記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ERJ Open Research  

DOI： 10.1183/23120541.00500-2023

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Hematology  

DOI： 10.1007/s00277-023-05391-3

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{eLife} Sciences Publications, Ltd  

<jats:p>Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.</jats:p>

DOI： 10.1101/2023.02.21.529383

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology  

Background: Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein–coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown. Objective: We aimed to elucidate whether—and if so, how—DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis. Methods: Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation. Results: Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation. Conclusion: DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis.

DOI： 10.1016/j.jaci.2023.01.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ERJ Open Research  

DOI： 10.1183/23120541.00033-2023

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Immunology  

During mucosal injury, intestinal immune cells play a crucial role in eliminating invading bacteria. However, as the excessive accumulation of immune cells promotes inflammation and delays tissue repair, it is essential to identify the mechanism that limits the infiltration of immune cells to the mucosal-luminal interface. Cholesterol sulfate (CS) is the lipid product of the sulfotransferase SULT2B1 and suppresses immune reactions by inhibiting DOCK2-mediated Rac activation. In this study, we aimed to elucidate the physiological role of CS in the intestinal tract. We found that, in the small intestine and colon, CS is predominantly produced in the epithelial cells close to the lumen. While dextran sodium sulfate (DSS)-induced colitis was exacerbated in Sult2b1-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in Sult2b1-deficient mice attenuated disease development. Similar results were obtained when the Dock2 was genetically deleted in Sult2b1-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in Sult2b1-deficient mice and was ameliorated by CS administration. Thus, our results uncover that CS acts on inflammatory neutrophils, and prevents excessive gut inflammation by inhibiting the Rac activator DOCK2. The administration of CS may be a novel therapeutic strategy for inflammatory bowel disease and non-steroidal anti-inflammatory drug-induced ulcers.

DOI： 10.3389/fimmu.2023.1131146

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Immunology  

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hiCCR2– monocyte populations in IPF. These CD14+ CD36hi CD84hi CCR2– subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+ B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+ TIGIT+ LAG3+ CD4+ T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

DOI： 10.3389/fimmu.2023.1145814

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：eLife  

Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

DOI： 10.7554/eLife.87288.1

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.celrep.2019.10.091

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The American Association of Immunologists  

<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Introduction</jats:title>
<jats:p>To establish immunological self-tolerance in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. In this study, we aimed to examine the possible roleof Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, in controlling Aire expression.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Material and methods</jats:title>
<jats:p>As conventional Jmjd6 KO mice die during perinatal period, 2DG-treated fetal thymi were prepared from the KO mice and control mice, and subjected to FACS analyses, immunohistochemical analyses and RNAseq analyses. The 2DG-treated fetal thymi were also grafted into C57BL/6 nude mice to examine its effect on self-tolerance induction in vivo. In addition, the conditional Jmjd6 KO mice (Foxn1-Cre Jmjd6lox/lox mice) were developed and crossed with a diabetes mouse model (OT1+RIP-mOVA+ mice) to analyze immunological tolerance under more physiological condition.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>Although Jmjd6 deficiency did not affect abundance of Aire transcript in mTECs, the intron 2 of Aire gene was not effectively spliced out in the absence of Jmjd6. As a result, the expression of mature Aire protein and TSAs were markedly reduced in Jmjd6-deficient mTECs, resulting in multi-organ autoimmunity when Jmjd6-deficient thymi were grafted into C57BL/6 nude mice. In addition, we found that TEC-specific deletion of Jmjd6 exacerbated development of autoimmune diabetes in a mouse model.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>Jmjd6 controls Aire protein expression in mTECs for induction of self-tolerance in the thymus.</jats:p>
</jats:sec>

DOI： 10.4049/jimmunol.202.supp.116.7