Hironori Kurisaki

Autoimmune Regulator (AIRE) Gene Is Expressed in Human Activated CD4 T-Cells and Regulated by Mitogen-Activated Protein Kinase Pathway

The autoimmune regulator (AIRE) gene is a gene responsible for autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy. Here we show that AIRE is expressed in human peripheral CD4‐positive T‐cells, and most highly in antigen‐ and interleukin 2‐stimulated T (IL‐2T) cells. Mitogen‐activated protein kinases (MAPKs), including MAPK kinase (MEK) 1/2 and p38 MAPK, were phosphorylated in IL‐2T cells and the expression of the AIRE gene was inhibited by a specific p38 MAPK inhibitor (SB203580), thereby indicating that AIRE gene expression is controlled by the MAPK pathway in IL‐2T cells. These data suggested the possible significance of the AIRE gene in the peripheral immune system.

Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes

Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.

Recurrent herpes simplex virus infection in a patient with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy associated with L29P and IVS9-1G>C compound heterozygous autoimmune regulator gene mutations

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) has characteristic clinical features with organ‐specific autoimmune polyendocrine diseases and candidiasis, caused by the mutations of autoimmune regulator (AIRE) gene. Although almost all patients are complicated with mucocutaneous candidiasis, no apparent susceptibility to other infections has yet been reported. We herein report that a patient with APECED suffered from recurrent herpes simplex virus type 1 (HSV‐1) infection after severe primary herpetic stomatitis, associated with sequential HSV‐1 isolates of the same genomic profile, consistent with endogeneous recurrence. Thus, not only candidiasis but also HSV infection should receive more attention in patients with APECED, with treatment being administered accordingly.

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese

Background Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2). Methods Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese. Findings A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody. Interpretation The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans. Funding Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.

Autoimmune Gastro-Pancreatitis with Anti-Protein Disulfide Isomerase-Associated 2 Autoantibody in Aire-Deficient BALB/cAnN Mice

Although the autoimmune regulator (Aire) knockout (KO) mouse model has been reported to present various organ-specific autoimmune diseases depending on genetic background, autoimmune pancreatitis in mice of BALB/c background has not yet been reported. Here, we report that Aire KO mice with BALB/cAnN background showed significant lymphoid cell infiltration in the pancreas and stomach. To examine whether the phenotype in the pancreas and stomach is due to autoimmune reaction associated with autoantibody production, indirect immunofluorescence staining followed by Western blot analysis was performed. Consequently, the autoantibody against pancreas and stomach was detected in the sera of Aire KO mice, and the target antigen of the autoantibody was identified as protein disulfide isomerase-associated 2 (Pdia2), which was reported to be expressed preferentially in the pancreas and stomach. Thus, Aire KO mice of BALB/cAnN background can serve as a useful animal model for autoimmune gastro-pancreatitis with anti-Pdia2 autoantibody production.

Subtyping of Type 1 Diabetes as Classified by Anti-GAD Antibody, IgE Levels, and Tyrosine kinase 2 (TYK2) Promoter Variant in the Japanese

Objective Type 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. Research Design and Methods We assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese. Results T1D patients had elevated IgE (median, 56.7 U/ml; p < 0.0001) compared with T2D patients (22.5 U/ml) and controls (43.3 U/ml). Contrary to our expectations, there was no correlation between TYK2 promoter variant and IgE levels. We found that T1D could be subtyped as four groups based on anti-GAD Ab and IgE profile: Subtype 1, anti-GAD Ab positive and non-elevated IgE (47.0%); Subtype 2, anti-GAD Ab negative and non-elevated IgE (35.1%); Subtype 3, anti-GAD Ab positive and elevated IgE (10.9%); and Subtype 4, anti-GAD Ab negative and elevated IgE (7.0%). In Subtype 2, a significantly higher incidence was observed in T1D cases carrying the TYK2 promoter variant (OR, 2.60; 95%CI, 1.03–6.97; p = 0.032), and also showing a flu-like syndrome at diabetes onset (OR, 2.34; 95%CI, 1.27–4.35; p = 0.003). Interpretation Anti-GAD Ab and IgE profiling helps classifying T1D into four groups that recognize variable pathogenic bases of T1D.