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1-Methylimidazolium triflate([HMIM][TfO])は常温で固体であり、85℃で相転移をおこない柔粘性結晶となる。[HMIM][TfO]に6-hydroxyquinolineや2-aminopyrizineをドープした蛍光測定の結果から、固相や柔粘性結晶中で[HMIM][TfO]のプロトン供与性が非常に高いことがわかった。一方でtrisodium 8-hydroxypyrene-1,3,6-trisulfonate(HPTS)をドープしたところ、そのままではプロトン移動は起こらないが1-methylimidazole(MIM)を添加すると固相で会合体を生成し、HTPSからMIMへプロトン移動が生じることが明らかとなった。一方柔粘性結晶相では、分子の自由回転のために会合体が消失し特有のプロトン移動は起こらないことが分かった。, Proton transfer reactions of various photoacids or photobases in 1-methylimidazolium triflate ([HMIM][TfO]) has been studied by steady-state fluorescence spectroscopy and time-resolved fluorescence spectroscopy. The fluorescence and excitation spectra of 2-aminopyridine and 6-hydroxyquinoline indicated a high acidity of [HMIM][TfO]. We also observed the proton transfer from trisodium 8-hydroxypyrene-1,3,6-trisulfonate (HPTS) to 1-methylimidazole (MIM) or water added to [HMIM][TfO] as co-solvent. The fluorescence excitation spectra indicated that the existence of the complex between HPTS and MIM. The fluorescence dynamics indicated that the site selective proton transfer occurred in solid [HMIM][TfO]. In a PC phase, such an unique process was not observed, suggesting that the rotational dynamics in PC was similar to that in liquids phase.

Although the development of autoimmune disorders is recognized in drug‐induced hypersensitivity syndrome (DIHS), the serial change of B‐cell activity has not been well‐addressed. Herein, the serum levels of IL‐6, IL‐10, B‐cell activating factor of the tumor necrosis factor family (BAFF), and a proliferation‐inducing ligand (APRIL) in three DIHS patients were tracked over time. While IL‐6 and IL‐10 tended to be elevated according to the disease activity, BAFF and APRIL increased during the improved phase. Our results imply that the continuous activation of B cells may be involved in the prolonged disease activity of DIHS and the development of autoimmune disorders.

Vitiligo is a common depigmenting skin disease that is often difficult to treat. Even if repigmentation is achieved by treatment, recurrence in the same lesion is often found within a year after stopping treatment. As a background of these issues, a subset of CD8

Background The efficacy of small molecule inhibitors for intracellular signal mediators varies among the individuals, and their mechanism of action is broad. A phosphodiesterase 4 inhibitor apremilast shows a dramatic effect on a certain proportion of psoriatic patients by modulating the cellular metabolism and regulating the production of pro-inflammatory molecules. However, it is unclear to which disease subtype this drug benefits. While psoriasis is a Th17-mediated disease, how immune cells are affected by the modulation of cellular metabolism is not fully evaluated, either. Objective This study aims to identify the indices which predict the efficacy of apremilast in psoriasis, and to investigate the impact of metabolic activity in immune cells on the psoriatic pathogenesis. Methods The association of treatment efficacy with clinical and laboratory data of the 58 psoriatic patients was evaluated. The reflector of the associated index was also sought among the indices of cellular metabolic pathways by use of an extracellular flux analyzer. Results There was a correlation between clinical improvement and the serum lactate dehydrogenase (LDH) level in the patients treated with apremilast but not in those with biologics. Serum LDH level did not correlate with the cutaneous disease severity but correlated with the oxygen consumption rate of blood T cells. Conclusion Psoriatic patients with high serum LDH level can be benefitted by apremilast. The serum LDH level reflects the augmented respiratory activity of T cells in psoriasis. Our results would highlight the importance of regarding metabolic skew in immune cells as a treatment target in psoriasis.

B cells include immune-suppressive fractions, called regulatory B cells (Bregs), which regulate inflammation primarily through an interleukin 10 (IL-10)-mediated inhibitory mechanism. Several B-cell fractions have been reported as IL-10-producing Bregs in murine disease models and human inflammatory responses including autoimmune diseases, infectious diseases, cancer and organ-transplant rejection. Although the suppressive functions of Bregs have been explored through the hallmark molecule IL-10, inhibitory cytokines and membrane-binding molecules other than IL-10 have also been demonstrated to contribute to Breg activities. Transcription factors and surface antigens that are characteristically expressed in Bregs are also being elucidated. Nevertheless, defining Bregs is still challenging because their active periods and differentiation stages vary among disease models. The identity of the diverse Breg fractions is also under debate. In the first place, since regulatory functions of Bregs are mostly evaluated by ex vivo stimulation, the actual in vivo phenotypes and functions may not be reflected by the ex vivo observations. In this article, we provide a historical overview of studies that established the characteristics of Bregs and review the various suppressive mechanisms that have been reported to be used by Bregs in murine and human disease conditions. We are only part-way through but the common phenotypes and functions of Bregs are still emerging.

ObjectivesTo investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy.MethodsWild-type, β2-microglobulin-null, perforin-null, Igμ‐null and interferon α/β receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8+ or CD4+ T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib.ResultsImmunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in β₂-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igμ‐null mice developed myositis normally. Adoptive transfer of CD8+ T cells induced myositis in recipients, while transfer of CD4+ T cells or IgG did not. Treatment with tofacitinib inhibited TIF1γ-induced myositis.ConclusionsHere we show that TIF1γ is immunogenic enough to cause experimental myositis, in which CD8+ T cells and type I interferons, but not CD4+ T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.

The circulating precursor cells that give rise to human resident memory T cells (T RM ) are poorly characterized. We used an in vitro differentiation system and human skin–grafted mice to study T RM generation from circulating human memory T cell subsets. In vitro T RM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4 + T cells and granzyme B production in CD8 + T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (T EM ) had the highest conversion rate to T RM in vitro and in vivo, but central memory T cells (T CM ) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of T RM . In summary, T CM are highly efficient precursors of human skin T RM , a feature that may underlie their known association with effective long-term immunity.

Introduction The stratum corneum protects against the entry of pathogens, allergens, and irritants while preventing dehydration. The Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) system maintains skin barrier homeostasis. Aggregated evidence suggests that NRF2-mediated antioxidative response is hardwired into the stratified squamous epithelia. Honey and chamomile have long been regarded as natural antioxidants. Nonetheless, it is still unclear whether they activate the KEAP1/NRF2 system in the epidermis and could promote epidermal barrier recovery. Methods To address the abovementioned issue, we explored the antioxidative property of honey/chamomile extract by using non-cell-based KEAP1-inhibition assay and cultured human epidermal keratinocytes. Results Herein we report that the extract inhibited KEAP1-NRF2 interaction and induced keratinocyte production of antioxidant small proline-rich protein. Conclusion Our results may offer an opportunity to develop cosmetic products that boost NRF2-mediated antioxidative/antiaging, epidermis-intrinsic bio-responses.

Elucidation of the binding mode of protein–ligand interactions provides insights for the design of new pharmacological tools and drug leads. Specific labeling of target proteins with chemical probes, in which the ligands are conjugated with reacting and detecting groups, can establish the binding positions of ligands. Label-assisted laser desorption/ionization mass spectrometry (LA-LDI MS) is a promising detection method to selectively detect labeled molecules. However, previous LDI MS tags, such as nitrogen-substituted pyrenes, had problems with low sensitivity and stability. Here we show 6-N,N-dimethylaminopyrene (dmpy) as a versatile mass tag, which was detected at an amount of 0.1 fmol by LA-LDI MS and applicable for MS/MS analysis. By using ligand-dissociation-type dmpy probes and affinity purification with a polystyrene gel, we demonstrated that dmpy-labeled peptides were predominantly detected by MALDI MS. Our dmpy-probe-labeling method might be highly useful for determining the target biomacromolecules of various ligands and their binding sites.

Angiomatoid Spitz nevus (ASN) is a rare histological variant of Spitz nevus (SN) that is characterized by prominent blood vessel proliferation around the intradermal melanocytes of SN. In contrast, SN may have pagetoid components, which are characterized by epidermal proliferation of single melanocytes. However, cases of ASN with predominant pagetoid melanocytic proliferation in the epidermis have not been reported. Here, we report a case of ASN with surrounding pagetoid melanocytic proliferation without formation of tumor nests in the epidermis in the plantar region. A 12-year-old girl presented with a bright red nodule surrounded by a brown macule on the sole of her right foot. Histologically, the nodule showed tumor nests in the dermis, composed of spindle or epithelioid melanocytes containing abundant cytoplasm and large nuclei. Around the nests, numerous blood vessels were seen. In the overlying epidermis of the nodule, numerous eosinophilic Kamino bodies were found along the dermal-epidermal interface. In the macule, proliferation of oval melanocytes was present as single-cell units in the epidermis. Theses melanocytes had abundant cytoplasm with large nuclei, which were larger than those of the surrounding keratinocytes. From these findings, a diagnosis of ASN with surrounding pagetoid melanocytic proliferation was made. Vascular endothelial growth factor and fibroblast growth factor 2 were strongly expressed in the melanocytes as well as in the endothelial cells in our case. Therefore, angiogenic factors produced by the melanocytes of SN might have played important roles in the surrounding angiogenesis of this case.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma, including various clinical manifestations, such as mycosis fungoides (MF) and Sézary syndrome (SS). CTCL mostly develops from CD4 T cells with the skin-tropic memory phenotype. Malignant T cells in MF lesions show the phenotype of skin resident memory T cells (TRM), which reside in the peripheral tissues for long periods and do not recirculate. On the other hand, malignant T cells in SS represent the phenotype of central memory T cells (TCM), which are characterized by recirculation to and from the blood and lymphoid tissues. The kinetics and the functional characteristics of malignant cells in CTCL are still unclear due, in part, to the fact that both the malignant cells and the T cells exerting anti-tumor activity possess the same characteristics as T cells. Capturing the features of both the malignant and the benign T cells is necessary for understanding the pathogenesis of CTCL and would lead to new therapeutic strategies specifically targeting the skin malignant T cells or benign T cells.

Simple Summary Imiquimod (IMQ), a synthetic ligand of Toll-like receptor 7, is known to exert antitumor effects. However, the exact mechanisms of the IMQ-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. In our study using a murine tumor model, we show that IFN-γ produced by CD8+ T cells may play a crucial role in the IMQ-induced antitumor effect. In addition, IMQ upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells. Furthermore, we also found that combination therapy of topical IMQ with anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy. Therefore, the combination therapy of topical IMQ plus anti-PD-1 antibody is promising therapy for skin cancer. Abstract The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

Tissue-resident memory T cells (TRM) stay in the peripheral tissues for long periods of time, do not recirculate, and provide the first line of adaptive immune response in the residing tissues. Although TRM originate from circulating T cells, TRM are physiologically distinct from circulating T cells with the expression of tissue-residency markers, such as CD69 and CD103, and the characteristic profile of transcription factors. Besides defense against pathogens, the functional skew of skin TRM is indicated in chronic skin inflammatory diseases. In psoriasis, IL-17A-producing CD8+ TRM are regarded as one of the pathogenic populations in skin. Although no licensed drugs that directly and specifically inhibit the activity of skin TRM are available to date, psoriatic skin TRM are affected in the current treatments of psoriasis. Targeting skin TRM or using TRM as a potential index for disease severity can be an attractive strategy in psoriasis.

Some bone lesions are reported to mimic bone metastasis on imaging tests. Herein, we report a case of a 55-year-old Japanese man who presented with a skin tumor on the left lower extremity. He also had a history of recurrent generalized cutaneous blister and erosion formation since childhood. His skin lesions were diagnosed as cutaneous squamous cell carcinoma complicated by recessive dystrophic epidermolysis bullosa. Magnetic resonance imaging of the left lower extremity detected multiple focal bone lesions mimicking bone metastases in the left femur and tibia. However, bone biopsy revealed that the bone lesions were osteonecrosis without tumor cells. We suggest that cancer-induced osteonecrosis should be included in the differential diagnosis of bone lesions suspected of being metastases on magnetic resonance imaging.

The human skin is populated by recirculating T cells and skin-sessile resident memory T cells (TRM). Skin TRM are constructed during immune responses against antigens that the host immune system encounters in the skin. TRM persist in the same sites for a long time and play important protective roles in skin immune responses in collaboration with other skin-composing cells such as dendritic cells and keratinocytes. These TRM with strong effector functions possibly also engender skin inflammatory disorders. Since human skin T cells, especially TRM, are phenotypically distinct from T cells in the blood circulation, T cells residing in the skin should be directly investigated, without presuming from the activities of blood T cells, in order to understand the functional characteristics of skin T cells in skin disorders. This review summarizes the features of human skin TRM and reviews the immunopathological involvement of TRM in human skin disorders such as infectious disease, inflammatory skin disease, and malignant skin tumors.

Recent studies have highlighted that human resident memory T cells (TRM) are functionally distinct from circulating T cells. Thus, it can be postulated that skin T cells age differently from blood-circulating T cells. We assessed T-cell density, diversity, and function in individuals of various ages to study the immunologic effects of aging on human skin from two different countries. No decline in the density of T cells was noted with advancing age, and the frequency of epidermal CD49a+ CD8 TRM was increased in elderly individuals regardless of ethnicity. T-cell diversity and antipathogen responses were maintained in the skin of elderly individuals but declined in the blood. Our findings demonstrate that in elderly individuals, skin T cells maintain their density, diversity, and protective cytokine production despite the reduced T-cell diversity and function in blood. Skin resident T cells may represent a long-lived, highly protective reservoir of immunity in elderly people., Koguchi-Yoshioka et al. demonstrate that functional activities and diversity of T cells are highly maintained in the skin of elderly people when compared with those in the blood regardless of the ethnicity of the participants or the experimental procedures. They also find the accumulation of epidermal T cells with maintained cytokine production in the elderly participants.

Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors (ICIs) for treating melanoma. However, these previous studies comprised mainly Caucasian populations, in which cutaneous melanoma (CM) is the major clinical type. In contrast, Asian populations have a distinct profile of melanoma and show much higher frequencies of acral lentiginous melanoma (ALM) and mucosal melanoma (MCM). Compared with CM, ALM and MCM show poorer response to ICIs, but the mechanisms have not been fully understood. To evaluate the immune status in each melanoma subtype, we examined the number of total tumor-infiltrating lymphocytes (TILs), CD4+ TILs, CD8+ TILs, and tumor-infiltrating FoxP3+ regulatory T cells (Tregs) to evaluate the immune status in each melanoma subtype using data from 137 patients with melanoma. Total TIL numbers in ALM and MCM were significantly lower than that in CM. CD4+ TIL number in MCM was also lower than CM although CD4+ TIL number in ALM was comparable with CM. In contrast, CD8+ TIL numbers in both ALM and MCM were significantly lower than that in CM. Although number of tumor-infiltrating Tregs was comparable among the 3 subtypes, the proportion of tumor-infiltrating Tregs in CD4+ T cells in MCM was significantly higher than in CM and ALM. Multivariate regression analysis revealed that ALM and MCM were significantly associated with a lower total TIL number, but only MCM was significantly associated with a lower CD4+ TIL number. Multivariate regression analysis also revealed that both ALM and MCM were significantly associated with a lower CD8+ TIL number. Our results suggest that both ALM and MCM are independent factors of lower total TIL number, which may be associated with poorer responses to ICIs in ALM and MCM.