GAD65 as a prototypic autoantigen

Fenalti, Gustavo; Rowley, Merrill J.

doi:10.1016/j.jaut.2008.04.013

Cited by 23 publications

(11 citation statements)

References 46 publications

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“…The GADA showed SPS-characteristic inhibition of GAD65 enzymatic activity and showed reactivity towards a SPS-associated antibody epitope (b78). [17] However, reactivity to a T1D-associated GADA epitope (b96.11) [39] was also observed. This antibody recognizes a conformational epitope formed by the three-dimensional structure of amino acid residues 308–365, including the peptide sequence that dominated the T-cell response.…”

Section: Discussionmentioning

confidence: 99%

“…[10–12] While GAD65 is a common target of humoral autoimmunity in both T1D and SPS [13–16], the larger isoform is rarely recognized by autoantibodies, possibly due to differences in the enzymes’ conformations. [17] Approximately ~80% of T1D patients test positive for GADA [18–19], although the serum levels are 10–1000 fold lower than in SPS. [20] GADA in T1D patients recognize different GAD65 epitopes as compared to GADA in SPS patients [21–22], and in strong contrast with SPS-related GADA, do not inhibit GAD65 enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff‐person syndrome but without type 1 diabetes

Hänninen

Soilu‐Hänninen

Hampe

et al. 2010

Diabetes Metabolism Res

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Background Glutamic acid decarboxylase (GAD) is a rate-limiting enzyme in the synthesis of gamma-amino butyric acid (GABA) and an important autoantigen both in patients with type 1 diabetes (T1D) and stiff-person syndrome (SPS). Autoantibodies (GADA) to the 65-kDa isoform of GAD are a characteristic feature in both diseases. Approximately 30% of patients with SPS develop diabetes, yet, it is unclear to which extent co-existing autoimmunity to GAD65 and other islet autoantigens determines the risk of developing T1D.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff‐person syndrome but without type 1 diabetes

Hänninen

Soilu‐Hänninen

Hampe

et al. 2010

Diabetes Metabolism Res

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“…Indeed, the reason why GAD is a major auto-antigen in autoimmune diabetes is not known. The reason why only some proteins become auto-antigens is unclear, but is likely associated with structural features [36]. Antibodies against two isoforms of GAD were described [37].…”

Section: Rationale For the Use Of The Drug In Type 1 Diabetes At Diagmentioning

confidence: 99%

Therapy with GAD in diabetes

Ludvigsson

2009

Diabetes Metabolism Res

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The enzyme glutamic acid decarboxylase (GAD) is of great importance for the neurotransmission in the central nervous system, and therefore of interest for treatment of pain and neurological disease. However, it is also released in pancreas although its role is not quite clear. GAD is a major auto-antigen in the process leading to type 1 diabetes with both a clear cell-mediated immune response to GAD and auto-antibodies to GAD (GADA), which can be used as a predictor of diabetes. Administration of the isoform GAD65 can prevent autoimmune destruction of pancreatic beta cells in non-obese diabetic (NOD) mice and the subsequent need for exogenous insulin replacement. In Phase I and II studies an alum-formulated vaccine (Diamyd) has shown to be safe, and in a dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients 20-microg was given subcutaneously one month apart indicating preservation of residual insulin secretion. A double-blind randomized Phase II trial in 70 patients (10-18 years old) with recent-onset type 1 diabetes showed significant preservation of residual insulin secretion and a GAD-specific immune response, both humoral and cell-mediated, but no treatment-related adverse events. With this promising background further studies are on their way, both intervention in newly diagnosed type 1 diabetic patients, and trials to prevent the disease.

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“…Second, there are striking differences between these isoforms in their electrostatic charge distribution [15], [16]. These structural and physicochemical differences correlate with known epitope regions in the antigenic isoform GAD65, revealing how the immunodominant epitopes on GAD65 are highly mobile and charged, relative to the corresponding regions in the non-antigenic isoform GAD67 [11], [15], [16]. Although anti-GAD67 antibodies are rare, these antibodies may represent a cross-reactive population of anti-GAD65 [17], [18], but this has not been formally tested.…”

Section: Introductionmentioning

confidence: 96%

“…Serum autoantibodies to GAD65 are an important marker in the early prediction and diagnosis of T1D [8], [9]. The closely related 67 kDa isoform, GAD67, is 71% identical in its amino acid sequence but is rarely an autoantigen in T1D [1], [10], [11], interacts differently with the pyridoxal-5′-phosphate (PLP) co-factor, and has different kinetics for GABA synthesis in enzyme activity assays [12].…”

Section: Introductionmentioning

confidence: 99%

An Analysis of the Cross-Reactivity of Autoantibodies to GAD65 and GAD67 in Diabetes

et al. 2011

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BackgroundAutoantibodies to GAD65 (anti-GAD65) are present in the sera of 70–80% of patients with type 1 diabetes (T1D), but antibodies to the structurally similar 67 kDa isoform GAD67 are rare. Antibodies to GAD67 may represent a cross-reactive population of anti-GAD65, but this has not been formally tested.Methodology/Principal FindingsIn this study we examined the frequency, levels and affinity of anti-GAD67 in diabetes sera that contained anti-GAD65, and compared the specificity of GAD65 and GAD67 reactivity. Anti-GAD65 and anti-GAD67 were measured by radioimmunoprecipitation (RIP) using 125I labeled recombinant GAD65 and GAD67. For each antibody population, the specificity of the binding was measured by incubation with 100-fold excess of unlabeled GAD in homologous and heterologous inhibition assays, and the affinity of binding with GAD65 and GAD67 was measured in selected sera. Sera were also tested for reactivity to GAD65 and GAD67 by immunoblotting. Of the 85 sera that contained antibodies to GAD65, 28 contained anti–GAD67 measured by RIP. Inhibition with unlabeled GAD65 substantially or completely reduced antibody reactivity with both 125I GAD65 and with 125I GAD67. In contrast, unlabeled GAD67 reduced autoantibody reactivity with 125I GAD67 but not with 125I GAD65. Both populations of antibodies were of high affinity (>1010 l/mol).ConclusionsOur findings show that autoantibodies to GAD67 represent a minor population of anti-GAD65 that are reactive with a cross-reactive epitope found also on GAD67. Experimental results confirm that GAD65 is the major autoantigen in T1D, and that GAD67 per se has very low immunogenicity. We discuss our findings in light of the known similarities between the structures of the GAD isoforms, in particular the location of a minor cross-reactive epitope that could be induced by epitope spreading.

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GAD65 as a prototypic autoantigen

Cited by 23 publications

References 46 publications

Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff‐person syndrome but without type 1 diabetes

Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff‐person syndrome but without type 1 diabetes

Therapy with GAD in diabetes

An Analysis of the Cross-Reactivity of Autoantibodies to GAD65 and GAD67 in Diabetes

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