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

Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.

DOI： 10.1073/pnas.2302903120

PubMed

researchmap

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

BACKGROUND: Allergic rhinitis is a growing problem worldwide. Currently the only treatment that can modify the disease is antigen-specific immunotherapy, but its mechanism of action is not fully understood. OBJECTIVE: We comprehensively investigated the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. METHODS: We cultured peripheral blood mononuclear cells obtained both before and 1 year after initiating SLIT and used a combination of single-cell RNA sequencing and repertoire sequencing. To investigate biomarkers, we used cells from patients participating a phase 2/3 trial of SLIT tablets for Japanese cedar pollinosis and cells from outpatients with good and poor response. RESULTS: Antigen-stimulated culturing after SLIT led to clonal expansion of TH2 and regulatory T cells, and most of these CD4+ T cells retained their CDR3 regions before and after treatment, indicating antigen-specific clonal responses and differentiation resulting from SLIT. However, SLIT reduced the number of clonal functional TH2 cells but increased the trans-type TH2 cell population that expresses musculin (MSC), TGF-β, and IL-2. Trajectory analysis suggested that SLIT induced clonal differentiation of the trans-type TH2 cells differentiated into regulatory T cells. Using real-time PCR, we found that the MSC levels increased in the active SLIT group and those with good response after 1 year of treatment. CONCLUSION: The combination of single-cell RNA sequencing and repertoire analysis helped reveal part of the underlying mechanism: SLIT promotes the expression of MSC on pathogenic TH2 cells and suppresses their function. MSC may be a potential biomarker of SLIT for allergic rhinitis.

DOI： 10.1016/j.jaci.2022.06.024

PubMed

researchmap

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

BACKGROUND: Prognostic factors have yet to be established for patients with interstitial lung disease (ILD). We aimed to clarify whether the Charlson Comorbidity Index score (CCIS) could help predict disease prognosis in patients with ILD. METHODS: Among ILD patients treated between April 2013 and April 2017, we retrospectively assessed the relationship between baseline clinical parameters including age, sex, CCIS, ILD diagnosis, pulmonary function test results, and 3-year ILD-related events including cause-specific death and first acute exacerbation (AE). RESULTS: We assessed 180 patients (mean age, 74 years), all of whom underwent pulmonary function testing including percentage predicted diffusion capacity for carbon monoxide (%DLco). Underlying pathologies included idiopathic pulmonary fibrosis (IPF) in 57 cases, idiopathic nonspecific interstitial pneumonia (iNSIP) and collagen vascular disease-related interstitial pneumonia in 117 cases, and chronic hypersensitivity pneumonia (CHP) in 6 cases. A composite scoring system comprising IPF diagnosis, CCIS, and %DLco provided a favorable C-index (0.825) for predicting 3-year ILD-related events. The nomogram for 3-year prognosis revealed the largest contributions from CCIS, %DLco and IPF diagnosis. CONCLUSIONS: This composite scoring system accounting for IPF diagnosis, CCIS, and %DLco could provide a useful tool for predicting prognosis in relatively mild ILD patients tolerated to pulmonary diffusion capacity testing.

DOI： 10.21037/jtd-20-1302

PubMed

researchmap

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

The mechanisms underlying interstitial lung disease (ILD) are characterized by variable inflammation or fibrosis of the pulmonary interstitium. A negative heart sign (NHS) on 67Ga scintigrams of patients with ILD is due to considerably increased inflammatory activity in the lungs. We retrospectively analyzed relationships between NHS and established biomarkers of disease severity in patients with ILD. Among 81 consecutive non-smoking patients with ILD (mean age, 63 years) who had been hospitalized between April 2009 and October 2011, we selected 52 who had been assessed by 67Ga scintigraphy. We then evaluated relationships between NHS and blood biomarkers, pulmonary function and high-resolution computed tomography (HRCT). Among these 52 patients, 10 showed idiopathic pulmonary fibrosis and 42 had other ILD. Multivariate analysis with stepwise variable selection, serum surfactant protein (SP)-A (OR (odds ratio), 1.026; 95%CI (confidence interval), 1.003-1.050; P = 0.024) and inflammation index calculated from HRCT findings (OR, 1.358; 95%CI, 1.079-1.709; P = 0.009) were significant predictors of an NHS. Serum SP-A offered 85% sensitivity and 75% specificity for predicting NHS at an optimal cut-off of 45.8 ng/mL. Serum SP-A concentrations correlated positively with inflammation index (r = 0.344, P = 0.015). In conclusion, serum SP-A might serve as a surrogate biomarker for predicting an NHS in patients with ILD.

DOI： 10.18999/nagjms.82.3.499

PubMed

researchmap

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

BACKGROUND The incidence of solitary fibrous tumor of the pleura (SFTP) is less than 5% of all pleural tumors. It is important to determine whether the tumor is benign or malignant in deciding on treatment and estimating prognosis, but this can sometimes be difficult. CASE REPORT A 59-year-old woman with no prior medical history presented with a 4-month history of right back pain and dyspnea. Contrast-enhanced computed tomography revealed a giant oval mass with inhomogeneous intensities, and bloody pleural effusion in the right thoracic cavity, proved to be solitary fibrous tumor of pleura (SFTP) under the complete thoracoscopic resection. The resected tumor seemed to have several malignant features, including large size of tumor, inhomogeneous intensities, and pleural effusion due to intratumor hemorrhage; however, Ki-67 (MIB-I) proliferation index was less than 1%, with no recurrence seen within 2 year after symptom onset. CONCLUSIONS We managed a case of SFTP presenting both malignant and benign features. In patients with SFTP, multi-disciplinary discussion among the clinician, radiologist, and pathologist was considered to be needed for estimating disease prognosis.

DOI： 10.12659/AJCR.919639

PubMed

researchmap

Language：Japanese   Publisher：医歯薬出版(株)  

気道や肺組織における慢性炎症は、気管支喘息や慢性閉塞性肺疾患(COPD)、間質性肺疾患(ILD)などを代表とする多くの呼吸器疾患の病態形成に関わる。慢性炎症の発症には環境因子と遺伝的素因が重要であることが知られているが、病態形成に関わる分子機構はいまだ不明点が多い。持続する慢性炎症は肺組織の病的線維化につながり、臨床的に大きな問題となる。2型免疫応答は寄生虫感染時や組織修復において生体保護的に働くが、その過剰な活性化は慢性炎症や病的線維化につながることがわかってきた。本稿ではまず、有害な外的環境因子を感知するセンサーとしての気道上皮細胞の役割と、病原性2型免疫応答を介した慢性炎症や病的線維化の誘導機構について解説する。また本来、生体防御に役立つはずの免疫記憶が生体にとって有害な反応を起こしてしまう。病原性免疫記憶による慢性気道炎症や組織病的線維化の病態形成機構について、近年明らかになった知見を紹介する。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20220705010004&doc_link_id=issn%3D0039-2359%26volume%3D282%26issue%3D1%26spage%3D19&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D282%26issue%3D1%26spage%3D19&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap