Association Between IA-2 Autoantibody Epitope Specificities and Age of Onset in Japanese Patients with Autoimmune Diabetes

Kawasaki, Eiji; Sera, Yoshihisa; Fujita, Naruhiro; Yamauchi, Mikako; Ozaki, Masako; Abe, Takahiro; Yamakawa, Kenji; Uotani, Shigeo; Takino, Hirofumi; Yamasaki, Hironori; Yamaguchi, Yoshihiko; Uchigata, Yasuko; Matsuura, Nobuo; Eguchi, Katsumi

doi:10.1006/jaut.2001.0551

Cited by 17 publications

(13 citation statements)

References 44 publications

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“…Finally, our data, related to Caucasian patients, confirm and extend those reported in Japanese diabetic populations (17), in which an association between IA-2 autoantibody epitope specificities and age at onset was found. These results suggest that the mechanisms responsible for the generation of IA-2A in Caucasian and Japanese LADA patients are similar and that different genetic backgrounds probably do not influence IA-2A epitope specificity, in contrast with what has been reported for GAD epitope immunoreactivity (12).…”

Section: Discussionsupporting

confidence: 91%

“…No data are currently available regarding which construct among IA-2 FL (1-979) , IA-2 BDC (256 -556:630 -979) , and IA-2 IC (605-979) has the highest sensitivity and specificity for detecting IA-2As in LADA patients and whether other IA-2 constructs may identify additional immunoreactivities in the sera of these patients. An association between IA-2 epitope specificities and age of onset in recent-onset Japanese type 1 diabetic and long-standing type 2 diabetic patients was demonstrated (17). To our knowledge, no information is at present available on IA-2 epitope specificity in Caucasian LADA patients.…”

Section: -1283 2008mentioning

confidence: 89%

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Identification of Tyrosine Phosphatase 2(256–760) Construct as a New, Sensitive Marker for the Detection of Islet Autoimmunity in Type 2 Diabetic Patients

et al. 2008

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OBJECTIVE—The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The aim of this study was to dissect humoral anti–IA-2 immune response in Caucasian LADA patients, identifying the most sensitive construct to evaluate IA-2 immunoreactivity and comparing LADA IA-2 epitope specificities to those found in type 1 diabetes. RESEARCH DESIGN AND METHODS—We analyzed 177 LADA and 978 type 2 diabetic patients with different disease duration, collected in a nationwide Italian survey, the Non–Insulin Requiring Autoimmune Diabetes (NIRAD) study aimed at assessing prevalence and characteristics of autoimmune diabetes in type 2 diabetic patients and 106 newly diagnosed type 1 diabetic patients (53 children, 53 adults). By radioimmunoassay, we analyzed humoral immunoreactivity to seven IA-2 constructs: IA-2PTP (687–979), IA-2(761–964), IA-2(256–760), IA-2JM (601–630), IA-2IC (605–979), IA-2BDC (256–556:630–979), and IA-2FL (1–979). RESULTS—IA-2(256–760) fragment was identified as the marker with the highest sensitivity for detection of humoral IA-2 immunoreactivity in LADA patients, identifying IA-2 autoantibodies in ∼30% of GAD antibody (GADA)-positive LADA patients and in 3.4% of GADA-negative type 2 diabetic patients. LADA IA-2(256–760)A positivity was associated with an increased frequency of autoimmune diabetes HLA-susceptible genotypes and with a higher risk for developing thyroid autoimmunity compared with autoantibody-negative type 2 diabetic patients. At disease diagnosis, adult-onset type 1 diabetic and LADA patients showed a lower IA-2 COOH-terminal immunoreactivity compared with childhood-onset type 1 diabetic patients. CONCLUSIONS—IA-2 immunoreactivity in LADA patients has thus far been underestimated, and IA-2(256–760) autoantibody detection may represent a novel diagnostic tool for the identification of islet autoimmunity in these patients.

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Section: Discussionsupporting

confidence: 91%

Section: -1283 2008mentioning

confidence: 89%

Identification of Tyrosine Phosphatase 2(256–760) Construct as a New, Sensitive Marker for the Detection of Islet Autoimmunity in Type 2 Diabetic Patients

et al. 2008

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“…However, the amino acid chain that includes 325Arg has a protein kinase A and protein kinase C recognition motif (R-X-S/T) and rs13266634 SNP disrupts this motif, indicating the possible alteration of zinc transporter function. As differences in the epitope specificity of autoantibodies to GAD65 and insulinoma-associated antigen-2 are linked to the progression or the clinical heterogeneity of type 1 diabetes in Japanese patients [8,9], it is worth investigating the clinical role of ZnT8 CW and CR autoantibodies in the Japanese population.…”

Section: Discussionmentioning

confidence: 99%

Association between anti-ZnT8 autoantibody specificities and SLC30A8 Arg325Trp variant in Japanese patients with type 1 diabetes

et al. 2008

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Aims/hypothesis We analysed the association between humoral autoreactivity to zinc transporter-8 (ZnT8) and the SLC30A8 rs13266634 polymorphism (Arg325Trp), which is located at the most distal loop in the ZnT8 protein.Methods Autoantibodies to ZnT8 were determined by RIA in 270 patients with type 1 diabetes using ZnT8 carboxyterminal constructs (amino acids 268-369) carrying 325Trp (CW) and 325Arg(CR) and a hybrid construct (CW-CR). Forty-four ZnT8 autoantibody-positive sera with genomic DNA were used to examine the association between reactivity to ZnT8 constructs and the rs13266634 genotype. Results Seventy-five patients reacted to the CW-CR hybrid construct, whereas 37 and 36 patients reacted to the CW and CR constructs, respectively. All sera positive for either CW or CR autoantibodies were positive for CW-CR autoantibodies. Among 19 patients with a 325Arg(CC) genotype, 5% had CW-specific autoantibodies, 42% had CR-specific autoantibodies and 32% had dual reactivity. Conversely, 73% of 15 patients with the 325Trp(TT) genotype had CW-specific autoantibodies, no patients had CR-specific autoantibodies and 13% had dual reactivity. Nine of the ten patients (90%) with the CT genotype reacted with either CR or CW constructs. The titre of CR autoantibodies in patients carrying the C allele was significantly higher than that in TT homozygotes (p<0.0001). In contrast, the titre of CW autoantibodies in patients carrying a T allele was significantly higher than that in CC homozygotes (p<0.005). No evidence of an association between rs13266634 and type 1 diabetes was observed. Conclusions/interpretation These results indicate that variant residue at amino acid 325 is a key determinant of humoral autoreactivity to ZnT8 and that the SLC30A8 genotype is an important determinant of autoantibody specificity.

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“…HLA-DRB1 and DQB1 types were defined by DNA analysis using PCR-SSO and PCR-RFLP method with sequence-specific oligonucleotide probes as described previously [18]. Genotyping of an A/G transition at position 49 (codon 17) in exon 1 of CTLA-4 gene (CTLA-4 49A/G) was performed by the PCR-RFLP method as previously described [19].…”

Section: Determination Of Hla Genotypes and Ctla-4 Gene Polymorphismmentioning

confidence: 99%

Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes

Ide

Kawasaki

Abiru

et al. 2004

Journal of Autoimmunity

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Association Between IA-2 Autoantibody Epitope Specificities and Age of Onset in Japanese Patients with Autoimmune Diabetes

Cited by 17 publications

References 44 publications

Identification of Tyrosine Phosphatase 2(256–760) Construct as a New, Sensitive Marker for the Detection of Islet Autoimmunity in Type 2 Diabetic Patients

Identification of Tyrosine Phosphatase 2(256–760) Construct as a New, Sensitive Marker for the Detection of Islet Autoimmunity in Type 2 Diabetic Patients

Association between anti-ZnT8 autoantibody specificities and SLC30A8 Arg325Trp variant in Japanese patients with type 1 diabetes

Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes

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