Akira Hoshioka

A common T-cell epitope between human thyroglobulin and human thyroid peroxidase is related to murine experimental autoimmune thyroiditis

We have investigated functional common T-cell epitopes between human thyroglobulin (hTg) and human thyroid peroxidase (hTPO) in mice. Four hTg peptides, Tg-P1, Tg-P2, Tg-P3 and Tg-P4, in which 5 amino acid residues are identical to those of hTPO, and 1 hTPO peptide, TPO-P4 relevant to Tg-P4, were prepared. Among these peptides, only Tg-P4 (residues 2730-2743) and TPO-P4 (residues 118-131) were highly antigenic and both peptides shared the common T-cell epitope. In addition, when the spleen cells from mice immunized with mouse Tg (mTg) were restimulated in vitro by Tg-P4 or TPO-P4 as well as by mTg, these cells transferred thyroiditis to naive recipient mice. These findings indicate that this common T-cell epitope between hTg and hTPO is immunogenic and related to the development of murine experimental autoimmune thyroiditis.

Diminished interferon‐gamma (IFN‐γ) production by bacterial antigen‐specific T cells in atopic patients

In this study, we established and studied cytokine production of T cell lines (TCL) specific to either a purified protein derivative of Mycobacterium tuberculosis (PPD) or Dermatophagoides farinae (Df) from atopic patients and non‐atopic healthy subjects. IFN‐γ was detected in the culture supernatants of all of 36 PPD‐specific TCL established from healthy controls, whereas only 24 of 38 PPD‐specific TCL from patients produced IFN‐γ. Furthermore, the amounts of IFN‐γ produced by PPD‐specific TCL from patients were significantly lower than those from healthy controls. No IL‐4 was detected in any PPD‐specific TCL from either healthy controls or atopic patients. The amounts of IL‐4 production from Df‐specific TCL from atopic patients were much higher than from healthy controls, while few TCL produced IFN‐γ. These results suggest that the skewing to the Th2‐type T cell response in atopic patients is a response not only to allergens, but also to bacterial antigens, compared with non‐atopic subjects. Activation of PPD‐specific TCL from patients with calcium ionophore A23187 plus phorbol myristate acetate resulted in much higher IFN‐γ production than in TCL established from healthy controls, indicating that the low production of IFN‐γ by PPD‐specific T cells from atopic patients is not due to an intrinsic T cell defect but to some regulatory mechanisms.

Association Study of Matrix Metalloproteinase-12 Gene Polymorphisms and Asthma in a Japanese Population

Background: Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population. Methods: We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro. Results: N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00–2.56, p = 0.047; OR 1.40, 95% CI 1.04–1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-β. Conclusions: Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue.