Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1183/23120541.00500-2023

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

DOI： 10.1007/s00277-023-05391-3

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：{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

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.jaci.2023.01.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Respiratory Society ({ERS})  

DOI： 10.1183/23120541.00033-2023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media {SA}  

<jats:p>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 <jats:italic>Sult2b1</jats:italic>-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in <jats:italic>Sult2b1</jats:italic>-deficient mice attenuated disease development. Similar results were obtained when the <jats:italic>Dock2</jats:italic> was genetically deleted in <jats:italic>Sult2b1</jats:italic>-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in <jats:italic>Sult2b1</jats:italic>-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.</jats:p>

DOI： 10.3389/fimmu.2023.1131146

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.celrep.2019.10.091

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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