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.
Key words
Diabetes mellitus type 1 - heat shock protein 65 - neopterin - microvascular complications
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
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