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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administered at a suitably low dose, the toxin streptozotocin (STZ) can trigger an autoimmune process leading to destruction of the beta-cells of the pancreatic islets. In this study, we examined specific immunological reactions in mice before and during the development of STZ-induced autoimmune diabetes. We now report that the development of spontaneous autoantibodies to insulin can serve as a marker of susceptibility to a low dose of STZ. Susceptible male mice of the C57BL/KsJ strain manifested such anti-insulin antibodies, and resistant female mice did not. Administration of a low dose of STZ (five daily doses each of 30 mg/kg) induced transient hyperglycemia approximately 20-30 days later, which temporarily remitted but was followed by intractable diabetes approximately 2.5 months later. The diabetogenic process triggered by the low dose of STZ was associated with an increase in the level of anti-insulin antibodies bearing the Dana and Micha (DM) idiotype, later followed by the appearance of anti-idiotypic antibodies that peaked before the onset of diabetes. Antibodies and T-cells reactive to hsp60 (heat shock protein) were triggered by the low-dose STZ administration and persisted throughout the period that preceded clinical diabetes. T-cells reactive to the p277 peptide of hsp60 were also observed. Finally, active immunization to hsp60 caused transient hyperglycemia by itself and also aggravated the hyperglycemia induced by low-dose STZ. Thus, autoantibodies to insulin can indicate susceptibility to a toxic trigger of diabetes, and a low dose of a toxin can activate the insulin and hsp60 autoimmunity that has been detected previously in the spontaneous autoimmune diabetes of NOD strain mice.
Diabetes 1994 Aug
PMID:Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin. 803 7

To determine whether antibodies to mycobacterial heat shock protein of 65 kD molecular weight (hsp 65) could be important in the pathogenesis of Type 1 diabetes we tested patients before and at diagnosis of diabetes, as well as patients with rheumatoid arthritis. Using ELISA, increased hsp 65 antibodies were detected in 2 of 8 pre-diabetic twins, 1 of 13 newly diagnosed untreated diabetic patients and 3 of 10 rheumatoid arthritis patients. Levels of hsp 65 antibodies in pre-diabetic twins, median (range), 0.25 (0.104-1.904) and newly diagnosed diabetic patients (mean +/- SD) (0.299 +/- 0.220), did not differ significantly either from each other or from their control subjects (0.134 +/- 0.123). In contrast, levels of hsp 65 antibodies in rheumatoid patients (0.59 +/- 0.42) were significantly higher than in their control subjects (0.21 +/- 0.18; p = 0.02). Of twins studied prospectively before diagnosis, at diagnosis but before insulin treatment, and soon after diagnosis, three of four had hsp 65 antibodies at some stage. We conclude that serological immunity to mycobacterial hsp 65 can occur in Type 1 diabetes, but it is neither a characteristic nor a specific feature of the disease.
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PMID:Antibodies to heat shock protein 65 kD in type 1 diabetes mellitus. 818 Dec 56

We have investigated whether antibodies to heat shock protein (hsp) 65 are present in sera from patients with insulin-dependent diabetes mellitus by using Mycobacterium leprae hsp65. Fifty-two sera from patients with IDDM, 36 from patients with unclassified insulin-treated diabetes mellitus and 41 from normal healthy controls were examined by ELISA assay. Seventeen (32.7%) out of 52 IDDM sera and 10 (27.8%) out of unclassified insulin-treated diabetic sera were positive for anti-Mycobacterium (anti-M. leprae) hsp65 antibodies while none of the healthy control sera were positive. Based on western blot analysis, 12 of the 17 IDDM sera and 1 of 2 sera from the unclassified insulin-treated diabetics were positive for anti-M.leprae hsp65 antibodies while all normal control sera were negative. These results support the idea that hsp65 may play a role in the pathogenesis of IDDM. Future studies are necessary to elucidate the role of hsp65 in the pathogenesis of IDDM.
Diabetes Res Clin Pract 1993 Jul
PMID:Detection of heat shock protein in patients with insulin-dependent diabetes mellitus. 825 18

The 60-kD heat shock protein (hsp60) has been implicated in the etiology and pathogenesis of both experimental and naturally occurring autoimmune diseases such as juvenile chronic arthritis (JCA). Human hsp60 is expressed in inflamed synovial tissue, and T lymphocytes both from peripheral blood and synovial fluid show reactivity to human hsp60. Because the anti-hsp60 B lymphocyte response has been less well studied, we have determined the occurrence of IgG anti-human hsp60 antibodies in patients with JCA and various other autoimmune diseases of childhood. Serum IgG anti-human hsp60 antibodies in JCA patients were significantly higher compared with control children (358 and 163 U/mL, respectively). Within the group of JCA patients, the highest antibody titers were found in the subgroup with a polyarticular onset of JCA. IgG anti-human hsp60 antibody levels in synovial fluid were 3- to 4-fold higher compared with paired serum samples. Because this difference was not found for total IgG or for irrelevant antibodies (anti-polyribosylribitol phosphate), this suggests local anti-hsp60 antibody production in the synovial compartment. The occurrence of anti-hsp60 antibodies is not specific for JCA but also is found in children with systemic lupus erythematosus and in cystic fibrosis, whereas mixed connective tissue disease and insulin-dependent diabetes are negative in this respect. Whether the anti-human hsp60 antibodies are directed toward species-specific sequences or to conserved sequences of the hsp60 molecule remains to be determined.
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PMID:Antibodies to human HSP60 in patients with juvenile chronic arthritis, diabetes mellitus, and cystic fibrosis. 825 71

Patients with insulin-dependent diabetes (IDDM) possess antibodies to islet proteins of M(r)-64,000. Potential autoantigens of this M(r) include glutamate decarboxylase (GAD) and 65 kD heat shock protein. We have detected two distinct antibody specificities in IDDM that bind 50,000 M(r) or 37,000/40,000 M(r) proteolytic fragments of 64,000 M(r) proteins. In this study, we investigated relationships of these proteolytic fragments to GAD and heat shock proteins. Polyclonal antibodies to GAD bound 50,000 M(r) fragments of islet antigen. Recombinant GAD65, but not GAD67, blocked binding to this antigen, suggesting that 50,000 M(r) fragments are derived from islet GAD65. In contrast, GAD antibodies did not recognize 37,000/40,000 M(r) fragments, and neither GAD isoforms blocked autoantibody binding to precursors of these fragments. The 37,000/40,000 M(r) fragments, but not the 50,000 M(r) fragments, were detected after trypsin treatment of immunoprecipitates from insulinoma cells that lacked expression of major GAD isoforms. Antibodies in IDDM did not bind native or trypsinized islet heat shock proteins. Thus, IDDM patients possess antibodies to GAD, but also distinct antibodies to a 64,000 M(r) protein that is not related to known GAD isoforms or heat shock proteins.
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PMID:Detection of pancreatic islet 64,000 M(r) autoantigens in insulin-dependent diabetes distinct from glutamate decarboxylase. 832 89

In the NOD mouse, the onset of beta-cell destruction is associated with spontaneous development of T-lymphocytes reactive to members of the 60 kDa heat shock protein (hsp60) family, including the Mycobacterial (MT) and the human (H) hsp60 molecules. Diabetes in the NOD mouse is a spontaneous tissue-specific autoimmune disease occurring without prior immunization. Therefore, it has been suggested that the anti-hsp60 T cells involved in the autoimmune diabetes of NOD mice might reflect molecular mimicry between MT-hsp60 and a beta-cell tissue specific molecule sharing similar T cell epitopes, the p277 peptide of hsp60 in particular. We cloned and expressed the mouse hsp60 cDNA from a beta-cell tumour. This mouse beta-cell hsp60 cDNA was found to be identical in sequence to the hsp60 of mouse fibroblasts. We further report that NOD spleen cells and an NOD diabetogenic T cell clone C9 responded to the recombinant mouse hsp60 and to its peptide M-p277 to the same extent as to H-hsp60 and H-p277. Splenocytes of mice of other strains did not respond to p277. Moreover, treatment of 3 month old NOD mice with the non-modified self M-p277 peptide was as efficient as H-p277, from which it differs in one amino acid, in halting progression of the disease. Thus, anti-H-p277 T cells modulating diabetes in the NOD mouse are autoreactive, and are targeted at the mouse beta-cell hsp60, which is not tissue specific. These findings raise the question of how a non-tissue specific molecule may be a target of a tissue-specific autoimmune disease.
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PMID:NOD mouse diabetes: the ubiquitous mouse hsp60 is a beta-cell target antigen of autoimmune T cells. 873 59

The development of autoimmune diabetes in the NOD strain of mice (H-2g7) is marked by the presence of T-cells reactive to the p277 peptide of the 6O-kDa heat shock protein (hsp60). We have found that the p277 peptide can be used as a therapeutic vaccine to arrest NOD diabetes. Recently, we found that T-cell autoimmunity to p277 also develops spontaneously in C57BL/KsJ mice (H-2d) during the induction of autoimmune diabetes by a very low dose of the beta-cell toxin streptozotocin (STZ). We now report the inhibition of STZ toxin-induced autoimmune diabetes by p277 peptide therapy. Administration of two doses each of 100 micrograms of peptide p277 in mineral oil given 1 week after toxin induction and 85 days later was most effective. The effect of p277 on STZ toxin-induced diabetes was marked by a shift in p277 autoimmunity from a T-cell proliferative response to the production of anti-p277 antibodies. The anti-p277 antibodies were predominantly of the IgG1 and IgG2b isotypes, known to be regulated by Th2 type cytokines; IgG2a antibody, known to be dependent on interferon (IFN)-gamma, was induced to a much lesser degree. Peptide p277 therapy was specific: treatment of the mice with an immunogenic peptide from the sequence of another antigen, GADp34, failed to prevent the development of diabetes. The GADp34 peptide induced lower titers of specific antibodies, and the antibodies were predominantly of the IgG2a class. Thus, p277 peptide therapy, marked by the induction of Th2-type antibodies, can be effective in toxin-induced autoimmune diabetes.
Diabetes 1996 Sep
PMID:The hsp60 peptide p277 arrests the autoimmune diabetes induced by the toxin streptozotocin. 877 17

Autoantibodies against heat shock protein (hsp) 60 have been reported to be detected in sera of non-obese diabetic mice, in an experimental model of IDDM. However, there are only a few studies which have examined IDDM patients for antibodies against mammalian hsp60. We produced murine hsp60 derived from pancreatic beta cells which has high homology to human hsp60 and examined antibodies against the hsp60 in IDDM patients using an enzyme-linked immunosorbent assay. We extended the analysis to patients with other immune-mediated diseases and non-insulin-dependent diabetes mellitus (NIDDM). Positive sera for hsp60 antibody were more frequently detected in 13 out of 84 IDDM (15.5%) and 5 out of 25 rheumatoid arthritis patients (20%), when compared to healthy subjects (1/85; 1.2%, P < 0.001 and P < 0.01, respectively). The levels of hsp60 antibodies of IDDM (0.218 +/- 0.227) and rheumatoid arthritis patients (0.259 +/- 0.191) were significantly higher than those of healthy subjects (0.076 +/- 0.131, P < 0.001, P < 0.01, respectively). Patients with slowly progressive IDDM (n = 26), autoimmune thyroid disease (n = 42), or NIDDM (n = 40) had levels of hsp60 antibodies similar to those in healthy subjects. We found no relationship between the levels of hsp60 antibodies and islet cell antibodies (ICA) or antibodies to glutamic acid decarboxylase (GAD65) in IDDM patients. In conclusion, hsp60 antibodies were detected in Japanese IDDM as well as in rheumatoid arthritis patients. Although the positivity was low, the detection of hsp60 antibodies may be helpful for diagnosis of IDDM especially in GAD65 Ab- or JCA-negative Japanese patients.
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PMID:Detection of autoantibodies to the pancreatic islet heat shock protein 60 in insulin-dependent diabetes mellitus. 886 27

In diabetes prone BB rat pancreas the Th1/ Th2 cytokine balance and the expression of inducible nitric oxide synthase (iNOS) was determined by mRNA analysis before and after the onset of insulitis. Specific mRNA was amplified by reverse transcriptase polymerase chain reaction, quantitated with radiolabelled probes by phosphoimaging and calibrated with the amount of co-amplified beta-actin mRNA. At 50 days of age, prior to recognizable insulitis, there was already significantly enhanced expression of both, Th1 and Th2 cytokines, and of iNOS mRNA, when compared to Wistar rat pancreas (p < 0.001). This supports the concept of an inconspicuous early phase of islet infiltration by single immunocytes, called single cell insulitis. At 70 days of age mononuclear infiltration of islets had begun and was associated with upregulation of interferon gamma (IFN gamma) and iNOS, but downregulation of interleukin-10 and transforming growth factor beta mRNA (p < 0.001). These findings correlate the onset of insulitis with a shift of the Th1/Th2 cytokine balance towards Th1 cell reactivity. Indeed there was a close correlation of the Th1/Th2 cytokine ratio but not of absolute IFN gamma mRNA levels with the insulitis score. Vaccination at day 50 with tetanus toxoid did not affect cytokine gene expression while diphtheria toxoid and even more strongly BCG administration induced a shift towards Th2 reactivity (p < 0.001) while iNOS mRNA was decreased (p < 0.01). Oral dosing with immunostimulatory components of Escherichia coli also changed the quality of inflammation. Oral lipopolysaccharide (LPS) from E. coli and OM-89, an endotoxin free extract containing immunostimulatory glycolipopeptides and heat shock protein (hsp) 65, both downregulated IFN gamma mRNA while only OM-89 in addition suppressed iNOS mRNA and enhanced Th2 cytokine gene expression (p < 0.001). We conclude that the onset of insulitis is associated with a shift towards Th1 cytokine and iNOS gene expression. Diphtheria toxoid and BCG vaccination stimulates Th2 reactivity but does not downregulate Th1. The latter can be achieved through oral administration of LPS or a glycopeptide fraction (OM-89) from E. coli.
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PMID:Cytokine gene expression in the BB rat pancreas: natural course and impact of bacterial vaccines. 896 Aug 25

In islet cells isolated from normal outbred Wistar rats, the known high vulnerability of islet cells toward oxygen radicals or nitric oxide can be abolished by inducing a stress response, such as by heat shock. We show here that islet cells from diabetes-prone BB rats are unable to mount such a protective response. Islet cells from diabetes-prone BB rats without recognizable insulitis were heat stressed. Subsequently, cells were exposed to nitric oxide, to oxygen radicals, or to the beta-cell toxin streptozotocin. While prior heat shock substantially increased the survival of toxin-treated Wistar rat islet cells, no protective stress response was noted for islet cells from diabetes-prone BB rats. Islet cells from diabetes-resistant BB rats were protected by heat stress to the same extent as Wistar rats. A survey of four additional major histocompatibility complex (MHC)-disparate rat strains confirmed the existence of a low and high responder type to stress. Parallel analysis of heat shock protein (hsp)70 induction by Western blot showed a low and high hsp70 response phenotype. A high hsp70 response coincided with a protective stress response. The presence (or absence) of a protective stress response correlated with the preservation (or loss) of intracellular NAD+ in toxin-treated islet cells. The lack of a protective stress response in islet cells from diabetes-prone BB rats, but not in diabetes-resistant BB rats, may promote beta-cell lysis and autoantigen release, and hence could be important for initiation or propagation of the disease process.
Diabetes 1997 Feb
PMID:Low stress response enhances vulnerability of islet cells in diabetes-prone BB rats. 900 Jun 99


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