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Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

DOI： 10.1080/25785826.2025.2460910

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DOI： 10.1111/1756-185X.70108

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We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

DOI： 10.1080/25785826.2024.2430812

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/qjmed/hcae215

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In systemic lupus erythematosus (SLE) loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here, we set out to dissect layers and hierarchies of autoimmune kidney inflammation in order to identify tissue-specific cellular hubs that amplify auto-inflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blocking and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILC) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signaling in a distinct subset of ILC1 instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILC promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody mNCR1.152) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data support that NKp46+ ILC1 promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1 thus constitutes a previously unrecognized, critical tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.

DOI： 10.1038/s41586-024-07907-x

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BACKGROUND: The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart. METHODS: Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species. RESULTS: We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. Esm1-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism. CONCLUSIONS: A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.s.

DOI： 10.1161/CIRCRESAHA.124.324868

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Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.

DOI： 10.1016/j.clim.2024.110255

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DOI： 10.1111/1756-185X.15206

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DOI： 10.55563/clinexprheumatol/std9t8

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DOI： 10.1111/1440-1681.13840

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DOI： 10.1093/rheumatology/kead421

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DOI： 10.1111/1756-185X.15083

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A 27-year-old man presented with quotidian fever, rash, knee arthralgia, sore throat, and bloody diarrhea. Laboratory findings showed neutrophilia, elevated CRP, ferritin, and liver enzyme levels, and decreased hemoglobin levels. Radiological investigations revealed splenomegaly, systemic lymphadenopathy, thickening of the descending colon wall, and an abnormal uptake in the bone marrow and spleen as seen in F-fluorodeoxyglucose positron emission tomography. Malignant lymphoma was initially suspected, but biopsies showed no malignant findings. Colonoscopy revealed mucosal friability, erosions, and shallow ulcers, and pathological findings included crypt abscesses suggestive of either acute infectious colitis or inflammatory bowel disease. The patient was eventually diagnosed with adult-onset Still's disease (AOSD) and started on prednisolone, which resolved bloody diarrhea, leading to the diagnosis of comorbid ulcerative colitis (UC). The combination of AOSD and UC presents a diagnostic challenge due to overlapping symptoms. An accurate diagnosis requires careful exclusion of other diseases and a comprehensive assessment.

DOI： 10.31662/jmaj.2023-0103

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1756-185X.15029

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Dexmedetomidine (DEX), a highly selective alpha2-adrenoceptors agonist, is not only a sedative drug used during mechanical ventilation in the intensive care unit but also a cardio-protective drug against ischemia-reperfusion injury (IRI). Numerous preclinical in vivo and ex vivo studies, mostly evaluating the effect of DEX pretreatment in healthy rodents, have shown the efficacy of DEX in protecting the hearts from IRI. However, whether DEX can maintain its cardio-protective effect in hearts with comorbidities such as diabetes has not been fully elucidated. Multiple clinical trials have reported promising results, showing that pretreatment with DEX can attenuate cardiac damage in patients undergoing cardiac surgery. However, evidence of the post-treatment effects of DEX in clinical practice remains limited. In this narrative review, we summarize the previously reported evidence of DEX-induced cardio-protection against IRI and clarify the condition of the hearts and the timing of DEX administration that has not been tested. With further investigations evaluating these knowledge gaps, the use of DEX as a cardio-protective drug could be further facilitated in the management of patients undergoing cardiac surgery and might be considered in a broader area of clinical settings beyond cardiac surgery, including patients with acute myocardial infarction.

DOI： 10.1007/s00540-023-03261-w

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Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.

DOI： 10.1038/s41420-023-01584-x

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Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed pro-inflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase (MPO)-ANCA titers with a reduction in NETs formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

DOI： 10.1172/jci.insight.167486

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DOI： 10.1002/art.42443

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DOI： 10.1093/qjmed/hcad157

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DOI： 10.1093/cercor/bhad120

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DOI： 10.3899/jrheum.220649

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OBJECTIVES: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multi-organ dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30~40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. Herein, we explored new therapeutic targets for NPSLE focusing on microglia. METHODS: RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified and its role on microglial activation and phagocytosis was investigated using specific inhibitors and siRNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lpr was also evaluated. RESULTS: Transcriptome analysis revealed the upregulation of Ikbke, which encodes the inhibitor of nuclear factor kappa-B kinase epsilon (IKBKE) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKE inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKE inhibition reduced glycolysis, which dampened microglial activation and phagocytosis. CONCLUSIONS: These findings suggest that IKBKE plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.

DOI： 10.1002/art.42352

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Dupilumab (DUP) is a monoclonal antibody that acts on the interleukin (IL)-4 receptor alpha, which inhibits IL-4 and IL-13 signalling and is approved for type 2 inflammatory diseases such as asthma, chronic rhinosinusitis with nasal polyposis and atopic dermatitis; however, the efficacy of DUP to IgG4-related disease (IgG4-RD) is under discussion due to the controversial outcomes based on the several case reports. Here, we reviewed the efficacy of DUP in four consecutive patients with IgG4-RD in our institute and the previous literature.All patients administered DUP fulfilled the 2019 ACR/EULAR classification criteria for IgG4-RD complicated with severe asthma and chronic rhinosinusitis with nasal polyposis. Two cases were administered DUP without systemic glucocorticoids (GCs), and in 6 months, the volume of swollen submandibular glands (SMGs) was reduced by approximately 70%. Two cases receiving GCs successfully reduced their daily dose of GCs (10 and 50% reduction, respectively) with dupilumab in 6 months. In all four cases, serum IgG4 concentration and IgG4-RD responder index decreased in 6 months.DUP reduced the volume of the swollen SMGs, serum IgG4 levels, responder index and the daily dose of GCs in patients with IgG4-RD with severe asthma or eosinophilic rhinosinusitis in 6 months.The efficacy of DUP to IgG4-RD is under discussion due to the limited case reports with controversial outcomes. Here, we demonstrated that two patients with IgG4-RD treated by DUP without systemic GCs, showed volume reduction of swollen SMGs and two cases showed GC-sparing effects by DUP. DUP can ameliorate the disease activity and be a steroid-sparing agent in patients with IgG4-RD.

DOI： 10.1136/rmdopen-2023-003026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.

Other Link： https://www.nature.com/articles/s41467-023-36594-x

DOI： 10.1038/s41467-023-36594-x

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A 67-year-old woman with a 5-year history of recurrent swollen eyelids and epistaxis, diagnosed as immunoglobulin4-related diseases (IgG4-RD) based on hyper-IgG4-emia and IgG4-positive cell infiltration to the lesion, was referred to our department due to recurrent symptoms despite corticosteroid therapies. Computed tomography revealed an osteoclastic sinus mass with prominent neutrophil infiltration and necrosis that was incompatible with IgG4-RD histopathologically. Finally, she was diagnosed with a tumefactive fibroinflammatory lesion (TFIL) of the head and neck and treated with high-dose corticosteroids. Physicians should remember that TFIL can mimic IgG4-RD in the head and neck region with prominent neutrophil infiltration and necrosis.

DOI： 10.2169/internalmedicine.9760-22

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Severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome and multiple organ dysfunction, in which the host immune response plays a pivotal role. Excessive neutrophil activation and subsequent superfluity of neutrophil extracellular traps (NETs) can lead to tissue damage, and several studies have shown the involvement of neutrophils in severe COVID-19. However, the detailed responses of each neutrophil subset to SARS-CoV-2 infection has not been fully described. To explore this issue, we incubated normal-density granulocytes (NDGs) and low-density granulocytes (LDGs) with different viral titers of SARS-CoV-2. NDGs form NETs with chromatin fibers in response to SARS-CoV-2, whereas LDGs incubated with SARS-CoV-2 display a distinct morphology with condensed nuclei and moderate transcriptional changes. Based on these transcriptional changes, we suggest that AGO2 possibly plays a role in LDG regulation in response to SARS-CoV-2.

DOI： 10.1002/2211-5463.13500

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OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis where ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial necrosis occurs. Cyclophilin D (CypD) plays an important role in mediating cell necrosis and inflammation via opening of mitochondrial permeability transition pores (mPTP). Here, we examined the role of CypD in AAV pathogenesis. METHODS: In vitro, the role and mechanism of CypD in ANCA-stimulated neutrophils were assessed by immunostaining and electron microscopy. A comprehensive RNA sequencing analysis was performed on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, an-anti-MPO IgG-transfer AAV model or spontaneous AAV model mice were induced in CypD knockout or wild-type mice. RESULTS: In vitro, pharmacological and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species/cytochrome c release from the mitochondria. The analysis of RNA sequencing in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, and CypD deficiency reduced ANCA-induced alterations in gene expression. Furthermore, the upstream regulator analysis revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that CypD-dependent mPTP opening is associated with ANCA-induced neutrophil activation and NETosis. In both AAV models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSIONS: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.

DOI： 10.1002/art.42314

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Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by the infiltration of IgG4-positive plasma cells and fibrosis in organs throughout the body. IgG4-RD involvement in the gastrointestinal (GI) tract (IgG4-related GI disease; IgG4-GID) is rare, and the disease concept remains unclear. Generally, IgG4-GID has been reported with morphological changes, including ulcers, strictures, and submucosal tumors. Here, we report a case of IgG4-GID with persistent diarrhea and abdominal pain in which typical endoscopic findings were absent. This case suggests the unidentified clinical features of IgG4-GID.

DOI： 10.1016/j.gastha.2023.07.009

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DOI： 10.1101/2022.12.20.517740

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BACKGROUND: Tubarial glands (TGs) are a collection of unidentified salivary glands overlying the torus tubarius in the nasopharyngeal wall. Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibroinflammatory state that often has multiple organ involvement. Involvement of the head and neck, especially the salivary glands, is common in IgG4-RD. AIMS/OBJECTIVES: This study aimed to elucidate the clinical significance of TGs in IgG4-RD. MATERIALS AND METHODS: We investigated the local findings of TGs in ten patients with IgG4-RD. RESULTS: Nasopharyngeal endoscopic examination revealed oedematous swelling of the nasopharyngeal wall surrounding the TGs, which improved after steroid treatment. Moreover, sonotubometry showed a stenotic pattern in three out of seven patients with IgG4-RD. CONCLUSIONS AND SIGNIFICANCE: TGs may be involved in IgG4-RD. The swollen TGs may be responsible for obstructive Eustachian tube dysfunction. Further studies are required to clarify the clinical significance and physiological roles of TGs in IgG4-RD.

DOI： 10.1080/00016489.2022.2104368

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Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.

DOI： 10.1126/science.abo1984

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BACKGROUND: Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI). PATIENTS AND METHODS: Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics. RESULTS: The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets. CONCLUSION: Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA.

DOI： 10.1016/j.semarthrit.2022.151994

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

OBJECTIVES: Tubarial glands (TGs) are recently refocused gland tissues localized near the tori tubarius in the nasopharynx and their clinical relevance is not clear yet. IgG4-related disease (IgG4-RD) is a progressive fibrosing condition and salivary glands are well-affected lesions. The aim of the present study is to examine [18F]fluorodeoxyglucose ([18F]FDG) accumulation to the tori tubarius in IgG4-related disease (IgG4-RD). METHODS: 48 patients with IgG4-RD who underwent positron emission tomography (PET) scanning with [18F]FDG were included and semi-quantitative analysis of [18F]FDG accumulation to tori tubarius was performed along with the clinical features and histopathological analysis. RESULTS: Of the 48 patients, abnormal [18F]FDG accumulation (metabolic tumour volume ≥ 1) to tori tubarius was observed in 15 (31.3%), all of whom had lesions in other head and neck glands. IgG4-RD patients with abnormal [18F]FDG accumulation to tori tubarius showed swollen nasopharyngeal walls around tori tubarius and forceps biopsy of the lesion revealed acinar cells and IgG4-positive plasma cells histologically. Abnormal [18F]FDG accumulation (maximum standard uptake value, metabolic tumour volume and total lesion glycolysis) to tori tubarius correlated with higher IgG4 and lower IgA serum concentrations. CONCLUSIONS: Abnormal [18F]FDG accumulation to tori tubarius can be observed in patients with IgG4-RD and the abnormal [18F]FDG accumulation to tori tubarius can be a clue of TG involvement in IgG4-RD.

DOI： 10.1007/s12149-021-01691-8

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Type B insulin resistance syndrome (TBIR) is a rare disease characterized by refractory diabetes due to severe insulin resistance caused by anti-insulin receptor autoantibodies, and a standard treatment regimen for TBIR has not been established, leading to therapeutic difficulties and high mortality. Since TBIR is known to be associated with autoimmune diseases such as systemic lupus erythematosus (SLE), glucocorticoids are often used as key immunosuppressive agents. However, glucocorticoids have the potential to exacerbate the pathophysiology of TBIR by worsening insulin sensitivity, which leads to hyperglycemia and muscle wasting. Here, we report a case history of a 66-year-old man who was diagnosed as having TBIR in combination with SLE and Sjögren's syndrome with marked hyperglycemia, ketosis, and muscle wasting. He was successfully treated with combination therapy of double-filtration plasmapheresis (DFPP) and administration of the anti-CD20 monoclonal antibody rituximab without induction of glucocorticoid therapy while using a sensor-augmented insulin pump (SAP) to prevent hypoglycemia. Remission of diabetes was achieved without severe hypoglycemic events and his circulating insulin receptor antibodies became negative after seven months of initiation of these treatments. Based on the successful clinical courses of this case, our report suggests the possibility of an effective therapeutic regimen with DFPP and rituximab under the condition of the use of an SAP for a patient with TBIR without induction of glucocorticoids.

DOI： 10.3389/fendo.2022.997296

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DOI： 10.1093/qjmed/hcac101

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Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.

DOI： 10.1038/s41586-020-2797-4

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DOI： 10.1101/2020.04.03.024075

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Essentials The mechanism of antiphospholipid antibodies (aPL) production remains unclear. We investigated lymphocyte subset, single nucleotide polymorphisms (SNP), and aPL-producing cells. The increase of circulating plasmablasts was associated with type I interferon upregulation. Our novel ex vivo assay revealed circulating plasmablasts as a major source of aPL. SUMMARY: Background/objective Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). This study aimed to clarify the mechanism of aPL production. Methods T cell and B cell subsets were evaluated in peripheral blood mononuclear cells (PBMCs) of 26 primary APS (PAPS), 19 systemic lupus erythematosus-associated APS (SLE/APS) patients and 10 healthy controls. The SLE-related or APS-related single nucleotide polymorphisms (SNP) were analyzed in those patients. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1, and IFIT3 in PBMCs. The PBMCs obtained from APS patients were cultured ex vivo following depletion of CD20 positive or negative B cells and the culture supernatants were applied to aPL measurements. Results In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls. Genetic analysis revealed that the increase of plasmablasts was more pronounced in patients carrying a risk allele of toll like receptor (TLR) 7 SNP rs3853839. The IFN score was significantly higher in the risk allele carriers. Ex vivo experiments showed that aPL were present in the culture supernatant of PBMCs lacking CD20+CD19+ subset, but not in that of cells lacking CD20-CD19+ subset. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, the increase of plasmablasts was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel immunological therapeutic approach in the treatment of APS.

DOI： 10.1111/jth.14427

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Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.

DOI： 10.1016/j.cell.2019.05.010

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Recurrent pregnancy loss (RPL) is often considered idiopathic, however excessive complement activation has been observed in pregnancy related manifestations. Anti-C1q antibodies (anti-C1q) are associated with the activation of complement pathway in lupus patients, while it remains unclear in RPL. Firstly, we showed that both the prevalence and titre of anti-C1q were significantly higher in unexplained RPL than in healthy parous individuals. Secondly, we established the murine model of anti-C1q induced pregnancy loss using a monoclonal anti-mouse C1q antibody, JL-1. In mice treated with JL-1, high ratio of pregnancy loss and fetal growth restriction were frequently observed and complement activation occurred. C5a receptor (C5aR) blockade cancelled these pathogenic changes in mice treated with JL-1. In conclusion, our study reveals an association between the prevalence of anti-C1q and RPL. Additionally, our murine model has indicated that anti-C1q can induce reproductive failure, which might be ameliorated by therapy targeting the C5-C5aR axis.

DOI： 10.1016/j.clim.2019.04.005

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：{SAGE} Publications  

DOI： 10.1177/0961203318784654

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In patients with systemic lupus erythematosus (SLE), neuropsychiatric (NP) symptoms sometimes occur after administration of corticosteroids, making differential diagnosis between NPSLE and steroid-induced psychosis challenging for clinicians. The aim of this study was to clarify the characteristics of post-steroid NP disease (PSNP) in patients with SLE. Clinical courses of 146 patients with SLE and 162 with other systemic autoimmune diseases, all in the absence of NP manifestations on admission, were retrospectively analyzed. Forty-three NPSLE patients on admission (de novo NPSLE) were also investigated. All patients were consecutively recruited and treated with 40mg/day or more of prednisolone in Hokkaido University Hospital between April 2002 and March 2015. The prevalence of PSNP was strikingly higher in SLE patients than other systemic autoimmune diseases (24.7% vs. 7.4%, OR 4.09, 95% CI 2.04-8.22). As independent risk factors to develop PSNP in SLE patients, past history of mental disorder and the presence of antiphospholipid syndrome were identified using multiple logistic regression analysis. In patients with PSNP-SLE, mood disorder was significantly more frequent than in de novo NPSLE (47.2% vs. 20.9%, OR 3.38, 95% CI 1.26-9.04). Of PSNP-SLE patients, two-thirds were with one or more abnormal findings in cerebrospinal fluid, electroencephalogram, MRI or SPECT. Majority of our PSNP-SLE patients received intensified immunosuppressive treatments and experienced improvement in most cases. PSNP-SLE had better relapse-free survival than de novo NPSLE (p<0.05, log rank test). In conclusion, PSNP frequently occurred in patients with SLE and treated successfully with immunosuppressive therapy, indicating that NPSLE is likely to harbor patients with PSNP-SLE.

DOI： 10.1016/j.autrev.2016.03.017

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Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

DOI： 10.1073/pnas.1604178113

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DOI： 10.2340/00015555-1706

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Authorship：Lead author   Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.102.1461

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DOI： 10.1111/j.1365-2133.2011.10696.x

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A 66-year-old male with acute type adult T-cell leukemia that was refractory to chemotherapy underwent unrelated allogeneic bone marrow transplantation after non-myeloablative conditioning with fludarabine, busulfan and total body irradiation. During an episode of neutropenia on day 12 after transplantation, pneumonia and sepsis due to multi-drug resistant Pseudomonas aeruginosa developed. Drug susceptibility tests demonstrated resistance to all kinds of intravenous antibiotics available for P. aeruginosa in Japan. Multi-drug susceptibility tests by the breakpoint-checkerboard plate method were then performed and combination therapy with meropenem hydrate and colistin was started based on the test results. After starting treatment, clinical symptoms and laboratory data immediately improved and engraftment of neutrophils was achieved on day 18. Infections with multi-drug-resistant P. aeruginosa are often critical for patients after hematopoietic stem cell transplantation and are difficult to control. In this paper, we report a case of severe multi-drug-resistant P. aeruginosa infection that was successfully treated by combination therapy selected using the breakpoint-checkerboard plate method.

DOI： 10.11406/rinketsu.52.118

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DOI： 10.1111/j.1365-2133.2008.08983.x

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Language：Japanese   Publisher：東京 : 日本臨床社  

Other Link:： https://ndlsearch.ndl.go.jp/books/R000000004-I033352998

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Other Link:： https://ndlsearch.ndl.go.jp/books/R000000004-I033070838

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【背景と目的】免疫抑制状態におけるサイトメガロウイルス（CMV）感染症は致死的な感染症の一つである．その主要臓器病変であるCMV胃腸炎をまとめた報告は少ないため臨床像を検討した．【方法】2011年4月から2017年5月までに当院で病理学的にCMV陽性の消化管病変を認め，抗ウイルス薬で治療した自己免疫疾患・血液疾患（炎症性腸疾患を除く）を持つ患者を対象とした．背景因子，血液検査，病変の形態，治療内容を後向きに検討した．治癒後再発なく経過したものを予後良好，病理学的診断後に再発・死亡したものを予後不良とした．【結果】当該症例は24例で，男性14例，年齢中央値69［49-86］歳であった．16例が予後良好，8例が予後不良でうち2例が診断後60日以内に死亡した．背景疾患は関節リウマチ，血管炎，その他が8，5，11例であった．初発症状は腹痛が最多で，穿孔は1例，無症状は6例あった．病変部位は胃が14例，十二指腸，回腸，結腸，直腸が3，2，3，2例であった．内視鏡的所見では深い潰瘍が9例，発赤が17例，辺縁のびらんが20例，円形・直線状が11例，白苔ありが19例，多発が21例であった．血液検査ではリンパ球数やAlb，IgGが低値であった．治療薬はガンシクロビルが23例で使用された．全治療期間は中央値が15日で，9例で維持治療が行われた．18例が初期治療後内視鏡を施行され，5例が治癒確認後再燃していた．【結語】サイトメガロウイルス胃腸炎の臨床像に関して検討を行った．

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J01882&link_issn=&doc_id=20171006410111&doc_link_id=%2Fdy4jjoci%2F2017%2F004004%2F112%2F0303-0303%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2017%2F004004%2F112%2F0303-0303%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.40.303c

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【目的】骨塩量減少と動脈硬化との関連が指摘されている（Ye C et al. <i>PLoS One</i> 2016）．全身性エリテマトーデス（SLE）における動脈硬化の進展因子を検討する．【方法】2012年1月から2016年4月に当科外来を受診した全SLE患者のうち，経時的に動脈硬化性病変を評価した連続84（女性74）例を対象とした．動脈硬化性病変は，頚部血管エコー検査により頚動脈プラーク，内膜中膜複合体厚（IMT）を評価し，骨塩定量は腰椎（L2-4）においてDual-Energy X-ray Absorptiometry法で測定した．動脈硬化進展を平均最大IMTの10％以上の増加かつプラークスコア（頚動脈プラーク径の総和）の増加と定義し，初回検査時の患者背景，臨床検査所見，骨塩量および治療薬との関連を後ろ向きに解析した．【結果】対象の年齢，罹病期間，SLEDAI-2Kの中央値［四分位範囲］は，43［36-54］歳，10［3-21］年，2［2-4］で，腰椎骨塩量（g/m²）は，0.98±0.15であった．頚部血管エコー検査は，26［23-29］ヶ月間隔で施行され，プラークスコアは，34例（41％）で増加し，平均最大IMTの変化率は6.5±18.3％であった．動脈硬化進展は12例（14％）に認められ，動脈硬化進展に関連する因子として，頚動脈プラークの存在（p = 0.001），リンパ球数（p = 0.01），骨塩減少（p = 0.01），抗リン脂質抗体陽性（p = 0.03）が抽出された．【結語】SLEにおける動脈硬化進展は，疾患特異的なリスク因子とともに骨塩量との関連が示唆された．

Other Link:： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01882&link_issn=&doc_id=20160905390118&doc_link_id=%2Fdy4jjoci%2F2016%2F003904%2F118%2F0385-0385%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2016%2F003904%2F118%2F0385-0385%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.39.385b

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【目的】ループス腎炎（LN）に対する寛解導入期におけるミコフェノール酸モフェチル（MMF）の短期的治療効果を検討する．【方法】当院で寛解導入治療としてMMFを投与されたLN患者の治療成績について後向きに解析した．完全寛解（CR）を尿蛋白0.5g/gCre未満かつ正常GFRもしくは正常GFR下限から90％以内への改善，部分寛解（PR）を尿蛋白3.5g/gCre未満への半減，かつ正常GFRもしくは正常GFR下限から90％以内への改善と定義した．【結果】全24例（女性20例）のうち，13例が前治療不応例もしくは再燃例であり，11例は初回寛解導入例であった．全例の治療開始1，3，6ヶ月後のCR達成率は，それぞれ17％（4/24），33％（8/24），43％（10/23）であった．初回寛解導入例の1，3，6ヶ月後のCR達成率はそれぞれ27％（3/11），64％（7/11），80％（8/10）であり，PR達成率は1，3，6ヶ月で45％（5/11），91％（10/11），100％（9/9）であった．6ヶ月時点での治療抵抗性に関連する因子として尿蛋白 ≥ 3.5g/g・Cr（p = 0.019），CH50低値（p = 0.046），SLEDAI-2K高値（p = 0.023），V型を含む腎生検所見の既往（p = 0.040），前治療不応（p = 0.003）が挙げられた．【結語】LNの初回寛解導入治療としてMMFの治療成績は良好であり，再発・難治例に対してもMMFが有効である症例が存在する．また初回寛解導入例ではMMF治療開始後，比較的早期から効果発現が期待できる．

Other Link:： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01882&link_issn=&doc_id=20160905390119&doc_link_id=%2Fdy4jjoci%2F2016%2F003904%2F119%2F0386-0386%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2016%2F003904%2F119%2F0386-0386%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.39.386a

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【目的】抗核抗体検査の間接蛍光抗体法（以下IF法）は多くの施設で実施されているが，健常人でも陽性となるケースが増えている．今回我々はIF法のカットオフ値について検討を行なったので報告する．【検討内容】健康検診検査で協力検診者531名（女性474名 平均37.9歳，男性57名 平均42.6歳）とELISA法でSSA，SSB，RNP，Sm，dsDNAのいずれかが陽性となった438名の患者血清を用い通常通りIF法を実施した．尚，IF法はMBL社のフルオロHEPANAテストを使用し，落射蛍光顕微鏡BX50-34-FLA-2を用いて3名で判定を行った．【結果】健診者ではIF法抗体価40倍で26.4%が陽性，抗体価80倍で16%が陽性であった．また陽性となった染色パターンは均一型のものが多かった．ELISA法陽性の患者血清では殆んどがIF法抗体価80倍以上であった．SSAやdsDNA陽性患者で抗体価40倍が比較的多く認められたが，その多くは治療中で経過も良好な症例であったが，初診の症例も少数存在した．【考察】今回の検討からはIF法の健常人における特異度は抗体価40倍で74%，抗体価80倍で84%であり，ELISA法で陽性となった各種疾患における感度の平均は抗体価40倍で93.6%，抗体価80倍で88.7%であった．以上からカットオフ値は抗体価40～80倍の間が適当であると考えられた．カットオフ値を抗体価80倍まで引き上げるのにはまだ問題があるため，健常人でも抗体価40倍では約1/4が陽性となることを理解しておく必要がある．<br>

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J01882&link_issn=&doc_id=20131106410142&doc_link_id=%2Fdy4jjoci%2F2013%2F003605%2F08e%2F0407-0407%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2013%2F003605%2F08e%2F0407-0407%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.36.407b

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【目的】抗DNA抗体検査は膠原病，特にSLEの診断には極めて重要な検査である．今回我々はコスミック社製dsDNAのELISAキットを使用する機会を得たので臨床的な評価を中心に報告する．【検討内容】患者血清160症例（SLE79例，RA65例，その他16例）を用い，本キットのSLEでの感度，特異度，正診率についてA社のssDNA，dsDNA各ELISAキット，B社のRIA法と比較検討を行った．【結果】SLEでの感度，特異度，正診率は，本キットでは75.6%，84.1%，80.0%であり，A社dsDNAでは41.0%，95.1%，68.6%，A社ssDNAでは97.4%，3.7%，49.4%，B社RIA法では61.5%，72.5%，67.1%であった．またキット間の陽性・陰性結果の一致率は，本キットとA社dsDNAとでは69.4%，本キットとB社RIA法とでは76.3%，A社dsDNAとB社RIA法とでは70.6%であった．【考察】本キットはA社のキットやRIA法よりも感度や正診率ですぐれており，RIA法との一致率もA社より良好であった．また本キットは測定値の値が大きく設定されており，測定レンジも幅が広いことから陽性，陰性の区別が他社よりも明瞭になっていることも大きな特徴であった．【まとめ】本キットは感度，特異度，正診率ともに良好でSLEの診断には有用であると思われた．<br>

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J01882&link_issn=&doc_id=20131106410143&doc_link_id=%2Fdy4jjoci%2F2013%2F003605%2F08f%2F0408-0408%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2013%2F003605%2F08f%2F0408-0408%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.36.408a

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：北海道医学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：The Japanese Society for Clinical Rheumatology and Related Research  

Biologics for rheumatoid arthritis (RA) are new class of drugs that have been used since about 10 years ago. Abatacept is one of the biologics for RA with relatively low risk of infection; however, the long-standing safety of abatacept is not well known. In this paper, we will report an elderly Japanese RA patient with long-standing abatacept and methotrexate therapy became severe empyema by <i>Streptococcus intermedius</i>.<br>
    A 72-year-old woman with RA was suffering from severe dyspnea and right chest pain. The disease activity of RA was kept in check by abatacept and methotrexate for about six years. The radiological examination of the chest showed the capsuled pleural effusion on the right chest. A pleural cavity tube was inserted and pus with <i>Streptococcus intermedius</i> was drained. At first, the conservative therapy with antibiotics was performed, but it was ineffective and video-assisted thracolysis was carried out. During the thracolysis, there was a fistula on the right lower lobe and partial thorarectomy was performed. After the procedure, she became well.<br>
    As we know, there are no reports about primary empyema during abatacept therapy. Longstanding biologic therapy increases the risk of serious infections and the similar phenomena could be developed in the administration of abatacept. In our case, the empyema was caused by normal bacterial flora and abatacept was thought to relate to the pathogenesis of the empyema. We have to take note that the long-standing abatacept therapy would increase the risk of serious infections and would develop cases like ours.

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J02269&link_issn=&doc_id=20130725110008&doc_link_id=10.14961%2Fcra.25.125&url=https%3A%2F%2Fdoi.org%2F10.14961%2Fcra.25.125&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

DOI： 10.14961/cra.25.125

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Other Link:： http://id.nii.ac.jp/1599/00012948/

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Language：Japanese   Publisher：角化症研究会事務局  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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【背景】抗好中球細胞質抗体関連血管炎（AAV）において，血栓症は重篤な臓器病変の一つである．【目的】AAVにおける血栓症発症の危険因子を明らかにする．【方法】2000年1月から2012年12月の間で当科に入院し，副腎皮質ステロイド単剤あるいは免疫抑制剤との併用で治療を開始した初発のAAV（顕微鏡的多発血管炎，好酸球性多発血管炎性肉芽腫症，多発血管炎性肉芽腫症）の患者56例（女性39例，男性17例）を対象とした．血栓症の発症をエンドポイントとし，患者背景，初診時の疾患活動性，内服薬や動脈硬化促進因子などと血栓症との関連を後ろ向きに解析した．【結果】56例の年齢中央値は66歳（IQR 58-70歳），観察期間中央値は38ヶ月（IQR 11-57.5ヶ月）であった．10例（17.8%）が血栓症を発症し，その内訳は動脈血栓症4例（脳梗塞2例，眼動脈分枝閉塞症1例，網膜中心動脈閉塞症1例），静脈血栓症6例（深部静脈血栓症5例，下大静脈血栓症1例）であった．血栓症の危険因子について，Cox比例ハザードモデルを用いて多変量解析を行い，疾患活動性の指標であるfive factors score (FFS）1点以上（p=0.016），免疫抑制剤の非使用（p=0.010）が抽出された．【結語】初診時でのFFS1点以上は血栓症のリスクであった．免疫抑制剤の使用は，血栓症を予防する可能性が示唆された．<br>

DOI： 10.2177/jsci.36.406b

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&emsp;症例は21歳女性．20XX年3月25日から発熱，頭痛と両下肢に紫斑と紅色丘疹が出現した．その数日後には右4,5指の疼痛と運動困難，左下肢のしびれが出現した．4月11日に前医を受診し，下腿の皮膚生検では白血球破砕性血管炎の所見であった．プレドニゾロン（PSL）50 mgで治療が開始されたが皮疹と神経症状は改善せず，精査加療の目的に当科へ入院となった．神経伝導速度検査（NST）では右尺骨神経，左脛骨神経の振幅低下を認めた．下腿紫斑からの皮膚生検を再度行い，真皮下層の小動脈にフィブリノイド壊死を伴う血管炎の所見を認め，結節性多発動脈炎（PN）と診断した．入院後，左尺骨神経領域にも新たに知覚異常が出現しており，進行性の神経症状に対して寛解導入療法としてステロイドパルス療法とシクロフォスファミド間欠静注療法（IVCY）を開始した．治療開始後，皮疹およびNSTでの振幅低下において改善傾向を認めている．全身性血管炎の治療においてはステロイドとIVCYの併用による有効性が大規模臨床試験において確認されている．一方，中枢神経症状やその他の重要臓器病変を伴わず，末梢神経症状のみに限局した非全身性血管炎においては，ステロイド単剤での治療における再燃例は少なくない．進行性の神経症状を呈する血管炎に対しては，発症早期からの積極的な治療介入を行うことが神経学的予後を改善する上で重要であると考える．<br>

DOI： 10.2177/jsci.36.421b

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【背景】ループス腸炎は，全身性エリテマトーデス（SLE）患者に生じる腸炎のうち，感染性腸炎が除外され，下痢や腹痛などの臨床症状を呈し，画像上小腸病変を有するものとされる．免疫複合体が小動脈の血管壁に沈着し，血管炎が生じることが原因とされ，局所の虚血による粘膜浮腫や漿膜炎を起こす．ループス腸炎の疫学や病態は依然不明な点も多く，臨床的検討も少ない．<br> 【目的】当科におけるループス腸炎の特徴を明らかにする．<br> 【方法】2008年4月から2013年3月までの間に，当科でループス腸炎と診断された患者を後ろ向きに解析した．<br> 【結果】9名（女性8名，男性1名）のループス腸炎患者が抽出された．ループス腸炎診断時の年齢は33（18-41）歳，SLE発症からループス腸炎診断までの期間は1.9（0-15）年，観察期間は2.1（0.5-5.8）年であった．ループス腸炎の診断時のSLE disease activity indexは15（4-21）であり，腹水貯留5例（56%），胸水貯留2例（22%），膀胱炎を3例（33%）で合併していた．また，9例中3例（33%）で再発し，再発までの期間は，それぞれ5ヶ月，67ヶ月，67ヶ月であった．再発例と非再発例の臨床症状，検査所見を検討したところ，再発例では3例中2例で初発時に結腸，直腸粘膜浮腫を伴っていたが，非再発例では1例も結腸，直腸粘膜浮腫は認めなかった．<br> 【結語】9例のループス腸炎を経験した．初発時に結腸，直腸粘膜浮腫を伴う場合には再発に注意が必要と考えられた．<br>

DOI： 10.2177/jsci.36.408b

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Language：Japanese   Publisher：北海道医学会  

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Language：Japanese   Publisher：がんの子供を守る会  

Other Link:： https://search.jamas.or.jp/link/ui/2011331156

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Language：Japanese   Publisher：(NPO)日本小児がん学会  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2011&ichushi_jid=J00638&link_issn=&doc_id=20110901150007&doc_link_id=%2Fex9syoni%2F2011%2Fs04802%2F001%2F0140-0140%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fex9syoni%2F2011%2Fs04802%2F001%2F0140-0140%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：日本小児皮膚科学会  

先天性厚硬爪甲症(PC)は稀なケラチン病の一つであり、発症に関与するケラチン遺伝子により1型と2型(PC-2)に分類される。PCの臨床像と遺伝学的特徴を概説すると共に、PC-2に特徴的な所見である多発性脂腺嚢腫の形成機序について最新の知見を述べた。PC-2家系における脂腺嚢腫の遺伝学的および組織学的検討により、その形成には、遺伝子変異によって生じた異常なケラチン蛋白が正常に機能せずに凝集していることが関わっていることが示唆された。

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Language：Japanese   Publisher：日本小児皮膚科学会  

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