Peptide mapping and characterisation of glycation patterns of the glima 38 antigen recognised by autoantibodies in Type I diabetic patients

Roll, U; Turck, C. W.; Gitelman, Stephen E.; Rosenthal, Sanford M.; Nolte, M.; Masharani, Umesh; Ziegler, Anette‐G.; Baekkeskov, Steinunn

doi:10.1007/s001250051349

Cited by 15 publications

(12 citation statements)

References 33 publications

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“…Glima 38 is an N-glycosylated amphiphilic transmembrane protein of the pancreatic beta cell [1,2]. Two reports estimate the prevalence of glima 38 autoantibodies, measured by complex immuno-precipitation assays of radio-labelled cell lines, to be around 20 to 40% in patients with type 1 diabetes [1,3].…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin 7 autoantibodies in type 1 diabetes

et al. 2016

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Aims/hypothesis Autoantibodies to pancreatic beta cell proteins are markers of asymptomatic type 1 diabetes. The aim was to determine whether autoantibodies to the beta cell protein tetraspanin 7 would improve the ability to identify autoimmunity against pancreatic beta cells. Methods Full length and external domain fragments of tetraspanin 7 were expressed as luciferase-tagged fusion proteins and used in immunoprecipitation assays to measure autoantibodies in samples from 363 patients with type 1 diabetes at onset of disease, 503 beta cell autoantibody negative firstdegree relatives of patients, and 212 relatives with autoantibodies to insulin, glutamic acid decarboxylase, insulinoma antigen 2 or zinc transporter 8. Results Antibody binding was observed against the full length and external domains of tetraspanin 7, and was strongest against the full length protein. Autoantibodies that could be inhibited by untagged tetraspanin 7 were detected in 5 (1%) of 503 autoantibody negative relatives, 3 (3.2%) of 94 autoantibody negative patients, 95 (35.3%) of 269 autoantibody positive patients, 1 (1%) of 98 single autoantibody positive relatives and 25 (21.9%) of 114 multiple autoantibody positive relatives. Progression to diabetes did not differ between multiple autoantibody positive relatives with and without tetraspanin 7 autoantibodies. Conclusions/interpretation Tetraspanin 7 is an autoantigen in type 1 diabetes. Tetraspanin 7 autoantibodies are a marker of type 1 diabetes, but provide minor additional value to existing autoantibodies in identifying beta cell autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Tetraspanin 7 autoantibodies in type 1 diabetes

et al. 2016

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“…The incidence of glima 38 antibodies in IDDM (∼20%) is low compared to that of antibodies to GAD65, IA-2 and insulin. However, glima 38 antibodies can precede clinical onset of diabetes by several years and they can occur in patients who are GAD65 and IA-2 antibody negative [21,38]. Like GAD65 and IA-2, glima 38 is an intracellular membrane protein expressed in neurons as well as in pancreatic cells.…”

Section: Other Potential Autoantigens In Human Iddmmentioning

confidence: 97%

Does GAD Have a Unique Role in Triggering IDDM?

Baekkeskov

Kanaani

Jaume

et al. 2000

Journal of Autoimmunity

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“…detected by a modification of immunoprecipitation assays previously described (13)(14)(15) using the neuronal mouse cell line GT1.7 as source of antigen. Endogenous proteins in GT1.7 cells were labeled by incubation in methionine-free DMEM medium containing 4 MBq/ml 35 S-methionine for 7 h at 37°C.…”

Section: Screen Of Type 1 Diabetic Patient Sera For Glima Antibodiesmentioning

confidence: 99%

“…Four major humoral autoantigens have been identified in Type 1 diabetes by defining the specificity of autoantibodies in the disease: insulin (9), glutamate decarboxylase (10), IA-2 (11), and zinc transporter-8 (ZnT8) (12). Autoantibodies to a fifth, a 38kDa glycosylated membrane protein (Glima), have been detected in 19-38% of Type 1 diabetic patients, with significantly higher prevalence (up to 50%) in children (13)(14)(15). The molecular identity of Glima has for many years proved elusive, hampering the characterization of autoimmunity to the protein and the development of sensitive, specific autoantibody assays.…”

Section: Introductionmentioning

confidence: 99%

“…The molecular identity of Glima has for many years proved elusive, hampering the characterization of autoimmunity to the protein and the development of sensitive, specific autoantibody assays. Glima is expressed in pancreatic beta and neuronal cell lines, is hydrophobic, heavily N-glycosylated, having affinity for the lectin wheat germ agglutinin, and has a core protein backbone of approximately 22kDa (13)(14)(15). The aim of…”

Section: Introductionmentioning

confidence: 99%

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Identification of Tetraspanin-7 as a Target of Autoantibodies in Type 1 Diabetes

et al. 2016

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The presence of autoantibodies to multiple islet autoantigens confers high risk for development of Type 1 diabetes. Four major autoantigens are established (insulin, glutamate decarboxylase, IA-2, and zinc transporter-8), but the molecular identity of a fifth, a 38kDa membrane glycoprotein (Glima), is unknown. Glima antibodies have been detectable only by immunoprecipitation from extracts of radiolabeled islet or neuronal cells. We sought to identify Glima to enable efficient assay of these autoantibodies. Mouse brain and lung were shown to express Glima. Membrane glycoproteins from extracts of these organs were enriched by detergent phase separation, lectin affinity chromatography and SDS-PAGE. Proteins were also immunoaffinity purified from brain extracts using autoantibodies from diabetic patients' sera before SDS-PAGE. Eluates from gel regions equivalent to 38kDa were analyzed by LC-MS/MS for protein identification. Three proteins were detected in samples from the brain and lung extracts, and in the immunoaffinity purified sample, but not the negative control. Only tetraspanin-7, a multipass transmembrane glycoprotein with neuroendocrine expression, had physical characteristics expected of Glima. Tetraspanin-7 was confirmed as an autoantigen by demonstrating binding to autoantibodies in Type 1 diabetes. We identify tetraspanin-7 as a target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy.

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Peptide mapping and characterisation of glycation patterns of the glima 38 antigen recognised by autoantibodies in Type I diabetic patients

Cited by 15 publications

References 33 publications

Tetraspanin 7 autoantibodies in type 1 diabetes

Tetraspanin 7 autoantibodies in type 1 diabetes

Does GAD Have a Unique Role in Triggering IDDM?

Identification of Tetraspanin-7 as a Target of Autoantibodies in Type 1 Diabetes

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