is less prevalent among tubal ectopic pregnancy cases than individuals with normal reproductive history. Eur J Obstet Gynecol Reprod Biol. 223:119-122. https://doi.org/10.1016/j.ejogrb.2018.02.022; PMid:29518642

48. Padmini E, Lavanya S. (2011). HSP70-mediated control of endothelial cell apoptosis during pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 156(2):158-164. https://doi.org/10.1016/j.ejogrb.2011.01.026; PMid:21353370

49. Patton D, Sweeney Y, Kuo C. (1994). Demonstration of delayed hypersensitivity in Chlamydya trachomatis salpingitis in monkeys: a pathogenic mechanism of tubal damage. J. Infect. Dis. 169:680-683. https://doi.org/10.1093/infdis/169.3.680; PMid:8158051

50. Peng Y-B, Liu H, Huang S-H et al. (2017). The study of the relationship between aberrant expression of hot shock protein 70 (HSP70) and spontaneous abortion. European Review for Medical and Pharmacological Sciences 21:652-656. PMid:28272721

51. Pockley AG. (2003). Heat shock proteins as regulators of the immune response. Lancet. 362:469-476. https://doi.org/10.1016/S0140-6736(03)14075-5

52. Pires ES and Khole VV. (2009). A block in the road to fertility: autoantibodies to heat shock protein 90-b in human ovarian autoimmunity. Fertility and Sterility 92(4):1395-1409. https://doi.org/10.1016/j.fertnstert.2008.08.068; PMid:19022436

53. Pires ES. (2010). Multiplicity of molecular and cellular targets in human ovarian autoimmunity: an update. J Assist Reprod Genet. 27(9):519-524. https://doi.org/10.1007/s10815-010-9440-5; PMid:20521094 PMCid:PMC2965339

54. Pires E, Choudhury A, Idicula-Thomas S et al. (2011). Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380-389) of HSP90 beta protein. Reprod Biol Endocrinol. 9:1-16. https://doi.org/10.1186/1477-7827-9-16; PMid:21272367 PMCid:PMC3039567

55. Pires E, Parikh F, Mande P et al. (2011). Can anti-ovarian antibody testing be useful in an IVF-ET clinic? J Assist Reprod Genet. 28(1):55-64. https://doi.org/10.1007/s10815-010-9488-2; PMid:20938805 PMCid:PMC3045491

56. Perschinka H, Mayr M, Millonig G et al. (2003). Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arteriscler. Thromb. Vasc. Biol. 23(6):1060-1065. https://doi.org/10.1161/01.ATV.0000071701.62486.49; PMid:12702515

57. Qi Z, Shen L, Zhou H et al. (2014). Phosphorylation of heat shock protein 27 antagonizes TNF-a induced HeLa cell apoptosis via regulating TAK1 ubiquitination and activation of p38 and ERK signaling. Cell Signal. 26:1616–1625. https://doi.org/10.1016/j.cellsig.2014.03.015; PMid:24686082

58. Rajtar-Ciosek AWyroba JKacalska-Jansen O et al. (2016). Markers of implantation in ectopic and high-risk early eutopic pregnancies. Folia Med Cracov. 56(3):41-50. PMid:28275270

59. Rai R, Chauhan S, Singh V et al. (2015). Heat shock protein 27 and its regulatory molecules express differentially in SLE patients with distinct autoantibody profiles. Immunol Lett. 164:25-32. https://doi.org/10.1016/j.imlet.2015.01.007; PMid:25655337

60. Rodgers A, Wang JZhang Y et al. (2010). Association of tubal factor infertility with elevated antibodies to Chlamydia trachomatis caseinolytic protease P. Am J Obstet Gynecol. 203(5):1-13. https://doi.org/10.1016/j.ajog.2010.06.005; PMid:20643392 PMCid:PMC3223063

61. Ruiz-Argüelles ARivadeneyra-Espinoza LAlarcón-Segovia D. (2003). Antibody penetration into living cells: pathogenic, preventive and immuno-therapeutic implications. Curr Pharm Des. 9(23):1881-1887. https://doi.org/10.2174/1381612033454379; PMid:12871192

62. Schett G, Xu Q, Amberger А et al. (1995). Autoantibodies against Heat Shock Protein 60 Mediate Endothelial Cytotoxicity. The American Society for Clinical Investigation 96:2569-2577.

63. Srivastava P, Jha R, Bas S et al. (2008). In infertile women, cells from Chlamydya trachomatis infected site release higher levels of interferon-gamma, interleukin-10 and tumor necrosis factor-alpha upon heat shock protein stimulation than fertile women. Reprod.Biol. and Endocrin. 6:20-29. https://doi.org/10.1186/1477-7827-6-20; PMid:18489796 PMCid:PMC2412883

64. Stephens AAubuchon MSchust D. (2011). Antichlamydial antibodies, human fertility, and pregnancy wastage. Infect Dis Obstet Gynecol. Vol:1-9.

65. Sziller I, Witkin S, Ziegert M et al. (1998). Serological responses of patients with ectopic pregnancy to epitopes of the Chlamydya trachomatis 60 kDa heat shock protein. Hum. Reprod. 13:1088-1093. https://doi.org/10.1093/humrep/13.4.1088; PMid:9619577

66. Sziller IFedorcsák PCsapó Z et al. (2008). Circulating antibodies to a conserved epitope of the Chlamydia trachomatis 60-kDa heat shock protein is associated with decreased spontaneous fertility rate in ectopic pregnant women treated by salpingectomy. Am J Reprod Immunol. 59(2):99-104. https://doi.org/10.1111/j.1600-0897.2007.00553.x; PMid:18211535

67. Tan HXu YXu J et al. (2007). Association of increased heat shock protein 70 levels in the lymphocyte with high risk of adverse pregnancy outcomes in early pregnancy: a nested case-control study. Cell Stress Chaperones. 12(3):230-236. https://doi.org/10.1379/CSC-266.1; PMid:17915555 PMCid:PMC1971239

68. Tiitinen A, Surcel H-M, Halttunen M et al. (2006). Chlamydya trachomatis and chlamydial heat shock protein 60-specific antibody and cell-mediated responses predict tubal factor infertility. Hum Reprod. 21(6):1533-1538. https://doi.org/10.1093/humrep/del014; PMid:16478761

69. Tezel G, Wax MB. (2000). The mechanism of hsp antibody-mediated apoptosis in retinal neuronal cells. J Neurosci. 20:3552-3562. https://doi.org/10.1523/JNEUROSCI.20-10-03552.2000; PMid:10804196

70. Wataba K, Saito T, Takeuchi M et al. (2004). Changed expression of heat shock proteins in various pathological findings in placentas with intrauterine fetal growth restriction. Med Electron Microsc. 37:170-176. https://doi.org/10.1007/s00795-003-0244-x; PMid:15449110

71. Witkin S, Sultan K, Neal G. (1994). Unsuspected Chlamydya trachomatis infection in the femal genital tract and in vitro fertilization outcome. Am. J. Obstet. Gynecol. 171:1208-1214. https://doi.org/10.1016/0002-9378(94)90134-1

72. Witkin S. 1995. Immune pathogenesis of asymptomatic Chlamydia trachomatis infections in the female genital tract. Infect Dis Obstet Gynecol. 3:169-174. https://doi.org/10.1155/S1064744995000548; PMid:18476043 PMCid:PMC2364440

73. Witkin S, Jeremias J, Neuer A. (1996). Immune recognition of the 60 kD heat shock protein: Implications for subsequent fertility. Inf. Dis. Obstet. Gynecol. 4:152-158. https://doi.org/10.1002/(SICI)1098-0997(1996)4:3<152::AID-IDOG9>3.0.CO;2-2; https://doi.org/10.1155/S1064744996000336; PMid:18476087 PMCid:PMC2364488

74. Witkin S, Neuer A, Spandorfer S et al. (1997). Chlamydya trachomatis infection, immunity, and pregnancy outcome. Infect. Dis. Obstet Gynecol. 5:128-132. https://doi.org/10.1002/(SICI)1098-0997(1997)5:2<128::AID-IDOG7>3.0.CO;2-W

75. Witkin SAskienazy-Elbhar MHenry-Suchet J et al. (1998). Circulating antibodies to a conserved epitope of the Chlamydia trachomatis 60 kDa heat shock protein (hsp60) in infertile couples and its relationship to antibodies to C.trachomatis surface antigens and the Escherichia coli and human HSP60. Hum Reprod.  13(5):1175-1179. https://doi.org/10.1093/humrep/13.5.1175; PMid:9647542

76. Witkin SS. (1999). Immunity to heat shock proteins and pregnancy outcome, Infectious Diseases in Obstetrics and Gynecology 7(1-2):35-38. https://doi.org/10.1002/(SICI)1098-0997(1999)7:1/2<35::AID-IDOG8>3.0.CO;2-I

77. Witkin SS. (2002). Immunity to Heat Shock Proteins and Pregnancy Outcome. Infect. Dis. Obstet. Gynecol. 7:35-38. https://doi.org/10.1002/(SICI)1098-0997(1999)7:1/2<35::AID-IDOG8>3.0.CO;2-I

78. Yi Y, Zhong G, Brunham R. (1993). Continuous B-cell epitopes in Chlamydia trachomatis heat shock protein 60. Infect Immun. 61:1117–1120. PMid:7679373 PMCid:PMC302847

79. Yokota S, Minota S, Nobuhiro F. (2006). Anti-HSP auto-antibodies enhance HSP-induced pro-inflammatory cytokine production in human monocytic cells via Toll-like receptors. Intern. Immun. 18:573-580. https://doi.org/10.1093/intimm/dxh399; PMid:16481340

80. Ziegert M, Witkin S, Sziller I et al. (1999). Heat shock proteins and heat shock protein-antibody complexes in placental tissues. Infect. Dis. Obstet. Gynecol. 7:180-185. https://doi.org/10.1155/S1064744999000307; https://doi.org/10.1002/(SICI)1098-0997(1999)7:4<180::AID-IDOG3>3.0.CO;2-7