Does GAD Have a Unique Role in Triggering IDDM?

Baekkeskov, Steinunn; Kanaani, Jamil; Jaume, Juan Carlos; Kash, Shera

doi:10.1006/jaut.2000.0443

Cited by 32 publications

(20 citation statements)

References 85 publications

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“…Second, the detection of T cells in functional assays requires that the antigen be known. In human T1D, however, the target antigen is not yet known, and there are several equally attractive candidates for this role [5,[11][12][13]. Third, when T cells are tested in functional assays, the antigen presenting cells (APC) present in the blood will dictate the rules of antigen presentation.…”

Section: Introductionmentioning

confidence: 98%

Increased in vivo frequency of IA-2 peptide-reactive IFNγ+/IL-4− T cells in type 1 diabetic subjects

Herzog

Ott

Dittrich

et al. 2004

Journal of Autoimmunity

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Section: Introductionmentioning

confidence: 98%

Increased in vivo frequency of IA-2 peptide-reactive IFNγ+/IL-4− T cells in type 1 diabetic subjects

Herzog

Ott

Dittrich

et al. 2004

Journal of Autoimmunity

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“…However, the relationship between these autoantibodies and the pathogenesis of TID is not understood. GAD65, one of the primary target antigens of the autoimmune disease process, is thought to play a pathogenic role in the development of TID (reviewed in [4][5][6]). Moreover, modulation of GAD65 presentation to the T cells by diseaseassociated GAD65Ab has been implicated as a possible mechanism for the breakdown of tolerance to the pancreatic islets [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Multiplicity of the antibody response to GAD65 in Type I diabetes

Gilliam

Binder

Banga³

et al. 2004

Clinical and Experimental Immunology

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SUMMARYType I diabetes (TID) is an autoimmune disease characterized in part by the presence of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65), among other pancreatic islet antigens. We investigated the independent epitope specificities of these GAD65 antibodies (GAD65Ab) and their combinations in the sera of new onset TID patients and first-degree relatives positive for GAD65Ab. For our analysis, we used four GAD65-specific recombinant Fabs (rFabs) that recognize different conformational determinants of GAD65 located throughout the molecule, including the N-terminal, the middle and the C-terminal regions. We used these epitope-specific rFabs in competition assays to determine the binding specificity of the autoantibodies found in patient sera. Among the 61 sera from newly diagnosed GAD65Ab-positive TID patients GAD65 binding was competed for 23 sera by all four rFabs, 29 by at least two rFabs, and in nine sera were displaced by one or no rFab. In contrast, none of the 24 sera from GAD65Ab-positive first-degree relatives of TID patients were displaced by all four rFabs. When using all four rFabs simultaneously to compete with GAD65Ab binding, binding of sera from TID patients was reduced by an average of 70%. A significantly weaker competition was observed when evaluating sera of GAD65Ab-positive first-degree relatives ( P < 0·0001).

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“…Peptides of the T1D-associated autoantigens, HSP60 and IA-2, also caused an increased secretion of chemokines (CCL2, CCL3, and CXCL10). This result indicates that children exposed to, especially, serious life events have an increased inflammatory response to the T1D-associated autoantigen GAD 65 , one of several autoantigens associated with the destruction of the b cells and suggested to cause proliferation of Th1-like lymphocytes in T1D development (60)(61)(62)(63). Because lymphocytes specific for GAD 65 are among the first to enter inflamed islets in T1D (60), this autoantigen has, in recent clinical trials, been used in attempts to preserve b cell function in T1D (64,65).…”

Section: Discussionmentioning

confidence: 91%

Psychological Stress in Children May Alter the Immune Response

Carlsson

Frostell

Ludvigsson

et al. 2014

The Journal of Immunology

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Psychological stress is a public health issue even in children and has been associated with a number of immunological diseases. The aim of this study was to examine the relationship between psychological stress and immune response in healthy children, with special focus on autoimmunity. In this study, psychological stress was based on a composite measure of stress in the family across the domains: 1) serious life events, 2) parenting stress, 3) lack of social support, and 4) parental worries. PBMCs, collected from 5-y-old high-stressed children (n = 26) and from 5-y-old children without high stress within the family (n = 52), from the All Babies In Southeast Sweden cohort, were stimulated with Ags (tetanus toxoid and β-lactoglobulin) and diabetes-related autoantigens (glutamic acid decarboxylase 65, insulin, heat shock protein 60, and tyrosine phosphatase). Immune markers (cytokines and chemokines), clinical parameters (C-peptide, proinsulin, glucose), and cortisol, as an indicator of stress, were analyzed. Children from families with high psychological stress showed a low spontaneous immune activity (IL-5, IL-10, IL-13, IL-17, CCL2, CCL3, and CXCL10; p < 0.01) but an increased immune response to tetanus toxoid, β-lactoglobulin, and the autoantigens glutamic acid decarboxylase 65, heat shock protein 60, and tyrosine phosphatase (IL-5, IL-6, IL-10, IL-13, IL-17, IFN-γ, TNF-α, CCL2, CCL3, and CXCL10; p < 0.05). Children within the high-stress group showed high level of cortisol, but low level of C-peptide, compared with the control group (p < 0.05). This supports the hypothesis that psychological stress may contribute to an imbalance in the immune response but also to a pathological effect on the insulin-producing β cells.

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Does GAD Have a Unique Role in Triggering IDDM?

Cited by 32 publications

References 85 publications

Increased in vivo frequency of IA-2 peptide-reactive IFNγ+/IL-4− T cells in type 1 diabetic subjects

Increased in vivo frequency of IA-2 peptide-reactive IFNγ+/IL-4− T cells in type 1 diabetic subjects

Multiplicity of the antibody response to GAD65 in Type I diabetes

Psychological Stress in Children May Alter the Immune Response

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