Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM

Falorni, Alberto; Ackefors, Malin; Carlberg, Charlotte; Daniels, Terri; Persson, Bengt L.; Robertson, J.; Lernmark, �.

doi:10.1007/s001250050558

Cited by 6 publications

(6 citation statements)

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“…The finding of epitope spreading towards N-terminal epitopes confirms results from an earlier study of pre-diabetic children of parents with type 1 diabetes [31]. Early reactivity to the middle and C-terminal epitopes of GAD65 has previously been described in offspring of parents with type 1 diabetes [14,18,37,40]. Since the inclusion criterion for our study was GAD65Ab positivity, we do not have data on the transition from GAD65Ab negativity to GAD65Ab positivity.…”

Section: Discussionsupporting

confidence: 70%

“…Individuals that progressed to type 1 diabetes during follow-up are represented as white circles. Median binding is indicated by a horizontal line 18 17…”

Section: Gad65ab Specificities In the Last Sample From High-risk Indimentioning

confidence: 99%

“…We and others have established significant differences in the GAD65Ab epitope patterns present in patients with type 1 diabetes, compared with other GAD65Ab-positive phenotypes [13,[17][18][19]. Recently we described two conformational epitopes that are located in the middle region of GAD65 and were specifically recognised by GAD65Ab from type 1 diabetic patients [17].…”

Section: Introductionmentioning

confidence: 99%

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Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes

Schlosser

Banga²,

Madec

et al. 2005

Diabetologia

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In type 1 diabetes, GAD65 antibodies are initially generated against the middle and C-terminal regions of GAD65. In genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading towards epitopes on the N-terminus and further epitopes located in the middle. These findings clearly demonstrate that the GAD65 autoantibody response in the preclinical stage of type 1 diabetes is dynamic and related to the HLA genotypes that confer risk of diabetes. GAD65-specific Fab should prove useful in predicting progression from islet autoimmunity to clinical onset of type 1 diabetes.

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Section: Discussionsupporting

confidence: 70%

“…Individuals that progressed to type 1 diabetes during follow-up are represented as white circles. Median binding is indicated by a horizontal line 18 17…”

Section: Gad65ab Specificities In the Last Sample From High-risk Indimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes

Schlosser

Banga²,

Madec

et al. 2005

Diabetologia

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“…These findings suggest that the nature of GAD65Ab and clinical phenotype differ between SPIDDM and AIDDM. In typical AIDDM, epitope regions of GAD65Ab reside on central and carboxy-terminal regions of the GAD65 molecule (13)(14)(15). However, the epitopes and nature of GAD65Ab in SPIDDM are poorly defined.…”

Section: J Clin Endocrinol Metab 88: 4768 -4775 2003)mentioning

confidence: 97%

“…The digested GAD67 fragment was exchanged with a corresponding fragment of GAD65 cDNA using BamHI/StuI sites in the GAD65 cDNA. Chimera N, GAD65 (1-83)/GAD67 (89 -594), was donated by Dr. Falorni (University of Perugia) and was created as described previously (15).…”

Section: Construction Of Chimeric Gad Moleculesmentioning

confidence: 99%

Unique Epitopes of Glutamic Acid Decarboxylase Autoantibodies in Slowly Progressive Type 1 Diabetes

Kobayashi¹,

Tanaka²,

Okubo³

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

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Disease-specific epitope profiles of glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) were studied in slowly progressive type 1 (insulin-dependent) diabetes mellitus (SPIDDM) and acute onset type 1 (insulin-dependent) diabetes mellitus (AIDDM) using seven kinds of GAD65/67 chimeric molecules. Sera obtained from Japanese SPIDDM (n = 17) and AIDDM (n = 46) patients followed prospectively were analyzed by immunoprecipitation, ELISA, and Western blotting. GAD65Ab in all SPIDDM samples reacted specifically with an N-terminal linear epitope located on the membrane anchoring domain between amino acids 17-51 and C-terminal conformational epitope between amino acids 443-585 of GAD65. The binding of GAD65Ab with N-terminal 83 residues in SPIDDM inversely correlated with the period in which insulin was not required. GAD65Ab in AIDDM did not react with N-terminal epitope located between amino acids 1-83, irrespective of the titer of GAD65Ab. A novel epitope of GAD65Ab in AIDDM residing between amino acids 244-360 was identified in 17% (8 of 46) of patients whose age of onset was younger than other AIDDM patients. In conclusion, GADAb in SPIDDM has unique N-terminal linear epitopes that are located on the anchoring domain of GAD65 molecules. Association is suggested between GAD65Ab targeted to this region and slowly progressive beta-cell failure in SPIDDM.

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Heterogeneity in the occurrence of a subset of autoantibodies to glutamic acid decarboxylase in autoimmune polyendocrine patients with islet cell antibodies

Davenport

Radford

Albukhari

et al. 1998

Clinical and Experimental Immunology

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Glutamic acid decarboxylase-65 (GAD-65) is a major target for autoantibodies and autoreactive T cells in patients with insulin-dependent diabetes mellitus (IDDM). Autoantibodies to GAD are also found in patients with stiff man syndrome (SMS) or polyendocrine autoimmunity (PE). The epitope specificities of autoantibodies to GAD in IDDM and SMS have been well documented, but the locations of autoantibody epitopes of GAD in PE patients have not been mapped. Thus, the properties of anti-GAD antibodies in PE patients (with or without diabetes) were investigated. The ability of PE serum antibodies to inhibit the binding of the mouse monoclonal antibody, GAD-6, to native GAD in ELISA was determined. For PE patients without diabetes, levels of inhibition of GAD-6 binding ranged from 0% to almost 70% and were unrelated to the level of binding of serum antibodies to GAD (P = 0.351) or to the functional affinities of these antibodies. This suggests differences in the epitope specificities of anti-GAD antibodies in different patients. Levels of inhibition were also unrelated to clinical condition. SMS antibodies showed similar levels of inhibition of GAD-6 binding. Similar analysis was applied to PE patients with diabetes and levels of inhibition of GAD-6 binding to GAD were determined. These ranged from 0% to 80%, and levels of inhibition were similar in samples taken before or after diabetes onset. There was no significant difference between anti-GAD antibodies from PE patients with or without diabetes in the range of abilities to inhibit GAD-6 binding to GAD, although the highest levels of inhibition were given by sera from non-diabetic patients. This raises the possibility of differential expression of subsets of anti-GAD antibodies in progressive versus slow or non-progressive anti-islet autoimmune responses. Serum antibodies of PE and SMS patients did not inhibit the binding of antibodies specific for the extreme C-terminus of GAD, indicating that this is not the site of the epitopes for the patients' antibodies or for GAD-6.

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Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM

Cited by 6 publications

References 0 publications

Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes

Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes

Unique Epitopes of Glutamic Acid Decarboxylase Autoantibodies in Slowly Progressive Type 1 Diabetes

Heterogeneity in the occurrence of a subset of autoantibodies to glutamic acid decarboxylase in autoimmune polyendocrine patients with islet cell antibodies

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