Changes in GAD65Ab-Specific Antiidiotypic Antibody Levels Correlate with Changes in C-Peptide Levels and Progression to Islet Cell Autoimmunity

Örtqvist, Eva; Brooks-Worrell, Barbara; Lynch, Kristian; Radtke, Jared; Bekris, Lynn M.; Kockum, Ingrid; Agardh, Carl‐David; Cilio, Corrado; Lethagen, ÅsaLinda; Persson, Bengt; Lernmark, Åke; Reichow, Jessica; Oak, Shilpa; Palmer, Jerry P.; Hampe, Christiane S.

doi:10.1210/jc.2010-0785

Cited by 13 publications

(6 citation statements)

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“…This latter hypothesis has received further support from our finding that anti-Id specific to GAD65Ab are low or missing in T1D patients [88] and that anti-Id levels increase in T1D patients who experienced a temporary remission after diagnosis of disease (honeymoon period). In contrast, those patients who did not undergo a remission phase did not show an increase of anti-Id levels [103]. This correlation of increased anti-Id with improved beta cell function has also been found in Latent Autoimmune Diabetes in Adults (LADA) patients who received alum-GAD vaccination [103].…”

Section: Anti-id In Type 1 Diabetesmentioning

confidence: 83%

“…In contrast, those patients who did not undergo a remission phase did not show an increase of anti-Id levels [103]. This correlation of increased anti-Id with improved beta cell function has also been found in Latent Autoimmune Diabetes in Adults (LADA) patients who received alum-GAD vaccination [103]. In this instance, patients who experienced an improvement in beta-cell function also showed an increase in anti-Id levels, while patients in the placebo groups or patients who did not respond to the vaccination, did not demonstrate such an increase.…”

Section: Anti-id In Type 1 Diabetesmentioning

confidence: 99%

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Protective role of anti-idiotypic antibodies in autoimmunity – Lessons for type 1 diabetes

Hampe

2012

Autoimmunity

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Circulating autoantibodies to beta cell antigens are present in the majority of patients with Type 1 diabetes. These autoantibodies can be detected before and at time of clinical diagnosis of disease. Although the role of autoantibodies in the pathogenesis of the disease is debated, their presence indicates a dysregulation of the humoral immune response. Mechanisms regulating autoantibodies in Type 1 diabetes are not well understood. In contrast, in other autoimmune diseases there is acceptance that autoantibodies are regulated not only by antigen but also by other antibodies that bind to the antigen-binding site of these autoantibodies (anti-idiotypic antibodies). The proposed purpose of this network is to maintain an equilibrium between autoantibodies and their anti-idiotypic antibodies, preventing autoimmunity, while allowing a robust response to exogenous antigen. Anti-idiotypic antibodies regulate both autoantibody binding and their levels by a) neutralizing autoantibodies, and b) inhibiting the secretion of autoantibodies. Because it has been proposed that the B lymphocytes that produce autoantibodies function as autoantigen presenting cells, inhibiting their binding to autoantigen by anti-idiotypic antibodies may prevent development of autoimmune disease. This hypothesis is supported by the presence of anti-idiotypic antibodies in healthy individuals and in patients in remission from autoimmune diseases, and by the lack of anti-idiotypic antibodies during active disease. We recently reported the presence of autoantibodies to glutamate decarboxylase in the majority of healthy individuals, where their binding to autoantigen is prevented by anti-idiotypic antibodies. These anti-idiotypic antibodies are absent at clinical diagnosis of Type 1 diabetes, revealing the presence of autoantibodies. Type 1 diabetes (T1D) is an autoimmune disease characterized by the dysfunction and destruction of insulin-producing beta cells by autoreactive T cells. Although much progress has been made towards understanding the respective roles of effector and regulatory T cells in this beta cell destruction, the development of autoantibodies to beta cell proteins is widely considered simply a by-product of the autoimmune destruction of the beta cells, rather than having an active role in the pathogenesis. This view is starting to change based on increasing recognition that autoantibodies can have defined roles in other autoimmune diseases, and the emergence of new data on their role in T1D. This exploration of the role of autoantibodies in autoimmune disease has been spurred, in part, by increasing recognition that development of autoimmune diseases is influenced by regulatory antibodies (anti-idiotypic antibodies) directed against the unique binding site of autoantibodies. This review provides an overview of the development and function of these anti-idiotypic antibodies, and present evidence supporting their role in the development of autoimmune diseases. Finally, we conclude this review with a model of the events that may cause ...

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Section: Anti-id In Type 1 Diabetesmentioning

confidence: 83%

Section: Anti-id In Type 1 Diabetesmentioning

confidence: 99%

Protective role of anti-idiotypic antibodies in autoimmunity – Lessons for type 1 diabetes

Hampe

2012

Autoimmunity

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“…A recent observation suggests that anti-idiotypic antibodies (anti-Id) against GAD65 autoantibodies specific to the middle epitope of GAD65 are decreased or non-detectable in children with newly diagnosed type 1 diabetes [53]. Following the vaccination with 20 microgram alum-formulated GAD65, it was observed that anti-Id levels declined in seven of nine patients of the LADA patients receiving placebo, whereas four of five patients receiving 20 microgram alum-formulated GAD65 showed increasing anti-Id levels [54]. These results are consistent with the possibility that low level alum-formulated GAD65 has a tolerogenic effect on GAD65 autoreactivity.…”

Section: Gad65-specific Immunotherapy – Early Human Studiesmentioning

confidence: 99%

“…This phenomenon is known as epitope spreading [41][42][43]. CD4+ CD25+ Treg lymphocytes may be important as they may inhibit islet autoantigen-specific CD4+ T lymphocytes [54]. These cells express FOXp3 from the X chromosome and are important to maintain peripheral tolerance.…”

Section: Triggering the Beta-cell Autoimmune Responsementioning

confidence: 99%

Vaccination against type 1 diabetes

Larsson

Lernmark

2011

Journal of Internal Medicine

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The clinical onset of type 1 diabetes or autoimmune diabetes occurs after a prodrome of islet autoimmunity. The warning signals for the ensuing loss of pancreatic islet beta cells are autoantibodies against insulin, GAD65, IA-2, and ZnT8, alone or in combinations. Autoantibodies against e.g. insulin alone have only a minor risk for type 1 diabetes. However, progression to clinical onset is increased by the induction of multiple islet autoantibodies. At the time of clinical onset, insulitis may be manifest, which seem to reduce the efficacy of immunosuppression. Autoantigen-specific immunotherapy with alum-formulated GAD65 (Diamyd®) show promise to reduce the loss of beta-cell function after the clinical onset of type 1 diabetes. The mechanisms are unclear but may involve the induction of T regulatory cells, which may suppress islet autoantigen reactivity. Past and on-going clinical trials have been safe. Future clinical trials, perhaps as combination autoantigen-specific immunotherapy may increase the efficacy to prevent the clinical onset in subjects with islet autoantibodies or preserve residual beta-cell function in newly diagnosed type 1 diabetes patients.

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“…In some patient, a medical difference among T1DM and T2DM isn't conceivable at appearance and autoantibodies are used to describe the sort of diabetes. Beta-cell autoantibodies are found only in T1DM patients due to the obliteration of Beta cells and hence reduced Insulin secretion [3,4].…”

Section: Introductionmentioning

confidence: 99%

C-Peptide compound analysis in type 2 diabetic patients

Sagar¹,

Chandrudu²,

Madhubhushan³

et al. 2019

ijrls

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In adults, a fragment of diabetic individuals with βcell autoantibodies has initially non Insulin requiring diabetes clinically performing as type 2 diabetes mellitus (T2DM), named latent autoimmune diabetes in maturity (LADA) which on later years requires Insulin. LADA is either unnoticed or misdiagnosed in many cases. The occurrence GAD autoantibodies and positive levels of C-peptide analysis are tested to determine and finalize the patients’ Insulin dependency. The frequency of βcell autoantibodies (GAD) and C-Peptide analysis was determined in 31 Type 2 diabetic adults. The type of diabetes was classified by doing a Postprandial Blood Glucose test. Ten Type 1 diabetic patients and 10 ordinary people were also subjected to the three tests for comparative study. Twenty-three per cent of the adults with T2DM were tested positive for GAD autoantibody, and 61 per cent were tested positive (who came in T1DM range) for C-peptide analysis among them. 19% of the patients were tested positive for both GAD antibody and C-peptide analysis. Patients had the common symptoms of polyuria, polyphagia and polydipsia. In T2DM patients, 61% were females, and 39% were males, and all were non-obese. β‐cell autoantibodies were evident in a subcategory of initially non‐insulin needy diabetic adults with the clinical entrance of T2DM. This proves the existence and necessity for change in Insulin dependency.

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Changes in GAD65Ab-Specific Antiidiotypic Antibody Levels Correlate with Changes in C-Peptide Levels and Progression to Islet Cell Autoimmunity

Abstract: The close association between GAD65Ab-specific anti-Id levels and β-cell function may provide a novel marker for the progression of autoimmune diabetes.

Cited by 13 publications

References 42 publications

Protective role of anti-idiotypic antibodies in autoimmunity – Lessons for type 1 diabetes

Protective role of anti-idiotypic antibodies in autoimmunity – Lessons for type 1 diabetes

Vaccination against type 1 diabetes

C-Peptide compound analysis in type 2 diabetic patients

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