Detection of Autoantibodies to the Pancreatic Islet Heat Shock Protein 60 in Insulin-dependent Diabetes Mellitus

Ozawa, Yuji; Kasuga, Akira; Nomaguchi, Hiroko; Maruyama, Taro; Kasatani, Tomohiro; Shimada, Akira; Takei, Izumi; Miyazaki, Jun‐ichi; Saruta, Takao

doi:10.1006/jaut.1996.0069

Cited by 40 publications

(13 citation statements)

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“…A Th2 bias of the response to hsp60 in discordant twins of low diabetes risk is consistent with recent studies in NOD mice, where a Th1 bias of the T cell response to hsp60 was found to correlate with disease progression in mice whereas a Th2 bias was found in animals protected from diabetes development [6]. In man, previous studies of a possible association between hsp60 autoimmunity and Type I diabetes did not yield firm conclusions [3,7,8]. These studies did not, however, estimate the quality of the immune response as described by the cytokine profile or related variables.…”

Section: Discussionsupporting

confidence: 83%

Cytokine secretion patterns in twins discordant for Type I diabetes

et al. 1999

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Section: Discussionsupporting

confidence: 83%

Cytokine secretion patterns in twins discordant for Type I diabetes

et al. 1999

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“…Type 1 diabetes and its equivalent in animal models are considered autoimmune in origin, leading to a selective destruction of pancreatic ␤-cells. HSP65 has been proposed as a target candidate antigen in the immune-mediated destruction (12)(13)(14)(15)(16). Herein, we wished to study the progression of atherosclerosis in diabetic hyperlipidemic mice and to study the association with immunity to HSP65.…”

Section: Discussionmentioning

confidence: 99%

“…This assumption has gained predominant support in animal models, whereas in humans, further evidence is still lacking. Accordingly, nonobese diabetic (NOD) mice and streptozotocin-injected animals develop a heightened autoimmune response to HSP65 (12)(13)(14)(15)(16), which is proposed to contribute to pancreatic ␤-cell destruction and consequent hyperglycemia.…”

Section: Effect Of Hyperglycemia and Hyperlipidemia On Atherosclerosimentioning

confidence: 99%

Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice: establishment of a combined model and association with heat shock protein 65 immunity.

et al. 2000

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Diabetes and atherosclerosis have been proposed to be influenced by immune and autoimmune mechanisms. A common incriminated antigen in both disorders is the heat shock protein (HSP)-60/65. In the current study, we established a model combining hyperglycemia with hyperlipidemia in LDL receptor-deficient (LDL-RD) mice and assessed its possible influences on lipid profile, HSP60/65, and atherogenesis. LDL-RD mice were injected either with streptozotocin to induce hyperglycemia or with citrate buffer (control). When hyperglycemia was induced, both study groups were challenged with a high-fat (Western) diet for 6 weeks. Plasma fasting glucose, lipid profile, and antibody levels to HSP65 and oxidized LDL were assessed. At death, the spleens from both groups were evaluated for their proliferative response to HSP65 and the consequent cytokine production. The extent of atherosclerosis was assessed at the aortic sinus. Plasma glucose, cholesterol, and triglyceride levels were elevated in mice injected with streptozotocin compared with control mice. Atherosclerotic lesions were significantly larger in the streptozotocininjected hyperglycemic LDL-RD mice (132 ± 23 ؋ 10 5 µm 2 ) in comparison to their normoglycemic littermates (20 ± 6.6 ؋ 10 5 µm 2 ; P < 0.0001). Both humoral and cellular immune response to HSP65 was more pronounced in streptozotocin-injected mice. When challenged with HSP65 in vitro, splenocytes from streptozotocin-injected mice favored the production of the Thelper (TH)-1 cytokine ␥-interferon. In conclusion, we have established a mouse model that combines hyperglycemia with diet-induced hyperlipidemia in LDL-RD mice and studied its effect on atherosclerosis progression. The accelerated atherosclerotic process is associated with heightened immune response to HSP65 and a shift to a TH1 cytokine profile.

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“…This adds to more direct evidence indicating that hsp70, as other hsp, is involved in antigen presentation and mediates the induction of T helper 1-type cytokines in immune cells thus increasing cellular immunity (36,37). Fi-nally, the detection of antibodies against hsp in some autoimmune disorders including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus suggests that hsp are implicated in the autoimmune disease process (38,39).…”

Section: Overexpression Of Hsp70mentioning

confidence: 99%

p38-dependent Enhancement of Cytokine-induced Nitric-oxide Synthase Gene Expression by Heat Shock Protein 70

Bellmann¹,

Burkart²,

Bruckhoff³

et al. 2000

Journal of Biological Chemistry

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Heat shock protein (hsp) 70 protects cells against stress by means of its ability to chaperone denatured proteins and to modulate stress-activated signaling pathways. Because inflammatory processes are often accompanied by hsp expression and because stress and cytokines share several signaling pathways, we investigated the possibility that hsp70 might modulate the cellular response to cytokines. We found that stable cell clones overexpressing hsp70, or cells shortly after transfection with hsp70, produced 2 times more nitric oxide and inducible nitric-oxide synthase (iNOS) protein and mRNA in response to cytokines than control cells expressing undetectable amounts of hsp70. Since mitogenactivated protein kinases participate in the activation of iNOS by cytokines, we investigated whether hsp70 affected the activation of these signaling pathways. hsp70 overexpression led to a specific enhancement of the activation of the p38 pathway by cytokines, producing little or no effect on the activation of extracellular signal-regulated kinase or Jun N-terminal kinase. Blocking p38 activity with SB203580 totally abolished the enhancing effect of hsp70 on cytokine-induced endogenous iNOS mRNA accumulation or transcription of an iNOS promoter-driven luciferase gene, while having little effect on the cytokine response observed in control cells. We conclude that the p38 pathway acts as an enhancing factor in the activation of iNOS by cytokines and that hsp70 can modulate the cellular response to cytokines by acting on signaling elements upstream of p38.

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Detection of Autoantibodies to the Pancreatic Islet Heat Shock Protein 60 in Insulin-dependent Diabetes Mellitus

Cited by 40 publications

References 0 publications

Cytokine secretion patterns in twins discordant for Type I diabetes

Cytokine secretion patterns in twins discordant for Type I diabetes

Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice: establishment of a combined model and association with heat shock protein 65 immunity.

p38-dependent Enhancement of Cytokine-induced Nitric-oxide Synthase Gene Expression by Heat Shock Protein 70

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