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| 2. |
- Ortqvist, E, et al.
(författare)
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Changes in GAD65Ab-Specific Antiidiotypic Antibody Levels Correlate with Changes in C-Peptide Levels and Progression to Islet Cell Autoimmunity.
- 2010
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 310-318
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Tidskriftsartikel (refereegranskat)abstract
- Context: The previously reported absence of 65-kDa glutamate decarboxylase antibody (GAD65Ab)-specific antiidiotypic antibodies (anti-Id) in type 1 diabetes (T1D) patients at clinical onset could be due to an inability to mount an antibody response to GAD65Ab or a longitudinal decline in anti-Id levels. Objective and Design: We investigated anti-Id levels in longitudinal samples obtained from T1D patients (n = 41) (clinical diagnosis - 12 months), and latent autoimmune diabetes in adults (LADA) patients (n = 32) who received alum-formulated human recombinant GAD65 (baseline - 12 months). We also determined anti-Id levels in a small cohort of Type 2 diabetes patients during their development of autoimmune T cell responses. Results: At clinical onset T1D patients presented no or low anti-Id levels. However, 22/41 T1D patients showed >/=50% increase in GAD65Ab-specific anti-Id levels during follow-up; peaking at 3 (n = 1), 6 (n = 10), 9 (n = 10), or 12 (n = 1) months. Increasing anti-Id levels marked patients who experienced a temporary increase in C-peptide levels. Anti-Id levels correlated significantly with glycated hemoglobin and C-peptide levels at 6 and 9 months (P values ranged from <0.001 to <0.05). In LADA patients receiving placebo, anti-Id levels declined in seven of nine patients, whereas four of five patients receiving 20 mug alum-formulated human recombinant GAD65 showed increasing anti-Id levels. Changes in anti-Id and C-peptide levels closely correlated (P < 0.0001). The significant decline in anti-Id levels (P = 0.03) in T2D patients developing T cell autoimmune responses supports our hypothesis that declining anti-Id levels are associated with developing islet autoimmunity. Conclusions: The close association between GAD65Ab-specific anti-Id levels and beta-cell function may provide a novel marker for the progression of autoimmune diabetes.
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| 3. |
- Oak, Shilpa, et al.
(författare)
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Comparison of three assays for the detection of GAD65Ab-specific anti-idiotypic antibodies
- 2009
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Ingår i: Journal of Immunological Methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 351:1-2, s. 55-61
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Tidskriftsartikel (refereegranskat)abstract
- Anti-idiotypic antibodies (anti-Id) to autoantibodies are present in several autoimmune diseases and are hypothesized to have regulatory function. Recently we reported the presence of anti-Id to a major type 1 diabetes-associated autoantibody (CAD65Ab) in sera of healthy individuals. Our current assay for the detection of GAD65Ab-specific anti-Id requires the initial removal of anti-Id from the sera using immobilized monoclonal GAD65Ab, followed by detection of the now exposed GAD65Ab. However, anti-Id in samples that are GAD65Ab-negative cannot be detected in this assay. Furthermore, we cannot distinguish between serum GAD65Ab and the monoclonal GAD65Ab used in the absorption of anti-Id. In this study we evaluated two novel detection assays for GAD65Ab-specific anti-Id. The biotin/streptavidin based absorption assay utilizes the strong interaction of biotin and streptavidin to prevent possible leakage of the immobilized antibody. Moreover, this assay format allows to identify the origin of the detected GAD65Ab. The ECL-based assay allows the direct detection of anti-Id independent of the presence of GAD65Ab. We analyzed new-onset type 1 diabetes patients (n = 133) and matched healthy controls (n = 178) for the presence of GAD65Ab-specific anti-Id using both new detection assays and the original absorption assay. We found that all three assays can distinguish between the type 1 diabetes cohort and the healthy control samples. The biotin/streptavidin assay allowed us to positively exclude the monoclonal GAD65Ab as the source of the detected GAD65Ab. While the original absorption assay showed the highest sensitivity and specificity, the ECL format showed the highest peak signal-to-noise ratio and excellent linear correlation, making this assay our first choice for quantification of anti-Id. (C) 2009 Elsevier B.V. All rights reserved.
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| 4. |
- Oak, Shilpa, et al.
(författare)
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Immunoglobulin subclass profiles of anti-idiotypic antibodies to GAD65Ab differ between type 1 diabetes patients and healthy individuals.
- 2011
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 74, s. 363-367
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Tidskriftsartikel (refereegranskat)abstract
- Previously we reported the presence of anti-idiotypic antibodies (anti-Id) specific to autoantibodies against GAD65 (GAD65Ab) in healthy individuals while the activity of anti-Id directed to GAD65Ab in T1D patients was significantly lower. These anti-Id recognize the antigen binding site of GAD65Ab, thus preventing their binding to GAD65. Here we characterized the IgG subclass profile of these anti-Id (GAD65Ab-specific) and of the associated GAD65Ab themselves. The IgG subclass response of anti-Id in healthy individuals (n=16) was IgG3-dominated, while in T1D patients (n=8) IgG1 was the major IgG subclass. The GAD65Ab bound by anti-Id in both healthy individuals (n=38) and GAD65Ab-negative T1D patients (n=35) showed a predominant rank order of IgG1>IgG2>IgG4>IgG3. However, the frequency of GAD65Ab of the IgG4 subclass was significantly higher in T1D patients (p<0.05). We conclude that the IgG subclass profile of anti-Id (GAD65Ab-specific) in healthy individuals differs from that in T1D patients. These differences may provide insights in the development of these antibodies.
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| 5. |
- Oak, Shilpa, et al.
(författare)
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The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes
- 2008
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 105:14, s. 5471-5476
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Vaziri Sani, Fariba, et al.
(författare)
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ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset.
- 2010
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; Apr 7, s. 598-606
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibodies to the islet-specific zinc transporter isoform 8 (ZnT8) are detected in the majority of type 1 diabetes patients prior to and at clinical diagnosis. The presence of ZnT8Ab after diagnosis has not been investigated. This study analyzed the autoantibody response to ZnT8 in regard to age at onset and disease duration. Two new onset type 1 diabetes patient cohorts with different age distributions at onset (2-17 and 15-34 years of age at onset), a longitudinal subset of the younger type 1 diabetes patient cohort (n = 32), and a cohort of GAD65Ab-positive LADA patients (n = 47) was analyzed for the presence of autoantibodies directed to the two major isoforms, ZnT8-Arginine (ZnT8R) and ZnT8-Tryptophan (ZnT8W). The majority of type 1 diabetes patients tested positive for ZnT8Ab to both isoforms. ZnT8Ab titers were significantly higher in the younger type 1 diabetes patients as compared with the older cohort (ZnT8RAb at a median of 148 and 29 U/ml, respectively, p < 0.001) (ZnT8WAb at a median of 145 and 58 U/ml, respectively, p < 0.01). ZnT8RAb and ZnT8WAb titers were significantly lower in the LADA patients (ZnT8RAb at a median of 14 U/ml, ZnT8WAb at a median of 25 U/ml) as compared with either type 1 diabetes cohorts. In our longitudinal analysis of type 1 diabetes patients after clinical diagnosis, ZnT8Ab levels to both isoforms declined significantly during the initial year of disease (ZnT8RAb from a median of 320-162 U/ml, p = 0.0001; ZnT8WAb from a median of 128-46 U/ml, p = 0.0011). The antibody titers further declined during the following 4 years (p < 0.0001). We conclude that ZnT8Ab presents a useful marker for type 1 diabetes, especially in younger patients at disease diagnosis.
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