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One of the foremost Japanese Ruskinians, Ryuzo Mikimoto (1893–1971), held a Ruskin exhibition in Tokyo from 6 to 8 February 1926. Attracting about 2,000 visitors, it was the first exhibition in Japan of the nineteenth-century British art critic and social reformer John Ruskin. The exhibits included the first editions of The Seven Lamps of Architecture and The Stones of Venice, the Pre-Raphaelite journal The Germ, and Ruskin’s autograph manuscripts, drawings, photographs and letters Ryuzo collected in Britain in the 1920s, amounting to nearly 150 pieces in all. As the son of the ‘Pearl King’ Kokichi Mikimoto, Ryuzo was expected to succeed his father’s jewellery business, but instead devoted himself to the introduction of the life and works of the Victorian polymath. Later he organised Ruskin exhibitions again not only in Tokyo, but also in Kyoto and Kobe, where the Christian social movement provided significant momentum toward the labour and peace movements. As in the painting A Stray Child (1902) by Taikan Yokoyama, which shows a Japanese surrounded by Western and Eastern philosophers and redeemers, Japanese young intellectuals faced a spiritual crisis after a massive influx of Western thought and subsequent cultural and social changes to westernize Japan. Ryuzo, a Protestant Christian, stated that he had chosen Ruskin rather than Karl Marx, Buddha and Christ. In fact, he revered Ruskin as a kind of a saviour who could resolve the predicament of the modern industrialised country. Based on primary sources such as a 1926 exhibition catalogue, related newspaper articles, and The Journal of the Ruskin Society of Tokyo Ryuzo issued, this study reconstructs the exhibitions, reconsiders Ryuzo’s Ruskin in the context of the history of religious thought in modern Japan, and sheds light on his peace-oriented and non-elitist endeavours to disseminate Ruskin’s ideas on art and society in Japan.

Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.

Understanding the intricate relationship between peripheral blood immune profiles and the inflammatory environment within affected tissues is pivotal for uncovering mechanisms driving autoimmune diseases. This study aimed to characterize CD4 + T cell subsets in peripheral blood that mirror the immunological activation of labial salivary glands (LSG) infiltrating T cells in primary Sjögren’s disease (pSjD). Using multicolor flow cytometry and T cell receptor (TCR) sequencing, we identified CXCR3 + CXCR5 + T follicular helper 1 (Tfh1) cells as significantly elevated in the circulation of pSjD patients and even more prominently increased in the LSG, with blood PD-1 + ICOS + Tfh1 cells positively correlating with titers of antinuclear, anti-SS-A, and anti-SS-B antibodies. In contrast, CXCR3 + CXCR5 − Th1 cells were enriched in LSG but reduced in circulation. TCR analysis demonstrated that circulating Tfh1 cells shared a notable clonal similarity with LSG T cells. In the LSG, cytokines such as IL-6, IL-12, IL-21, and TGF-β were upregulated, with TGF-β and TCR recognition promoting Tfh1 differentiation. This microenvironment led to increased production of IL-2, TNF-α, and IL-21, promoting the expansion of CD19 + CD38 + B cells. These findings support the notion that circulating activated Tfh1 cells partially mirror glandular T cell activation and highlight TGF-β as a driver of Tfh1 differentiation, presenting a potential therapeutic target.

Adult onset Still disease (AOSD) is a systemic inflammatory disorder characterized by skin rash, spiking fever, arthritis, sore throat, lymphadenopathy, and hepatosplenomegaly. Although the etiology of this disease has not been fully clarified, both innate and acquired immune responses could contribute to its pathogenesis. Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity, as well as hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD. In innate immunity, activation of monocytes/macrophages might play central roles in the development of AOSD and macrophage activation syndrome (MAS), a severe life-threating complication of AOSD. Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA. These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1β and pro-IL-18 into mature forms. Thereafter, IL-1β and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD. We identified placenta-specific 8 (PLAC8) as a specifically increased molecule in monocytes of active AOSD, which correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Interestingly, PLAC8 could suppress the synthesis of pro-IL-1β and pro-IL-18 via enhanced autophagy; thus, PLAC8 seems to be a regulatory molecule in AOSD. These findings for the activation mechanisms of monocytes/macrophages could shed light on the pathogenesis and development of a novel therapeutic strategy for AOSD.

Epithelia continually undergo apoptosis, but the physiological importance of this is unclear. Shibuya and colleagues show that apoptotic epithelial cells bind the glycoprotein CD300a on a dendritic cell subset at barrier surfaces and this negatively regulates commensal-driven T reg cell proliferation. Epithelial tissues continually undergo apoptosis. Commensal organisms that inhabit the epithelium influence tissue homeostasis, in which regulatory T cells (T reg cells) have a central role. However, the physiological importance of epithelial cell apoptosis and how the number of T reg cells is regulated are both incompletely understood. Here we found that apoptotic epithelial cells negatively regulated the commensal-stimulated proliferation of T reg cells. Gut commensals stimulated CX3CR1 + CD103 − CD11b + dendritic cells (DCs) to produce interferon-β (IFN-β), which augmented the proliferation of T reg cells in the intestine. Conversely, phosphatidylserine exposed on apoptotic epithelial cells suppressed IFN-β production by the DCs via inhibitory signaling mediated by the cell-surface glycoprotein CD300a and thus suppressed T reg cell proliferation. Our findings reveal a regulatory role for apoptotic epithelial cells in maintaining the number of T reg cell and tissue homeostasis.

Fibroblasts mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen-driven inflammatory pathology. Diverse fibroblast subtypes with homeostasis-regulating or inflammatory profiles have been recognized in various tissues, but which mediators induce these alternate differentiation states remain largely unknown. We recently identified that TNFSF14/LIGHT promotes an inflammatory esophageal fibroblast in vitro. Herein we used esophageal biopsies and primary fibroblasts to investigate the role of the LIGHT receptors, herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR), and their downstream activated pathways, in EoE. In addition to promoting inflammatory gene expression, LIGHT down-regulated homeostatic factors including WNTs, BMPs and type 3 semaphorins. In vivo, WNT2B+ fibroblasts were decreased while ICAM-1+ and IL-34+ fibroblasts were expanded in EoE, suggesting that a LIGHT-driven gene signature was imprinted in EoE versus normal esophageal fibroblasts. HVEM and LTβR overexpression and deficiency experiments demonstrated that HVEM regulates a limited subset of LIGHT targets, whereas LTβR controls all transcriptional effects. Pharmacologic blockade of the non-canonical NIK/p100/p52-mediated NF-κB pathway potently silenced LIGHT's transcriptional effects, with a lesser role found for p65 canonical NF-κB. Collectively, our results show that LIGHT promotes differentiation of esophageal fibroblasts toward an inflammatory phenotype and represses homeostatic gene expression via a LTβR-NIK-p52 NF-κB dominant pathway. [Display omitted]

Recent studies have suggested that the clinical features of elderly-onset adult-onset Still’s disease (AOSD) differ from those of young and middle-aged-onset patients, whereas the details remain unclear, and cytokine profiles of elderly-onset AOSD have not been reported. To clarify the clinical features and cytokine profiles of elderly-onset AOSD, we examined patients with AOSD who developed the disease between January 2006 and September 2021. We divided the patients into the young and middle-aged-onset group (aged < 65 years) and the elderly-onset group (aged ≥ 65 years) and compared the groups in terms of patient characteristics, clinical symptoms, laboratory findings including serum interleukin (IL)-6 and IL-18, treatment, and prognosis. A total of 48 patients were examined (10 in the elderly-onset group). In the elderly-onset group, atypical rash was significantly more frequent, typical rash and splenomegaly were significantly less frequent, white blood cell count and neutrophil ratio were significantly higher and serum IL-6 levels were significantly lower. Serum IL-6 showed a significantly negative correlation with age at onset. Treatment and relapse were comparable between the 2 groups, whereas infections were significantly more frequent in the elderly-onset group. The clinical features and cytokine profiles of elderly-onset AOSD might differ from those of young and middle-aged-onset AOSD.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody positive clinically amyopathic dermatomyositis (CADM) is a subtype of inflammatory myopathy associated with a distinct clinical phenotype, characterized by rapidly progressing interstitial lung disease and limited muscle involvement. Although cases with onset of anti-MDA5 antibody positive CADM during pregnancy or the postpartum period are rare, they present unique challenges due to a potential pregnancy complications and the possible severity of the disease course. We present a case of anti-MDA5 antibody positive CADM that developed during the postpartum period following childbirth without any pregnancy complication. Additionally, we conducted a comprehensive review of case reports and series of similar cases to elucidate the clinical characteristics and outcomes. Our analysis revealed considerable variability in disease presentation, ranging from severe cases requiring multi-targeted therapy to well-controlled cases with less demanding treatments. The scarcity of evidence in this population underscores the importance of accumulating evidence from case series to inform treatment strategies. More precise prediction tools are needed to effectively manage this rare subset of patients.

IgG4-related disease (IgG4-RD) is a systemic condition in which IgG4+ plasma cell infiltration and fibrosis cause organ swelling and lead to diverse clinical manifestations. Although IgG4-RD typically responds to glucocorticoids (GCs), relapse during tapering occurs and an early GC-sparing approach might therefore be beneficial. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with multiple symptoms that is also treated with GCs as a first-line therapy. Recently, belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor, was approved, but reports of use for IgG4-RD are scarce. Here, we present a rare case of IgG4-RD complicated with SLE which was successfully treated with belimumab. A 67-year-old man was diagnosed with IgG4-RD based on a high serum IgG4 level and histopathological findings. Furthermore, he had pericardial effusion on echocardiography, and laboratory tests revealed thrombocytopenia, autoimmune hemolysis, positive anti-nuclear antibodies, positive anti-DNA antibodies, and hypocomplementemia. These data led to an SLE diagnosis. Treatment was started with prednisolone at 40 mg/day, plus hydroxychloroquine, which initially improved both the SLE and IgG4-RD symptoms. During the GC tapering, belimumab was added and clinical symptoms resolved completely. Our case and the literature review summarize reported rare overlapping cases of IgG4-RD and SLE and suggest that belimumab is a promising candidate for the treatment of IgG4-RD.

Epithelial tissues continually undergo apoptosis. Commensal organisms that inhabit the epithelium influence tissue homeostasis, in which regulatory T cells (T sub(reg) cells) have a central role. However, the physiological importance of epithelial cell apoptosis and how the number of T sub(reg) cells is regulated are both incompletely understood. Here we found that apoptotic epithelial cells negatively regulated the commensal-stimulated proliferation of T sub(reg) cells. Gut commensals stimulated CX3CR1 super(+)CD103 super(-)CD11b super(+) dendritic cells (DCs) to produce interferon- beta (IFN- beta ), which augmented the proliferation of T sub(reg) cells in the intestine. Conversely, phosphatidylserine exposed on apoptotic epithelial cells suppressed IFN- beta production by the DCs via inhibitory signaling mediated by the cell-surface glycoprotein CD300a and thus suppressed T sub(reg) cell proliferation. Our findings reveal a regulatory role for apoptotic epithelial cells in maintaining the number of T sub(reg) cell and tissue homeostasis.