Exp Clin Endocrinol Diabetes 2003; 111(3): 127-131
DOI: 10.1055/s-2003-39784
Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Antibodies to Heat-Shock Protein 65 and Neopterin Levels in Patients with Type 1 Diabetes Mellitus

R. Weitgasser 1 , M. Lechleitner 2 , T. Koch 2 , G. Galvan 1 , J. Mühlmann 3 , K. Steiner 3 , F. Hoppichler 2 , 3
  • 11st Department of Medicine, St.Johanns Spital, Salzburg General Hospital, Salzburg, Austria
  • 2Department of General Internal Medicine, University of Innsbruck, Innsbruck, Austria
  • 3Hospital Barmherzige Brüder, Salzburg, Austria
Further Information

Publication History

Received: April 17, 2002 First decision: July 3, 2002

Accepted: November 15, 2002

Publication Date:
04 June 2003 (online)

Abstract

Antibodies to heat shock protein (hsp) are strongly associated with atherosclerotic cardiovascular disease in the non-diabetic population as well as in patients with type 2 diabetes mellitus. In type 1 diabetes increased antibody titers to hsp were found to be a symptom of the autoimmune disease leading to beta-cell damage. We asked whether hsp antibody titers are related to metabolic control and late complications in type 1 diabetic patients. Serum neopterin, also an indicator of chronic inflammation, was also evaluated. The hsp65 antibody titer was determined in 138 patients with type 1 diabetes, 47 women and 91 men, aged 35.5 ± 12 years with a mean diabetes duration of 16.6 ± 10.5 years. A history of diabetic late complications and cardiovascular disease was taken. A fundoscopy and a neurological examination were performed, nephropathy was assessed by measurement of the urinary albumin excretion rate. For the measurement of the hsp antibody titer an enzyme-linked immunosorbent assay (ELISA) was applied, for neopterin a radio-immuno assay (RIA) was used. The hsp65 antibody titer was found to be positively related to the patients' age (r = 0.237; p < 0.035). Patients with retinopathy revealed significantly higher hsp65 antibody titers (307.2 ± 38.6) than those without retinopathy (150.0 ± 18.5;p < 0.003). No correlation was found between hsp antibody titer and metabolic control. Serum neopterin levels revealed a trend towards a positive relationship with diabetes duration (r = 0.205; p < 0.0539) and a significant correlation with serum cholesterol levels (r = 0.436; p < 0.001), but not with HbA1 c values.

Our data add further information to the role of inflammatory markers in the development of diabetic microangiopathy.

References

  • 1 Anwaar I, Gottsater A, Lindgarde F, Mattiasson I. Increasing plasma neopterin and persistent plasma endothelin during follow-up after acute cerebral ischemia.  Angiology. 1999;  50 1-8
  • 2 Child D F, Williams C P, Jones R P, Hudson P R, Jones M, Smith C J. Heat shock protein in type 1 and type 2 diabetes and human islet cell culture.  Diabet Med. 1995;  12 595-599
  • 3 Elias D, Markovits D, Reshef T, van der Zee R, Cohen I R. Induction of therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein.  Proc Natl Acad Sci USA. 1990;  87 1576-1580
  • 4 Figueredo A, Ibarra J L, Rodriguez A, Molino A M, Gomez-de la Concha E, Fernandez Cruz A, Patino R. Increased serum levels of IgA antibodies to hsp70 protein in patients with diabetes mellitus: their relationship with vascular complications.  Clin Immunol Immunopathol. 1996;  79 252-255
  • 5 Friedewald W T, Levy R I, Fredrickson D S. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge.  Clin Chem. 1972;  18 499-502
  • 6 Hoppichler F, Lechleitner M, Traweger C, Schett G, Dzien A, Sturm W, Xu Q. Changes of serum antibodies to heat-shock protein 65 in coronary heart disease and acute myocardial infarction.  Atherosclerosis. 1996;  126 333-338
  • 7 Hoppichler F, Koch T, Dzien A, Gschwandtner G, Lechleitner M. Prognostic value of antibody titer to heat-shock protein 65 on cardiovascular events.  Cardiology. 2000;  94 220-223
  • 8 Jones D B, Hunter N R, Duff G W. Heat-shock protein 65 as a beta cell antigen of insulin dependent diabetes.  Lancet. 1990;  336 583-585
  • 9 Kamatsuda A, Wakuil H, Imai H, Itoh H, Yasuda T, Miura A B. Expression of 90-KDa heat shock protein within regenerative tubular cells in a patient with oliguric renal failure due to malignant hypertension.  Ren Fail. 1999;  21 114-117
  • 10 Kennedy P G, Wakakura M, Foulds W S, Clements G B. Herpes simplex virus 1 infection upregulates stress protein expression in cultured retinal neurons.  J Neurol Neurosurg Psychiatry. 1990;  53 72-75
  • 11 Kluft C, Meijer P, Brussaard H E, Krans H M, Schuit A J. Serum neopterin in acute coronary syndromes.  Lancet. 1997;  349 1253
  • 12 Ohguro H, Ogawa K, Maeda T, Maeda A, Maruyoma I. Recoverin and Hsp 70 are found as autoantigens in patients with cancer-associated retinopathy.  Invest Ophthalmol Vis Sci. 1999;  40 82-89
  • 13 Patsch W, Brown S A, Morrisett J, Gotto A, Patsch J R. A dual precipitation method evaluated for measurement of cholesterol in high-density lipoprotein HDL2 and HDL3 in human plasma.  Clin Chem. 1989;  35 265-270
  • 14 Prohaszka Z, Duba J, Lakos G, Kiss E, Varga L, Janoskuti L, Csaszar A, Karadi I, Nagy K, Singh M, Romics L, Fürst G. Antibodies against human heat-shock protein (hsp) 60 and mycobacterial hsp 65 differ in their antigen specificity and complement-activating ability.  International Immunol. 1999;  11 1363-1370
  • 15 Shoenfeld Y, Sherer Y, George J, Harats D. Autoantibodies associated with atherosclerosis.  Ann Med. 2000;  32 (Suppl. 1) 37-40
  • 16 Takei I, Kasatani T, Watanabe K, Kasuga A, Shimada A, Maruyama T, Saruta T, Nomaguchi H. Detection of heat shock protein in patients with insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract. 1993;  21 25-29
  • 17 Tun R Y, Smith M D, Lo S S, Rook G A, Lydyard P, Leslie R D. Antibodies to heat shock protein 65 in type 1 diabetes mellitus.  Diabet Med. 1994;  11 66-70
  • 18 Wachter H, Fuchs D, Hausen A, Reibenegger G, Werner E R. Neopterin as a marker for activation of cellular immunity: immunologic basis and clinical application.  Adv Clin Chem. 1989;  27 81-141
  • 19 Weiss G, Willeit J, Kiechl S, Fuchs D, Jarosch E, Oberhollenzer F, Reibnegger G, Tilz G P, Gerstenbrand F, Wachter H. Increased concentrations of neopterin in carotid atherosclerosis.  Atherosclerosis. 1994;  106 263-271
  • 20 Weiss M F, Rodby R A, Justice A C, Hricik D E. Free pentosidine and neopterin as markers of progression rate in diabetic nephropathy. Collaborative Study Group.  Kidney Int. 1998;  54 193-202
  • 21 Wick G, Romen M, Amberger A, Metzler B, Mayr M, Falkensammer G, Xu Q. Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue.  FASEB J. 1997;  11 1199-1207
  • 22 Winfield J B, Jarjour W N. Stress proteins, autoimmunity, and autoimmune disease.  Curr Top Microbiol Immunol. 1991;  167 161-189
  • 23 Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G. Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis.  Lancet. 1993;  341 255-259
  • 24 Xu Q, Wick G, Wachter H, Reibnegger G. Relationship among serum hsp65 antibodies, neopterin, autoantibodies and atherosclerosis.  Pteridines. 1994;  5 139-141
  • 25 Yabunaka N, Ohtsuka Y, Watanabe I, Noro H, Fujisawa H, Agishi Y. Elevated levels of heat-shock protein 70 (HSP70) in the mononuclear cells of patients with non-insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract. 1995;  30 143-147
  • 26 Yamaguchi K, Gaur V P, Tytell M, Hollmann C R, Turner J E. Ocular distribution of 70-kDa heat-shock protein in rats with normal and dystrophic retinas.  Cell Tissue Res. 1991;  264 497-506

Friedrich Hoppichler

Hospital Barmherzige Brüder Salzburg,

Kajetanerplatz 1

5020 Salzburg

Austria

Phone: 0043 6628088218

Fax: 0043 6628088222

Email: friedrich.hoppichler@bbsalz.at