Differences in the humoral autoreactivity to zinc transporter 8 between childhood- and adult-onset type 1 diabetes in Japanese patients

Kawasaki, Eiji; Nakamura, K.; Kuriya, Genpei; Satoh, Tsuyoshi; Kobayashi, Masakazu; Kuwahara, Hironaga; Abiru, Norio; Yamasaki, Hironori; Matsuura, Nobuo; Miura, Junnosuke; Uchigata, Yasuko; Eguchi, Katsumi

doi:10.1016/j.clim.2010.10.007

Cited by 53 publications

(55 citation statements)

References 21 publications

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“…ZnT8A were also determined by radioligand binding assay (RBA) using human ZnT8 cDNA as described previously [7]. The human ZnT8 cDNA construct used in this assay was a fusion of the cytoplasmic carboxy-terminal domains (amino acids 268-369) of ZnT8 carrying either 325Trp or 325Arg with a linker peptide.…”

Section: Znt8 Autoantibody Radioligand Binding Assaymentioning

confidence: 99%

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Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies

Kawasaki

Tanaka²,

Miwa

et al. 2013

Acta Diabetol

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Autoantibodies to zinc transporter 8 (ZnT8A) is a powerful diagnostic or predictive marker in type 1 diabetes. However, the widely used current ZnT8A radioligand binding assay (RBA) has proved to be difficult for many laboratories to implement. The aim of this study was the development and characterization of the performance of a novel fluid phase ZnT8A enzyme-linked immunosorbent assay (ELISA) in relation to standard radioligand binding assay (RBA) in type 1 diabetes. Sera from 114 patients with type 1 diabetes and 140 blinded Islet Autoantibody Standardization Program (IASP2012) samples were studied. The sensitivity of ELISA-ZnT8A is equivalent or slightly higher than conventional RBA with similar specificity. Furthermore, the median SD score using this ELISA was significantly higher than that obtained with RBA (P<0.0001). Multiple logistic regression analysis revealed that ELISA-ZnT8A positivity was associated with younger age of onset (≤ 20 years; OR 15.91, P=0.0002), acute-onset form of type 1 diabetes (OR 3.38, P=0.019), and the presence of IA-2 autoantibodies (OR 3.75, P=0.014). Furthermore, the levels of ELISA-ZnT8A were associated with the reactivity to ZnT8-325Arg, but not ZnT8-325Trp. We conclude that this nonradioactive bivalent ZnT8A assay has high performance and should facilitate large-scale autoantibody screening.Moreover, these results suggest that the humoral autoimmunity against ZnT8 is related to a high risk of faster development of type 1 diabetes and the ZnT8A levels are associated with the known aa325 variants.

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Section: Znt8 Autoantibody Radioligand Binding Assaymentioning

confidence: 99%

“…TSH receptor autoantibodies were measured using an RIA kit provided by Yamasa Corporation (Chiba, Japan). IA-2A were determined by RBA as previously described [7].…”

Section: Detection Of Other Autoantibodiesmentioning

confidence: 99%

Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies

Kawasaki

Tanaka²,

Miwa

et al. 2013

Acta Diabetol

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“…Previous studies have reported that autoantibodies to ZnT8 (ZnT8A) are detected in 60-80 % of Caucasian patients with type 1 diabetes. With radioligand binding assay using in vitro transcribed/translated 35 S-labeled ZnT8 protein, we identified ZnT8A in 58% patients with acute-onset and in 20% with slow-onset type 1 diabetes in the Japanese population [28]. Furthermore, the prevalence of ZnT8A was inversely related to the onset age with the highest prevalence of 70% in patients aged < 10 years (Fig.…”

Section: Zinc Transportersmentioning

confidence: 85%

“…With the combination analysis using four biochemically characterized anti-islet autoantibodies, 94% of Japanese patients with type 1 diabetes are classified as type 1A diabetes [28] (Table 1). However, the clinical utility of ZnT8A is limited over testing GADA, IA-2A, and IAA; i.e.…”

Section: Znt8 Autoantibodies As a Diagnostic Tool For Type 1a Diabetesmentioning

confidence: 99%

ZnT8 and type 1 diabetes [Review]

Kawasaki

2012

Endocr J

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Abstract. Zinc is essential for the proper storage, secretion, and the action of insulin and is transported from cytoplasm to insulin secretory granules in the pancreatic β-cells by SLC30A zinc transporters (ZnT). ZnT8 is specifically expressed in the pancreatic β-cells and has been identified as a novel target autoantigen in patients with type 1 diabetes. Autoantibodies to ZnT8 (ZnT8A) are detected in 50-60% of Japanese patients with acute-onset and 20% with slow-onset type 1 diabetes. Furthermore, humoral autoreactivity to ZnT8 is unique in terms of a key determinant, which is not reported on other islet autoantigens such as insulin, glutamic acid decarboxylase, or the protein tyrosine phosphatase-related molecules IA-2. Type 2 diabetes-associated nonsynonymous single nucleotide polymorphism in SLC30A8 (the gene of ZnT8), rs13266634 (Arg325Trp), modulates ZnT8A specificities thereby indicating that this amino acid substitution has the critical role in antibody binding. The humoral autoreactivity to ZnT8 depends on the clinical phenotype, which may provide clues to understand the role of this protein in the pathogenesis of type 1 diabetes.

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“…Zinc is crucial for proper storage, secretion and function of insulin and ZnT8 is specifically expressed in pancreatic β cells. The proportion of T1D patients positive for ZnT8 autoantibodies ranges between 24%-80%, depending on the study (Kawasaki et al, 2011;Wenzlau et al, 2007).…”

Section: Other Autoantigensmentioning

confidence: 99%

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Reeves¹

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Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β cells. The current treatment for the fatal insulin-deficiency in T1D is injection of exogenous insulin. Despite the dramatic increase in survival from the use of exogenous insulin, complications develop from imperfect glycemic control and exogenous insulin does not rectify the underlying cause of disease, the diabetogenic autoimmune response. Hence, there is a need for an effective therapy that impedes the progress of the pathogenic autoimmune response. β cell-reactive CD8 + In the NOD mouse model of T1D, insulin is the primary β-cell antigen that elicits disease. As such, I have investigated T-cell tolerance to insulin in an adoptive transfer setting in which TCR transgenic (G9) CD8 + T cells specific for insulin B15-23 (InsB15-23) were transferred to transgenic mice over-expressing proinsulin in APC. Subsequently, I examined the effect of introducing transgenic proinsulin expression on diabetes development in wild type NOD mice.When transferred to mice transgenically expressing proinsulin, naïve G9 T cells proliferated extensively prior to undergoing rapid deletion. In proinsulin transgenic recipients, the remaining population of G9 T cells displayed reduced T-cell receptor (TCR) expression and bound less InsB15-23-loaded, H2-K d -tetramer compared to G9 T cells that had been transferred to non-transgenic NOD recipients. Interestingly, TCR down-regulation represented that which occurred for OVA-specific CD8 + T cells transferred to mice expressing OVA in APC in a non-autoimmune prone strain.Importantly, naïve G9 T cells did not expand or produce the important effector cytokine, interferon (IFN)-γ, in response to InsB15-23 immunisation after transfer to proinsulin transgenic mice. These data confirm naïve G9 T cells undergo rapid deletion and inactivation after transfer to mice transgenically-expressing proinsulin, despite genetic tolerance defects in NOD mice. Memory CD8 + T cells (Tmem) perpetuate β-cell autoimmunity and pose a distinct barrier to immunotherapy. It was pertinent to determine whether inactivation of insulin-specific CD8 + Tmem also occurs after transfer to mice expressing proinsulin in APC. To test inactivation of insulin-specific CD8 + Tmem, G9 Tmem were generated using an in vitro culture method. Cultured G9 Tmem were validated by assessing phenotypic markers and cytokine production. Similarly to naïve G9 T cells, G9 Tmem proliferated extensively and most G9 Tmem were rapidly deleted after transfer to mice overexpressing proinsulin in APC. The remaining, non-deleted population of G9 Tmem was infrequent ii and exhibited reduced TCR expression. Furthermore, G9 Tmem did not expand or produce IFN-γ in response to InsB15-23 immunisation, consistent with functional inactivation. These results demonstrate transgenic proinsulin expression in APC overcomes genetic defects in NOD mice to induce tolerance in insulin-specific CD8 + Tmem.From the data described above, transgenic proinsulin expression is tolerogenic for in...

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Differences in the humoral autoreactivity to zinc transporter 8 between childhood- and adult-onset type 1 diabetes in Japanese patients

Cited by 53 publications

References 21 publications

Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies

Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies

ZnT8 and type 1 diabetes [Review]

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

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