Cellular immune response to diverse islet cell antigens in IDDM

Durinovic‐Belló, Ivana; Hummel, M.; Ziegler, A. G.

doi:10.2337/diabetes.45.6.795

Cited by 72 publications

(91 citation statements)

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“…Activated cells were then added to a responder cell culture consisting of CD25 þ -depleted CD4 þ T cells of a DRB1*0401 donor activated by 5 mg ml À1 soluble anti-CD3 (UCHT1; BD Biosciences Pharmingen, San Diego, CA, USA), 5 mg ml À1 soluble anti-CD28 (CD28.2; Pharmingen) and irradiated autologous APCs (non-CD4 cells). The ability of each T-cell clone to suppress proliferation of the responder cells was determined by 3 H thymidine incorporation during the final 16 h of the 5-day assay.…”

Section: Resultsmentioning

confidence: 99%

“…T-cell reactivity to a major proinsulin epitope, PI(73-90), occurs as an early marker of disease progression in the pre-diabetic stage among genetically high-risk subjects. 2,3 Direct detection of these proinsulin-specific T cells was recently achieved using soluble, fluorescent human leukocyte antigen (HLA)-peptide tetramers containing the PI(73-90) epitope to bind to peripheral CD4 T cells proliferating in response to proinsulin peptide stimulation. 4 In humans, expression levels of insulin are regulated in part by a direct transcriptional influence of a polymorphic insulin gene variable number of tandem repeats (INS-VNTR) genetic element associated with the proinsulin gene promoter region.…”

Section: Introductionmentioning

confidence: 99%

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Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Durinovic‐Belló

Gersuk

et al. 2010

Genes Immun

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Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4 þ proinsulin (PI) 76-90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a 'protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Durinovic‐Belló

Gersuk

et al. 2010

Genes Immun

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“…Therefore, it is unlikely that the secondary beta cell destruction due to the T cell infiltration in the acinar tissue can lead to the detection of peripheral immune reaction to GAD or insulin by ELISPOT assay. It has been proposed that the development of Type 1 diabetes is controlled by autoreactive T cells of the Th1 arm which is primarily associated with cellular immunity, rather than of the Th2 arm which is mainly involved in humoral immunity and immunoregulatory suppression [17,18,19]. In our study, no GAD-reactive, IL-4-secreting T cells were detectable in fulminant Type 1 diabetic patients, whereas 10% of autoantibody-positive Type 1 diabetic subjects showed IL-4 spots.…”

Section: Discussionmentioning

confidence: 99%

T lymphocyte response against pancreatic beta cell antigens in fulminant Type 1 diabetes

et al. 2004

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Aims/hypothesis. Fulminant Type 1 diabetes is a novel subtype of Type 1 diabetes that involves the abrupt onset of insulin-deficient hyperglycaemia. This subtype appears to be non-autoimmune because of the absence of diabetes-related autoantibodies in the serum, and of insulitis in pancreatic biopsy specimens. The pathogenesis of the disease is still unknown. In this study, we investigated whether T cell autoimmune responses are involved in fulminant Type 1 diabetes. Methods. Cellular immune responses to beta cell autoantigens were studied by enzyme-linked immunospot (ELISPOT) assay in 13 fulminant Type 1 diabetic patients and 49 autoantibody-positive autoimmune Type 1 diabetic patients. Results were compared with those of 18 Type 2 diabetic patients, six secondary diabetic patients (diabetes due to chronic pancreatitis) and 35 healthy controls. Results. Nine of 13 (69.2%) GAD-reactive Th1 cells, and three of 12 (25%) insulin-B9-23-reactive Th1 cells were identified in fulminant Type 1 diabetic patients by ELISPOT, as in autoantibody-positive Type 1 diabetic patients. Four fulminant Type 1 diabetic patients possessed the highly diabetes-resistant allele DR2, three of whom had GAD-reactive Th1 cells in the periphery. Conclusions/interpretation. Peripheral immune reaction was observed in 69.2% of fulminant Type 1 diabetic patients, indicating that autoreactive T cells might contribute, at least in part, to the development of fulminant Type 1 diabetes.

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“…Autoantibodies to IA-2 were observed in 50-70% of newly diagnosed patients with type 1 diabetes (4,5) and in 49-64% of prediabetic subjects at high risk for rapid development of the disease (6)(7)(8). In addition, a specific T-cell response has been described in 42-60% of diabetic patients, suggesting that IA-2 is a dominant target of humoral and cellular autoimmunity (8)(9)(10)(11).…”

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confidence: 99%

Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells.

et al. 2000

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IA-2, a member of the protein tyrosine phosphatase family, represents a major target autoantigen in type 1 diabetes. To study the regulation of IA-2 gene expression, we used INS-1 insulinoma cells to analyze ␤-cell signal transduction pathways as well as the effect of metabolic and hormonal factors involved in the regulation of the insulin secretory pathway. Quantitative competitive reverse transcriptase-polymerase chain reaction revealed that an increase of cellular cAMP mediated by forskolin (10 µmol/l, 24 h) or 3-isobutyl-1-methylxanthine (100 µmol/l, 24 h) induced maximal stimulation of IA-2 mRNA levels (451 ± 85 and 338 ± 86% compared with basal conditions; P < 0.001). In contrast, activation of protein kinase C (PKC) by short-term treatment with phorbol 12-myristate 13-acetate (PMA) (1 µmol/l, 6 h) did not alter IA-2 expression, whereas depletion of PKC by prolonged culturing (24 h) exerted a significant inhibition (57 ± 24%; P < 0.05). cAMP-dependent upregulation was confirmed by the findings that glucagon (10 µmol/l, 24-48 h) increased levels of IA-2 mRNA (190 ± 35%; P < 0.05), whereas short-term incubation with high glucose concentration showed no effect. However, prolonged incubation in high glucose (21 mmol/l) induced a time-and dose-dependent increase of IA-2 mRNA expression, reaching maximal values after 144 h (285 ± 68%; P < 0.05). These studies demonstrate that stimuli of insulin secretion that operate by activation of adenylate cyclase generating cAMP significantly increase IA-2 gene expression. In contrast, activation of PKC by high glucose concentration or PMA exerted no effect, suggesting that IA-2 gene expression is not simply coupled to insulin secretion, but may be involved in the fine regulation of ␤-cell function. These findings may be important to clarify the function of IA-2 in ␤-cells and elucidate mechanisms involved in the induction of autoimmunity to IA-2.

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Cellular immune response to diverse islet cell antigens in IDDM

Cited by 72 publications

References 0 publications

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

T lymphocyte response against pancreatic beta cell antigens in fulminant Type 1 diabetes

Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells.

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