Showing papers by "Kenji Matsumoto published in 2019"

Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid.

Abstract: Background Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus clarification of the mechanisms that underlie regulation of ILC2 activation has received significant attention. Although innate lymphoid cells are divided into 3 major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T cells have not been well characterized. Objective We sought to determine the factors that induce regulatory innate lymphoid cells (ILCregs). Methods IL-10+ ILCregs induced from ILC2s by using retinoic acid (RA) were analyzed with RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissue from healthy subjects and patients with chronic rhinosinusitis with nasal polyps and lung tissue from house dust mite– or saline-treated mice. Results RA induced IL-10 secretion by human ILC2s but not type 2 cytokines. IL-10+ ILCregs, which were converted from ILC2s by means of RA stimulation, expressed a regulatory T cell–like signature with expression of IL-10, cytotoxic T lymphocyte–associated protein 4, and CD25, with downregulated effector type 2–related markers, such as chemoattractant receptor–homologous molecule on TH2 cells and ST2, and suppressed activation of CD4+ T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy subjects or lung tissue from saline-treated mice, but numbers were increased in nasal tissue from patients with chronic rhinosinusitis with nasal polyps and in lung tissue from house dust mite–treated mice. Enzymes for RA synthesis were upregulated in airway epithelial cells during type 2 inflammation in vivo and by IL-13 in vitro. Conclusion We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs.

Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts.

Abstract: Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.

Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion.

Abstract: Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion The incidence of MEF2D fusions overall was 24% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 533% relapse and subsequent death Stem cell transplantation was ineffective as salvage therapy Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features

IgE-class-specific immunosuppression in offspring by administration of anti-IgE to pregnant mice.

Abstract: Environmental events in early in life are critical to development of allergic diseases later in life. We found IgE-class-specific immunosuppression in offspring whose mothers had been administered anti-IgE during pregnancy.

Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity

Abstract: Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and -untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.

Allergy, depression and quality of life among pregnant women in the Japan Environment and Children’s Study (JECS)

Abstract: Erika Jensen-Jarolim, MD, Michael Kundi, Eva Untersmayr, Isabella Pali-Schoell, Berthold Reichardt, and Galateja Jordakieva; Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria, Medical University of Vienna, Vienna, Austria, Medical University of Vienna, Department of Pathophysiology and Allergy Research, Vienna, Austria, The Interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University of Vienna and University of Vienna, Austria, Vienna, Austria, Sickness Fund Burgenland, Eisenstadt, Austria. RATIONALE: Anti-ulcer drugs, such as proton pump inhibitors (PPI), are widely prescribed and used in developed countries worldwide. Recently concerns about the promotion of allergic sensitizations following gastric pH modulation have been raised in mechanistic and observational studies. We aimed to assess the frequency of anti-allergic drug prescription following gastric acid inhibitors use in a population-wide study in Austria. METHODS: In this cross-sectional study, age and gender controlled data from health insurance claim records between 2009 and 2013, covering 8.2 million subjects (approx. 97% of the Austrian population), were analyzed regarding prescriptions of i) gastric acid inhibitors (PPI, H2-receptor antagonists, sucralfate, prostaglandin E2) and anti-allergic medication (antihistamines, desensitization therapy). Other commonly prescribed drugs (lipid-modifying and antihypertensive substances) served as controls by Cox regression in a regional subgroup. RESULTS: Prescription of anti-allergic drugs following gastric acidinhibitors showed a rate ratio of 1.96 (95%CI:1.95-1.97) in overall Austrian data and 3.07 (95%-CI:2.89-3.27) in the regional data set, which wasmore prominent in women (P<0.001). Age and gender adjusted hazard ratio was found to be 2.05 (95%CI:1.91-2.19), and was elevated independent of prescribed gastric acid-inhibiting substances. Further, rate ratios increased from 1.47 (95%CI:1.45-1.49) in subjects <20 years of age, to 5.20 (95%-CI:5.15-5.25) in >60 year olds. CONCLUSIONS: The increased use of anti-allergy medication subsequent to gastric acid suppression suggests an association with the occurrence of allergic symptoms. Prescription of anti-ulcer drugs should be restricted to cases with clear indication and adequate diagnosis to minimize the risk for allergic comorbidities.