Multiplicity of the antibody response to GAD65 in Type I diabetes

Gilliam, Lisa K.; Binder, Katherine A.; Banga, J. Paul; Madec, Anne-Marie; Örtqvist, Eva; Kockum, Ingrid; Luo, Dong; Hampe, Christiane S.

doi:10.1111/j.1365-2249.2004.02610.x

Cited by 15 publications

(22 citation statements)

References 37 publications

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“…In light of recent evidence that autoantibodies may play a role in modulating the T cell response (11), it is notable that antibody specificity, rather than antibody titer, is associated with T1D and disease progression (13,34,35). The GAD65Ab response in T1D patients is characterized by GAD65Ab specificities similar to that of mAb b96.11 (13), whereas GAD65Ab in patients with SPS often recognize GAD65Ab epitopes similar to that bound by b78 (14).…”

Section: Discussionmentioning

confidence: 99%

“…GAD65Ab were determined by using the RIA as described (48). Briefly, recombinant [35] S-GAD65 was produced in an in vitro-coupled transcription and translation system with SP6 RNA polymerase and nuclease-treated rabbit reticulocyte lysate (Promega). Sera or IgG at the indicated concentrations were incubated with [35] S-GAD65 (25,000 of trichloroacetic acid-precipitable radioactivity).…”

Section: Methodsmentioning

confidence: 99%

“…(a) GAD65 binding by unmasked sera is competed by recombinant human GAD65 and not by BSA. Sera of FDR absorbed by b96.11-PAS were tested for binding to [35] S-GAD65 in the presence of recombinant human GAD65 (150 mM) (E), or BSA (150 nM) ({). Median binding is indicated.…”

Section: Sera From Healthy Individuals and Fdr Contain Gad65ab That Amentioning

confidence: 99%

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The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes

Oak

Gilliam

Landin‐Olsson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Autoantibodies to glutamate decarboxylase 65 (GAD65Ab) are commonly believed to be a major characteristic for type 1 diabetes (T1D). We investigated the presence of GAD65Ab in healthy individuals (n ‫؍‬ 238) and first-degree relatives (FDRs) of T1D patients (n ‫؍‬ 27) who tested negative for GAD65Ab in conventional RIAs. Sera were applied to affinity columns coated with GAD65-specific mAbs to absorb anti-idiotypic antibodies (anti-Ids). The absorbed sera were analyzed for binding to GAD65 by RIAs. Both healthy individuals and FDRs present GAD65Ab that are inhibited by anti-Id, masking them in conventional detection methods. The presence of GAD65Ab-specific anti-Ids was confirmed by competitive ELISA. Remarkably, T1D patients (n ‫؍‬ 54) and Stiff Person Syndrome patients (n ‫؍‬ 8) show a specific lack of anti-Ids to disease-associated GAD65Ab epitopes. Purified anti-Ids from healthy individuals and FDRs inhibited the binding of GAD65Ab from T1D patients to GAD65. We conclude that masked GAD65Ab are present in the healthy population and that a lack of particular anti-Ids, rather than GAD65Ab per se, is a characteristic of T1D. The lack of these inhibitory antibodies may contribute to T cell activation by GAD65Ab.T ype 1 diabetes (T1D) is an autoimmune disease characterized by the presence of serologically detectable autoantibodies to multiple islet cell autoantigens. Autoantibodies to glutamate decarboxylase 65 (GAD65Ab) can be detected in the majority of new-onset T1D patients (1), in patients with latent autoimmune diabetes in adults (for review see ref.2), diabetes-related polyendocrine diseases (for review see ref.3), and in some rare neurologic diseases, notably Stiff Person Syndrome (SPS) (4), but rarely in the general population. GAD65Ab often herald the onset of T1D by months or years and are used to predict disease together with other islet cell autoantibodies (5, 6). The function of these autoantibodies and their B cells in the pathogenesis of T1D is not clear, especially as a patient with severe B cell deficiency and diabetes was reported (7). Although GAD65Ab are often considered to be an epiphenomenon resulting from the autoimmune destruction of the pancreatic ␤ cells, some studies suggest that they may be involved in antigen processing and presentation and thus modulate the immune response (8-10). This hypothesis is supported by a recent study demonstrating a pathogenic role of autoantibodies by enhancing islet cell antigen presentation to autoreactive T cells (11). Harbers et al. (11) showed that both antigen-specific CD8 ϩ T cells and antigenspecific antibodies were necessary for the development of autoimmune diabetes in transgenic mice that express a membranebound form of ovalbumin in pancreatic ␤ cells.To investigate the possible role of GAD65Ab in T1D pathogenesis, we previously injected young nonobese diabetic (NOD) mice with the GAD65-specific mAb b96.11 (12). This antibody specificity was shown earlier to be predictive of the development of T1D in humans (13). We found that this treatment i...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes

Oak

Gilliam

Landin‐Olsson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Blocking experiments using monoclonal antibodies (90) and recombinant Fab derived from monoclonal antibodies (91,92) have been useful to study conformational GAD65Ab epitopes. When comparing the traditional epitope analysis of GAD65Abs using GAD65/67 fusion proteins with the recombinant Fab competition assay, we were able to ob-serve significant differences between the two approaches.…”

Section: Daa Epitopesmentioning

confidence: 99%

“…We were able to identify two middle epitopes that were significantly associated with type 1 diabetes (91,92). In a recent study, we compared GAD65Ab epitope changes in a longitudinal study of children at high risk for developing type 1 diabetes with those present in matched children with low risk (95).…”

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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