Amelioration of diabetes in NOD by additive Aire

Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms

A NEW LOOK AT TRANSCRIPTIONAL REGULATION BY AIRE IN mTECs

The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire’s primary targets while distinguishing them from the secondary targets

Interface structure of a-Si:H/ZnS multilayer films elucidated from electron-spin resonance and infrared-absorption measurements

金沢大学理工研究域電子情報通信学系Multilayer films consisting of hydrogenated amorphous silicon and zincsulfide (a-Si:H/ZnS) were prepared by glow-discharge decomposition of silane gas and diethylsulfur-diethylzinc gas mixture. Since a-Si:H/ZnS multilayer films do not have Si atoms in their barrier layer, they have an advantage of easy characterization of the a-Si:H well layer by using electron-spin resonance and infrared absorption. These measurements revealed that in an interface region within a distance of 10 nm from the interface, H atoms in a-Si:H are incorporated in the form of dihydride rather than in the form of monohydride. In accordance with the H bonding scheme, it was also found that the interface region in a-Si:H within a distance of several nanometers from the interface has a large Si dangling bond density of the order of 1018 cm-3. Transport properties in these films were also investigated

Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition

Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)

Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire

Distribution of chaetognaths in the Japan Sea in the winter of 1997 and in the autumn of 1999

There was no remarkable difference of chaetognath biomass among station in winter (10.6mg/m^3 in mean) in the Japan Sea. Biomass in autumn ranged from 1.4-45.4mg/m^3 (16.1mg/m^3 in mean) and high biomass was recognized in southern Japan Sea below than 38°N. Two genera ten species was collected in the autumn 1999. Warm water species were not collected in the winter 1997. Many warm water species were transported into the Japan Sea from the south by the Tsushima Current in the autumn and distributed in wide waters of the middle Japan Sea. The proportion of the number of sampling stations located in mixed water and warm water was 75.8% but 11.1% in the winter. Sagitta elegans was the dominant species and distributed below the thermocline in autumn and winter but abundance was high in the 0-100m layer in the northern Japan Sea where the surface layer was not coveved by Tsushima Current water