Publications by authors named "Atsushi Kumanogoh"

285 Publications

Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients.

J Exp Med 2021 12 14;218(12). Epub 2021 Oct 14.

Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864-882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2-specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.
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http://dx.doi.org/10.1084/jem.20211327DOI Listing
December 2021

Opposite response of lung adenocarcinoma and its choroidal metastases upon ramucirumab plus docetaxel therapy after immunotherapy: a case report.

Angiogenesis 2021 Sep 30. Epub 2021 Sep 30.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

We report a unique case of advanced non-small cell lung cancer that exhibited the opposite response to its unilateral choroidal metastases upon ramucirumab plus docetaxel treatment. A combination of cisplatin, pemetrexed, and pembrolizumab was administered as first-line treatment, resulting in shrinkage of all the lesions. However, although the patient was continued on a course of pembrolizumab, all the lesions had recurred approximately two months later. Ramucirumab plus docetaxel, administered as sequential treatment, resulted in maintained shrinkage of the choroidal lesions, yet all the other lesions progressed. Ramucirumab may be a suitable therapy for choroidal metastases, especially if administered immediately after immunotherapy.
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http://dx.doi.org/10.1007/s10456-021-09820-7DOI Listing
September 2021

COVID-19 in a patient with sporadic lymphangioleiomyomatosis awaiting lung transplantation.

Respir Med Case Rep 2021 3;34:101505. Epub 2021 Sep 3.

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.

Coronavirus disease 2019 (COVID-19) is an emerging viral disease with a mortality that depends on the individual's condition. Underlying comorbidities are major risk factors for COVID-19-related morbidity and mortality. However, information regarding the clinical course of COVID-19 in patients with rare respiratory system diseases is lacking. Here, we present a case of severe COVID-19 in a patient with advanced sporadic lymphangioleiomyomatosis (LAM) who was awaiting lung transplantation. She experienced a marked worsening of her respiratory status despite the limited size of the infiltrations seen on chest computed tomography. She responded to treatment with dexamethasone and remdesivir, and did not require mechanical ventilation. She recovered her pre-COVID-19 respiratory function. This case illustrates that patients with severe lung parenchymal destruction due to advanced LAM are at risk of worsening hypoxemia, but may not have a bad outcome if managed appropriately. Prevention and early diagnosis of COVID-19 are crucial in patients with advanced LAM. Future studies are needed to improve understanding of the clinical features and optimal treatment of COVID-19 in patients with LAM.
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http://dx.doi.org/10.1016/j.rmcr.2021.101505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413486PMC
September 2021

Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese.

Ann Rheum Dis 2021 Aug 23. Epub 2021 Aug 23.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

Objective: Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.

Methods: We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals ( =47, =203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.

Results: Via species level phylogenetic analysis, we identified and validated increases of and in the patients with SLE. Microbial gene analysis revealed increases of -derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with , an SLE-associated taxon.

Conclusion: Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.
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http://dx.doi.org/10.1136/annrheumdis-2021-220687DOI Listing
August 2021

Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats.

J Neuroinflammation 2021 Aug 21;18(1):181. Epub 2021 Aug 21.

Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain.

Methods: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases.

Results: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders.

Conclusion: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.
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http://dx.doi.org/10.1186/s12974-021-02232-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380350PMC
August 2021

IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity.

J Immunol 2021 09 11;207(5):1456-1467. Epub 2021 Aug 11.

Laboratory of Immunopathology, Immunology Frontier Research Center, World Premier International Research Center, Osaka University, Suita, Osaka, Japan;

Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-γ production by tumor-infiltrating CD8 T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.
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http://dx.doi.org/10.4049/jimmunol.2100076DOI Listing
September 2021

Distinct difference in tumor-infiltrating immune cells between Wilms' tumor gene 1 peptide vaccine and anti-programmed cell death-1 antibody therapies.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab091. Epub 2021 Jun 29.

Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Background: Wilms' tumor gene 1 (WT1) peptide vaccine and anti-programmed cell death-1 (anti-PD-1) antibody are expected as immunotherapies to improve the clinical outcome of glioblastoma. The aims of this study were to clarify how each immunotherapy affects tumor-infiltrating immune cells (TIIs) and to determine whether the combination of these two therapies could synergistically work.

Methods: Mice were transplanted with WT1 and programmed cell death-ligand 1 doubly expressing glioblastoma cells into brain followed by treatment with WT1 peptide vaccine, anti-PD-1 antibody, or the combination of the two, and survival of each therapy was compared. CD45 cells were positively selected as TIIs from the brains with tumors, and TIIs were compared between WT1 peptide vaccine and anti-PD-1 antibody therapies.

Results: Most mice seemed to be cured by the combination therapy with WT1 peptide vaccine and anti-PD-1 antibody, which was much better survival than each monotherapy. A large number of CD4 T cells, CD8 T cells, and NK cells including WT1-specific CD8 and CD4 T cells infiltrated into the glioblastoma in WT1 peptide vaccine-treated mice. On the other hand, the number of TIIs did not increase, but instead PD-1 molecule expression was decreased on the majority of the tumor-infiltrating CD8 T cells in the anti-PD-1 antibody-treated mice.

Conclusion: Our results clearly demonstrated that WT1 peptide vaccine and anti-PD-1 antibody therapies worked in the different steps of cancer-immunity cycle and that the combination of the two therapies could work synergistically against glioblastoma.
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http://dx.doi.org/10.1093/noajnl/vdab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331049PMC
June 2021

Cytomegalovirus infection in critically ill patients with COVID-19.

J Infect 2021 10 9;83(4):496-522. Epub 2021 Jul 9.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Osaka, Suita City 565-087, Japan.

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http://dx.doi.org/10.1016/j.jinf.2021.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268671PMC
October 2021

Imaging Assessment of Tumor Response in the Era of Immunotherapy.

Diagnostics (Basel) 2021 Jun 5;11(6). Epub 2021 Jun 5.

Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita City 565-0871, Osaka, Japan.

Assessment of tumor response during treatment is one of the most important purposes of imaging. Before the appearance of immunotherapy, response evaluation criteria in solid tumors (RECIST) and positron emission tomography response criteria in solid tumors (PERCIST) were, respectively, the established morphologic and metabolic response criteria, and cessation of treatment was recommended when progressive disease was detected according to these criteria. However, various types of immunotherapy have been developed over the past 20 years, which show novel false positive findings on images, as well as distinct response patterns from conventional therapies. Antitumor immune response itself causes 18F-fluorodeoxyglucose (FDG) uptake in tumor sites, known as "flare phenomenon", so that positron emission tomography using FDG can no longer accurately identify remaining tumors. Furthermore, tumors often initially increase, followed by stability or decrease resulting from immunotherapy, which is called "pseudoprogression", so that progressive disease cannot be confirmed by computed tomography or magnetic resonance imaging at a single time point. As a result, neither RECIST nor PERCIST can accurately predict the response to immunotherapy, and therefore several new response criteria fixed for immunotherapy have been proposed. However, these criteria are still controversial, and also require months for response confirmation. The establishment of optimal response criteria and the development of new imaging technologies other than FDG are therefore urgently needed. In this review, we summarize the false positive images and the revision of response criteria for each immunotherapy, in order to avoid discontinuation of a truly effective immunotherapy.
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http://dx.doi.org/10.3390/diagnostics11061041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226723PMC
June 2021

Neural guidance factors as hubs of immunometabolic crosstalk.

Int Immunol 2021 Jun 26. Epub 2021 Jun 26.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan.

Semaphorins were originally identified as axon-guidance molecules essential for neural development. In addition to their functions in the neural system, members of the semaphorin family have critical functions in many pathophysiological processes, including immune responses, bone homeostasis, cancer and metabolic disorders. In particular, several lines of evidence indicate that mammalian/mechanistic target of rapamycin (mTOR), a central regulator of cell metabolism, regulates the functions of semaphorins in various types of cells, revealing a novel link between semaphorins and cell metabolism. In this review, we discuss recent advances in the immunometabolic functions of semaphorins, with a particular focus on mTOR signaling.
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http://dx.doi.org/10.1093/intimm/dxab035DOI Listing
June 2021

Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease.

Proc Natl Acad Sci U S A 2021 Jun;118(26)

Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan;

Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that knockout ( ) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), redox-sensitive transcription factor, following HO stimulation. Conversely, overexpression inhibited nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.
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http://dx.doi.org/10.1073/pnas.2019167118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256015PMC
June 2021

Fatal cytomegalovirus pneumonia in a critically ill patient with COVID-19.

Respirol Case Rep 2021 Jul 8;9(7):e00801. Epub 2021 Jun 8.

Department of Respiratory Medicine and Clinical Immunology Osaka University Graduate School of Medicine Osaka Japan.

Coronavirus disease 2019 (COVID-19) can cause severe lymphopenia and respiratory failure requiring prolonged invasive mechanical ventilation (MV). COVID-19 patients with severe lymphopenia or respiratory failure are at risk of developing secondary infections. Here, we present the needle autopsy findings of a critically ill patient with COVID-19 who required reintubation and prolonged MV, and eventually died of secondary cytomegalovirus (CMV) pneumonia. This case highlights the potential risk of long-term steroid use and the need for routine monitoring for CMV infection in critically ill patients with COVID-19.
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http://dx.doi.org/10.1002/rcr2.801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185623PMC
July 2021

The lysosomal Ragulator complex plays an essential role in leukocyte trafficking by activating myosin II.

Nat Commun 2021 06 7;12(1):3333. Epub 2021 Jun 7.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Lysosomes are involved in nutrient sensing via the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is tethered to lysosomes by the Ragulator complex, a heteropentamer in which Lamtor1 wraps around Lamtor2-5. Although the Ragulator complex is required for cell migration, the mechanisms by which it participates in cell motility remain unknown. Here, we show that lysosomes move to the uropod in motile cells, providing the platform where Lamtor1 interacts with the myosin phosphatase Rho-interacting protein (MPRIP) independently of mTORC1 and interferes with the interaction between MPRIP and MYPT1, a subunit of myosin light chain phosphatase (MLCP), thereby increasing myosin II-mediated actomyosin contraction. Additionally, formation of the complete Ragulator complex is required for leukocyte migration and pathophysiological immune responses. Together, our findings demonstrate that the lysosomal Ragulator complex plays an essential role in leukocyte migration by activating myosin II through interacting with MPRIP.
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http://dx.doi.org/10.1038/s41467-021-23654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184920PMC
June 2021

Pulmonary artery hypertension prior to the relapse of adult-onset Still's disease.

Respirol Case Rep 2021 May 28;9(5):e00746. Epub 2021 Apr 28.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine Osaka University Osaka Japan.

Adult-onset Still's disease (AOSD) is a rare inflammatory autoimmune disorder characterized by fever, skin rash, and arthralgia. Pulmonary artery hypertension (PAH) rarely occurs with AOSD and has not been reported in the absence of typical symptoms of AOSD. A 33-year-old woman was admitted to our hospital with dyspnoea on exertion. Although she had not had symptoms of AOSD for 18 months before her admission, she presented with gradually progressing PAH. Because she had no typical symptoms of AOSD, she was treated with pulmonary vasodilators. However, her PAH did not improve. At one month after vasodilator treatment, she developed a high fever with elevation of ferritin. We determined that her AOSD had relapsed. Immunosuppressants were started and both her AOSD and PAH quickly improved. PAH may develop in the absence of typical symptoms of AOSD and immunosuppressants may be effective in such a case.
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http://dx.doi.org/10.1002/rcr2.746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080289PMC
May 2021

Comparison of efficacy between anti-IL-6 receptor antibody and other biological disease-modifying antirheumatic drugs in the patients with rheumatoid arthritis who have knee joint involvement: the ANSWER cohort, retrospective study.

Rheumatol Int 2021 Jul 26;41(7):1233-1241. Epub 2021 Apr 26.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.

Objective: We aimed to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) and other biologic disease-modifying antirheumatic drugs (bDMARDs), such as TNF inhibitor and CTLA4-Ig in the treatment of rheumatoid arthritis (RA) in patients with knee joint involvement.

Methods: We retrospectively analyzed 1059 treatment courses of patients with RA who visited our hospitals and were treated with bDMARDs. We categorized them into two groups, with or without knee joint involvement. We investigated the clinical disease activity index (CDAI) at baseline and 12 weeks after the initiation of bDMARDs. We compared the improvement of the markers between aIL-6 and other bDMARDs.

Results: Treatment with aIL-6 significantly increased ΔCDAI (n = 91, 15.4 ± 1.1; mean ± SEM) in patients with knee joint involvement, compared to other bDMARDs (n = 232, 11.0 ± 0.7) at 12 weeks (P = 0.006). Following the multivariate analysis adjusted by the CDAI levels at baseline, age, gender, concomitant use of methotrexate, and the first use of bDMARDs, ΔCDAI levels were significantly higher in aIL-6, compared to other bDMARDs (P = 0.02). However, there was no significant difference in ΔCDAI improvement between aIL-6 (n = 162, 5.9 ± 0.6) and other bDMARDs (n = 573, 6.2 ± 0.4) in patients without swollen knee joints. ΔCDAI levels were equally increased in patients with shoulder and elbow joint involvement.

Conclusion: aIL-6 was more effective in the patients with RA and knee joint involvement, compared to other bDMARDs.
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http://dx.doi.org/10.1007/s00296-021-04862-yDOI Listing
July 2021

Large-scale plasma-metabolome analysis identifies potential biomarkers of psoriasis and its clinical subtypes.

J Dermatol Sci 2021 May 26;102(2):78-84. Epub 2021 Mar 26.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan. Electronic address:

Background: Psoriasis is an immune-mediated skin disease for which the crosstalk between genetic and environmental factors is responsible. To date, no definitive diagnostic criteria for psoriasis yet, and specific biomarkers are required.

Objective: We performed metabolome analysis to identify metabolite biomarkers of psoriasis and its subtypes such as psoriatic arthritis (PsA) and cutaneous psoriasis (PsC).

Methods: We constructed metabolomics profiling of 130 plasma samples (42 PsA patients, 50 PsC patients, and 38 healthy controls) using a nontargeted metabolomics approach.

Results: Psoriasis-control association tests showed that one metabolite (ethanolamine phosphate) was significantly increased in psoriasis samples than in the controls, whereas three metabolites decreased (false discovery rate [FDR] < 0.05; XA0019, nicotinic acid, and 20α-hydroxyprogesterone). In the association test between PsA and PsC, tyramine significantly increased in PsA than in PsC, whereas mucic acid decreased (FDR < 0.05). Molecular pathway analysis of the PsA-PsC association test identified enrichment of vitamin digestion and absorption pathway in PsC (P = 1.3 × 10). Correlation network analyses elucidated that a subnetwork centered on aspartate was constructed among the psoriasis-associated metabolites; meanwhile, the major subnetwork among metabolites with differences between PsA and PsC was primarily formed from saturated fatty acids.

Conclusion: Our large-scale metabolome analysis highlights novel characteristics of plasma metabolites in psoriasis and the differences between PsA and PsC, which could be used as potential biomarkers of psoriasis and its clinical subtypes. These findings contribute to our understanding of psoriasis pathophysiology.
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http://dx.doi.org/10.1016/j.jdermsci.2021.03.006DOI Listing
May 2021

Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension.

Proc Natl Acad Sci U S A 2021 03;118(11)

Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, 564-8565 Suita, Japan;

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague-Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague-Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. -knockout ( ) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in rats, but not in rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4 IL-21 T cells and MRC1 macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.
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http://dx.doi.org/10.1073/pnas.2023899118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980441PMC
March 2021

Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres.

ERJ Open Res 2021 Jan 22;7(1). Epub 2021 Mar 22.

Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.

There is an unmet need for novel biomarkers in the diagnosis of multifactorial COPD. We applied next-generation proteomics to serum extracellular vesicles (EVs) to discover novel COPD biomarkers. EVs from 10 patients with COPD and six healthy controls were analysed by tandem mass tag-based non-targeted proteomics, and those from elastase-treated mouse models of emphysema were also analysed by non-targeted proteomics. For validation, EVs from 23 patients with COPD and 20 healthy controls were validated by targeted proteomics. Using non-targeted proteomics, we identified 406 proteins, 34 of which were significantly upregulated in patients with COPD. Of note, the EV protein signature from patients with COPD reflected inflammation and remodelling. We also identified 63 upregulated candidates from 1956 proteins by analysing EVs isolated from mouse models. Combining human and mouse biomarker candidates, we validated 45 proteins by targeted proteomics, selected reaction monitoring. Notably, levels of fibulin-3, tripeptidyl-peptidase 2, fibulin-1, and soluble scavenger receptor cysteine-rich domain-containing protein were significantly higher in patients with COPD. Moreover, six proteins; fibulin-3, tripeptidyl-peptidase 2, UTP-glucose-1-phosphate uridylyl transferase, CD81, CD177, and oncoprotein-induced transcript 3, were correlated with emphysema. Upregulation of fibulin-3 was confirmed by immunoblotting of EVs and immunohistochemistry in lungs. Strikingly, knockout mice spontaneously developed emphysema with age, as evidenced by alveolar enlargement and elastin destruction. We discovered potential pathogenic biomarkers for COPD using next-generation proteomics of EVs. This is a novel strategy for biomarker discovery and precision medicine.
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http://dx.doi.org/10.1183/23120541.00658-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983195PMC
January 2021

Greater reductions in blood flow after anti-angiogenic treatment in non-small cell lung cancer patients are associated with shorter progression-free survival.

Sci Rep 2021 03 24;11(1):6805. Epub 2021 Mar 24.

Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.

To evaluate tumor blood flow using O-water positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) before and after chemotherapy with bevacizumab, and to investigate the effects of bevacizumab on tumor blood flow changes and progression-free survival (PFS). Twelve patients with NSCLC were enrolled. Six patients underwent chemotherapy with bevacizumab and the other six without bevacizumab. O-water dynamic PET scans were performed within 1 week before the start of chemotherapy and within 1 week after the first day of chemotherapy. Tumor blood flow was analyzed quantitatively using a single one-tissue compartment model with the correction of pulmonary circulation blood volume and arterial blood volume via an image-derived input function. In the bevacizumab group, mean tumor blood flow was statistically significantly reduced post-chemotherapy (pre-chemotherapy 0.27 ± 0.14 mL/cm/min, post-chemotherapy 0.18 ± 0.12 mL/cm/min). In the no bevacizumab group, there was no significant difference between mean tumor perfusion pre-chemotherapy (0.42 ± 0.42 mL/cm/min) and post-chemotherapy (0.40 ± 0.27 mL/cm/min). In the bevacizumab group, there was a positive correlation between the blood flow ratio (tumor blood flow post-chemotherapy/tumor blood flow pre-chemotherapy) and PFS (correlation coefficient 0.94). Mean tumor blood flow decreases after bevacizumab administration and was positively correlated with longer PFS.
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http://dx.doi.org/10.1038/s41598-021-86405-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991665PMC
March 2021

Radioligand Assay-Based Detection of Antibodies against SARS-CoV-2 in Hospital Workers Treating Patients with Severe COVID-19 in Japan.

Viruses 2021 02 23;13(2). Epub 2021 Feb 23.

Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.

This study aimed to clarify whether infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is prevalent among the staff of a hospital providing treatment to patients with severe coronavirus disease 2019 (COVID-19) using radioligand assay (RLA). One thousand samples from the staff of a general hospital providing treatment to patients with severe COVID-19 were assayed for SARS-CoV-2 nucleocapsid protein (N) IgG using RLA. Nine patients with COVID-19 who had been treated in inpatient settings and had already recovered were used as control subjects, and 186 blood donor samples obtained more than 10 years ago were used as negative controls. Four of the 1000 samples showed apparently positive results, and approximately 10 or more samples showed slightly high counts. Interestingly, a few among the blood donor samples also showed slightly high values. To validate the results, antibody examinations using ELISA and neutralizing antibody tests were performed on 21 samples, and chemiluminescence immunoassay (CLIA) was performed on 201 samples, both resulting in a very high correlation. One blood donor sample showed slightly positive results in both RLA and CLIA, suggesting a cross-reaction. This study showed that five months after the pandemic began in Japan, the staff of a general hospital with a tertiary emergency medical facility had an extremely low seroprevalence of the antibodies against SARS-CoV-2. Further investigation will be needed to determine whether the slightly high results were due to cross-reactions or a low titer of anti-SARS-CoV-2 antibodies. The quantitative RLA was considered sensitive enough to detect low titers of antibodies.
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http://dx.doi.org/10.3390/v13020347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926924PMC
February 2021

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Nat Commun 2021 02 15;12(1):1032. Epub 2021 Feb 15.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
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http://dx.doi.org/10.1038/s41467-021-21011-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884840PMC
February 2021

Drug retention of sarilumab, baricitinib, and tofacitinib in patients with rheumatoid arthritis: the ANSWER cohort study.

Clin Rheumatol 2021 Jul 29;40(7):2673-2680. Epub 2021 Jan 29.

Department of Health and Sport Sciences, Osaka University, Graduate School of Medicine, Osaka, Japan.

Objectives: The aim of this multicenter, retrospective study was to clarify the retention rates of sarilumab (SAR), baricitinib (BAR), and tofacitinib (TOF) in patients with rheumatoid arthritis (RA).

Methods: Patients treated with either SAR (n = 62), BAR (n = 166), or TOF (n = 185) (females, 80.9%; age, 61.0 years; disease duration, 11.1 years; rheumatoid factor positivity, 84.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone dose, 5.3 mg/day [47.0%] and methotrexate dose, 8.8 mg/week [58.4%]; biologics- or Janus kinase inhibitors-switched cases 78.4%) were included. The reasons for drug discontinuation were classified into 4 major categories (lack of effectiveness, toxic adverse events, non-toxic reasons, and remission) by each attending physician. The drug retention rate was estimated at 18 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.

Results: The discontinuation rates of SAR, BAR, and TOF for the corresponding reasons were as follows, respectively: lack of effectiveness (15.7%, 15.6%, and 21.5%; P = 0.84), toxic adverse events (15.8%, 12.1%, and 12.3%; P = 0.35), non-toxic reasons (10.9%, 7.7%, and 6.8%; P = 0.35), and remission (0.0%, 2.8%, and 0.0%; P = 1.0). The overall retention rates excluding non-toxic reasons and remission were as follows: 68.8% for SAR, 72.5% for BAR, and 66.7% for TOF (P = 0.54).

Conclusions: After adjustment by potent confounders, SAR, BAR, and TOF showed similar discontinuation rates due to lack of effectiveness and toxic adverse events. Key Points • This is the first retrospective multicenter study that aimed to clarify the retention rates and reasons for discontinuation of SAR, BAR, and TOF in patients with RA.
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http://dx.doi.org/10.1007/s10067-021-05609-7DOI Listing
July 2021

Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis.

Cancer Res 2021 04 25;81(7):1813-1826. Epub 2021 Jan 25.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma. SIGNIFICANCE: This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137539PMC
April 2021

Integrative Analysis Reveals Common and Unique Roles of Tetraspanins in Fibrosis and Emphysema.

Front Genet 2020 10;11:585998. Epub 2020 Dec 10.

National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.

While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a "common core" of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.
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http://dx.doi.org/10.3389/fgene.2020.585998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793877PMC
December 2020

Oral intake of silica nanoparticles exacerbates intestinal inflammation.

Biochem Biophys Res Commun 2021 01 22;534:540-546. Epub 2020 Nov 22.

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan; Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan. Electronic address:

Nanoparticles, i.e., particles with a diameter of ≤100 nm regardless of their composing material, are added to various foods as moisturizers, coloring agents, and preservatives. Silicon dioxide (SiO, silica) nanoparticles in particular are widely used as food additives. However, the influence of SiO nanoparticle oral consumption on intestinal homeostasis remains unclear. The daily intake of 10-nm-sized SiO nanoparticles exacerbates dextran sulfate sodium (DSS)-induced colitis, whereas the daily intake of 30-nm-sized SiO nanoparticles has no influence on intestinal inflammation. The exacerbation of colitis induced by consuming 10-nm-sized SiO nanoparticles was abolished in mice deficient in apoptosis-associated speck-like protein containing a CARD (ASC). Our study indicates that the oral intake of small SiO nanoparticles poses a risk for worsening intestinal inflammation through activation of the ASC inflammasome.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.047DOI Listing
January 2021

Pulmonary metastases of lung adenocarcinoma mimicking COVID-19 pneumonia.

J Thorac Dis 2020 Oct;12(10):6125-6126

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.21037/jtd-20-2393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656342PMC
October 2020

PlexinA1 deficiency in BALB/cAJ mice leads to excessive self-grooming and reduced prepulse inhibition.

IBRO Rep 2020 Dec 22;9:276-289. Epub 2020 Oct 22.

Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.

PlexinA1 (PlxnA1) is a transmembrane receptor for semaphorins, a large family of proteins that act as axonal guidance cues during nervous system development. However, there are limited studies on PlxnA1 function in neurobehavior. The present study examined if PlxnA1 deficiency leads to behavioral abnormalities in BALB/cAJ mice. PlxnA1 knockout (KO) mice were generated by homologous recombination and compared to wild type (WT) littermates on a comprehensive battery of behavioral tests, including open field assessment of spontaneous ambulation, state anxiety, and grooming, home cage grooming, the wire hang test of muscle strength, motor coordination on the rotarod task, working memory on the Y maze alternation task, cued and contextual fear conditioning, anxiety on the elevated plus maze, sociability to intruders, and sensory processing as measured by prepulse inhibition (PPI). Measures of motor performance, working memory, fear memory, and sociability did not differ significantly between genotypes, while PlxnA1 KO mice displayed excessive self-grooming, impaired PPI, and slightly lower anxiety. These results suggest a crucial role for PlxnA1 in the development and function of brain regions controlling self-grooming and sensory gating. PlxnA1 KO mice may be a valuable model to investigate the repetitive behaviors and information processing deficits characteristic of many neurodevelopmental and psychiatric disorders.
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http://dx.doi.org/10.1016/j.ibror.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607060PMC
December 2020

Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review.

Thorac Cancer 2020 12 25;11(12):3625-3630. Epub 2020 Oct 25.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Combined small cell lung cancer (c-SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non-small cell carcinoma (NSCLC). Standard chemotherapy for patients with c-SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c-SCLC. However, little is known about anaplastic lymphoma kinase (ALK) rearrangement in c-SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK-positive c-SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR- or ALK-positive c-SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: • This is the first report describing the treatment course comprising immunochemotherapy and ALK-TKI in a patient with c-SCLC harboring ALK rearrangement. WHAT THIS STUDY ADDS: • Our case and literature review suggest that although ALK mutation is rare in patients with c-SCLC, its identification and treatment with ALK-TKIs may contribute to clinical benefits.
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http://dx.doi.org/10.1111/1759-7714.13716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705627PMC
December 2020
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