Insulin Autoantibodies as Markers for Type I Diabetes

Wilkin, Terence J.

doi:10.1210/edrv-11-1-92

Cited by 15 publications

(9 citation statements)

References 89 publications

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“…Further studies revealed the presence of IAA in first-degree relatives of diabetic patients and also in other unrelated autoimmune diseases [31,35,181]. However, the binding profiles of IAA positive sera to different epitopes of the insulin molecule Human Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Asp…”

Section: Insulin Autoantibodies In Type 1 Dm and Insulin Autoimmune Smentioning

confidence: 99%

“…In contrast to the RBA, which uses a small amount of high specific activity ligand (antigen) with an excess of antibody, the ELISA for the detection of IAA provides an excess of antigen over antibody. The interpretation of signals obtained therefore needs to take account of the different thermodynamics of antigen-antibody interaction in the RBA and ELISA (see Figure 5) [181]. The RBA -a fluid-phase assay -is affinity dependent, and the excess of antibody in the presence of minimum amounts of high specific activity ligand favours the binding of high-affinity IAA.…”

Section: Assay Techniques For Iaa and Their Limitationsmentioning

confidence: 99%

“…The ELISA -a capacity dependent assay -allows the simultaneous binding of IAA of varying affinity. The signal in the ELISA is the sum of all bound IAA and low affinity IAA increase, rather than decrease, the signal strength [181].…”

Section: Assay Techniques For Iaa and Their Limitationsmentioning

confidence: 99%

“…Although RBA perform better in detecting diabetesrelated IAA than ELISA, the fourth international workshop demonstrated also the significant variation of the RBA signal strength of individuals sera in the participating laboratories [209]. Possible reasons for the inter-assay variation include the type of ligand used (human or non-human insulin), the specific activity of the ligand, the length of the incubation period and the nature of the immunoprecipitant used for phase separation [181]. Subsequent international workshops have attempted to standardise and reduce the variation in the measurement of IAA using RBA.…”

Section: Assay Techniques For Iaa and Their Limitationsmentioning

confidence: 99%

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Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies

Franke

Galloway

Wilkin

2005

Diabetes Metab. Res. Rev.

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The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. There is general consensus that the presence of multiple Aab (> or = 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.

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Section: Insulin Autoantibodies In Type 1 Dm and Insulin Autoimmune Smentioning

confidence: 99%

Section: Assay Techniques For Iaa and Their Limitationsmentioning

confidence: 99%

Section: Assay Techniques For Iaa and Their Limitationsmentioning

confidence: 99%

Section: Assay Techniques For Iaa and Their Limitationsmentioning

confidence: 99%

See 2 more Smart Citations

Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies

Franke

Galloway

Wilkin

2005

Diabetes Metab. Res. Rev.

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“…IAA are found spontaneously, without injection of exogenous insulin, in polyendocrine patients and in association with viral infections, drug reactions and autoimmune diseases which do not develop into diabetes, in addition to pre-Type 1 diabetes [86]. IAA, therefore, are part of the natural or polyreactive repertoire.…”

Section: Idiotypes Of Iaa ± Clinical Observationsmentioning

confidence: 99%

The molecular specificity of insulin autoantibodies

Potter

Wilkin

2000

Diabetes Metab. Res. Rev.

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Insulin autoantibodies (IAA) are one of several markers for Type I (autoimmune) diabetes, but alone deserve special attention. Unlike the other markers, their ligand is unique to the beta cell. IAA are the first markers to appear during the symptomless period which precedes diabetes and they are present in the vast majority of young children destined to develop diabetes. The primary and tertiary structures of insulin have been known for decades. Binding studies with insulin variants have shown epitope restriction that can distinguish Type 1 diabetes-predictive from non-predictive IAA-positive sera, thereby improving specificity for the test. With two major international Type 1 diabetes prevention trials underway, there is a pressing need to refine markers that reliably indicate the presence of, and remission from, autoimmune insulitis. The binding regions of antibodies are assembled from three multi-gene families, and some of their diversity derives from random mutation during their antigen-driven maturation. There is evidence that mature IAA derive from germline-encoded 'natural' antibodies, and that the gene segments utilised by IAA may be influenced by clinical context. Monoclonal anti-idiotypic (anti-Id) antibodies can serve as probes for antibody variable region determinants, and antibodies to the different epitopes of beef and porcine insulins have already been analysed with monoclonal reagents. Used as antibodies in a radioimmunoassay format, monoclonal anti-Ids will identify and measure autoantibody idiotopes as if they were ligands. The challenge now is to replace the conventional radiobinding assays for IAA, which only detect and titrate, with radioimmunoassays that can be standardised in absolute units. There is sufficient evidence for the existence of Type 1 diabetes-predictive IAA idiotopes to justify the development of idiotope-specific radioimmunoassays which ignore Type 1 diabetes-unrelated IAA.

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