Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies

Richter, Wiltrud; Eiermann, Thomas; Endl, Josef; Seißler, Jochen; Wolfahrt, Sonja; Brandt, Michael R.; Jungfer, H.; Scherbaum, Werner A.

doi:10.1007/bf00401152

Cited by 18 publications

(15 citation statements)

References 20 publications

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“…A limited analysis of nine children with newly diagnosed type 1 diabetes suggested that MICA 1-6 represent a wide range of both common and unusual epitopes (94). However, no disease-specific GAD65Ab changes in the preclinical stages of type 1 diabetes were identified using these reagents (90).…”

Section: Daa Epitopesmentioning

confidence: 99%

Autoantibodies in Diabetes

et al. 2005

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Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens-GAD65, IA-2, or insulin-signals an autoimmune pathogenesis of ␤-cell killing. A ␤-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to ␤-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitopespecific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally. Diabetes 54 (Suppl. 2):S52-S61, 2005

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Section: Daa Epitopesmentioning

confidence: 99%

Autoantibodies in Diabetes

et al. 2005

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“…In most IDDM patients, ICAs only stain frozen and not fixed sections of human pancreas. Thus, ICA epitopes are dependent on conformation of the relevant antigen [22]. Similarly diabetes associated epitopes in the GAD6s molecule are predominantly conformational and only the sera of very few patients recognize a linear epitope in the protein [12,19].…”

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confidence: 99%

Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population

Aanstoot

Sigurdsson²,

Jaffe

et al. 1994

Diabetologia

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SummaryThe value of a test for islet cell cytoplasmic antibodies together with a test for GAD6s antibodies to predict the subsequent development of diabetes over a period of 11.5 years was assessed in an open childhood population comprising 2,805 individuals. A single serum sample was obtained from each individual between 1975 and 1977 and screened for islet cell cytoplasmic antibodies for which eight individuals were positive (0.29 %). During the average follow-up period of 11.5 years, four of eight islet cell antibody positive and three islet cell antibody negative individuals developed clinical diabetes. Sera from all individuals, who were islet cell antibody positive and/ or developed diabetes (total of 11) and from 100 randomly selected control subjects were analysed for GAD65 antibodies. Six of eight islet cell antibody positive individuals were GAD65 antibody positive including all four who subsequently developed IDDM. Furthermore, one of the three islet cell antibody negative individuals who developed IDDM was GAD65 antibody positive both in 1976 and in 1989. Thus, a positive test for GAD6s antibodies alone correctly predicted diabetes in five of seven children, who developed the disease. Only one of the children, who developed diabetes was positive for insulin autoantibodies and this individual was also positive for islet cell cytoplasmic antibodies and GAD65 antibodies. One of the 100 control subjects was positive for GAD6s antibodies (1%). The results suggest that a single GAD65 antibody test may have a higher sensitivity for predicting IDDM than a test for islet cell cytoplasmic antibodies, but that a combined positive test for both antibodies increases the specificity for predicting IDDM over a period of 11.5 years. [Diabetologia (1994) 37: 917-924] Key words GAD65 antibodies, islet cell cytoplasmic antibodies, predictive value, IDDM in childhood.The destruction of pancreatic beta cells, which precedes the clinical onset of IDDM, is mediated by autoimmune mechanisms [1]. The presence of islet specific autoantibodies in the pre-diabetic period [2-4] is likely to reflect the ongoing autoimmune process, one that eventually leads to critical beta-cell depletion and insulin dependency. A major goal of diabetes research is to develop immune interventions that block or otherwise interfere with the destruction of beta cells and the development of clinical diabetes. Concomitant with this goal is the necessity for methods for early accurate identification of susceptible individuals [5]. Antibody assays that detect early signs of humoral autoimmunity associated with beta-cell destruction are obvious candidates for this purpose. Furthermore, susceptibility to develop diabetes is associated with certain MHC-class II haplotypes [6] and analysis of both HLA haplotypes and autoantibodies provide a test of high predictive value in family members of IDDM patients [3,7]. Since most new cases of [DDM involve individuals without a first degree relative with the disease [8, 9], predictive meth-

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“…This suggests that amino acid residues in the middle and C-terminal regions of the protein interact to form a conformation-dependent GAD65Ab epitope that is easily destroyed by substituting glutamic acid with proline at position 517. We compared the binding of wild-type GAD65 and GAD65-E517P by GAD65 monoclonal antibodies recognising different regions of the GAD65 molecule (Group A, Table 1), including mAb144 [19], GAD6 [20] and MICA [11,21] (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…Type 1 diabetes sera primarily recognise conformational GAD65 epitopes, and GAD65Ab binding is easily lost when the target antigen is denatured, such as in ELISA and western blots or following mutagenesis [11,12,13]. The ability to identify diabetes-specific GAD65Ab that recognise conformation-dependent epitopes would enhance the value of GAD65Ab as a predictive marker.…”

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confidence: 99%

“…The aim of the present study was to determine whether the alteration of a C-terminal GAD65Ab epitope, by substituting GAD67-derived amino acids, defines GAD65Ab with increased diagnostic specificity for Type 1 diabetes. [19]; (ii) mouse monoclonal antibody GAD6, which recognises the C terminus of GAD65 [20]; and (iii) human monoclonal islet cell antibodies (MICA: MICA1, MICA2, MICA3, MICA4 and MICA6) [11,17,21]. Group B included standard sera from ten children (aged 11-16 years) newly diagnosed with Type 1 diabetes, which were obtained at the clinical onset of disease [22].…”

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confidence: 99%

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Conformation-dependent GAD65 autoantibodies in diabetes

et al. 2004

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Aims/hypothesis. Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. In this study we aimed to determine whether the substitution of GAD65 with GAD67 amino acids would affect the binding of conformation-dependent GAD65 autoantibodies. Methods. We used PCR-based site-directed mutagenesis to generate a series of mutated GAD65 cDNA constructs in which specific GAD65 coding sequences for regions of the protein critical for autoantibody binding were replaced with GAD67 coding sequences. Results. The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies. The binding of GAD65 antibodies to the E517P mutant was reduced in the sera of all newly diagnosed Type 1 diabetes patients (n=85) by a mean of 72% (p<0.0001) compared with binding to wild-type GAD65. Patients with latent autoimmune diabetes in adults (n=24) showed a similar reduction

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Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies

Cited by 18 publications

References 20 publications

Autoantibodies in Diabetes

Autoantibodies in Diabetes

Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population

Conformation-dependent GAD65 autoantibodies in diabetes

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