Comparison of T-Cell Interferon-γ Release Assays for Mycobacterium tuberculosis-Specific Antigens in Patients with Active and Latent Tuberculosis

Through the use of QuantiFERON-TB Gold, a commercial IFN-γ assay, we compared differences in quantitative T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens [QuantiFERON TB-2G (QFT-2G)] between patients with active tuberculosis (TB) disease and those with latent TB infection (LTBI). The patient group consisted of 180 patients with active TB disease (culture-positive for MTB) and 50 screening contacts with LTBI-positive response to the QFT-2G test. We prospectively performed a tuberculin skin test (TST) and a QFT-2G test for all subjects. The median IFN-γ levels upon the application of both antigens, ESAT-6 and CFP-10, were significantly higher in patients with active TB disease than in those with LTBI. A combined positive response to both antigens occurred at a higher rate in patients with active TB disease than in those with LTBI. There were no significant relationships between the quantitative responses of IFN-γ to both antigens and the maximum induration on TST in both patient groups. We demonstrated significant differences in the quantitative responses of IFN-γ to MTB between patients with active TB disease and those with LTBI in this study. However, there was an overlap in the IFN-γ levels between active TB disease and LTBI groups. Therefore, it would be difficult to use the QFT-2G test to completely discriminate active TB disease from LTBI

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

食事性肥満から肝炎発症に関わる制御因子の同定 --中鎖脂肪酸油による予防・GPR84標的NASH治療薬の可能性--. 京都大学プレスリリース. 2023-01-18.Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH

Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti–Programmed Cell Death-1 Therapy in NSCLC

Introduction: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits. Methods: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8+ T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004). Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers

Isolation and characterization of human lung cancer antigens by serological screening with autologous antibodies

Serological analysis of a recombinant cDNA expression library (SEREX) derived from two lung adenocarcinoma cancer cell lines using autologous sera led to the isolation of 41 positive cDNA clones comprising 28 different antigens. They coded for a variety of nuclear and cytoplasmic proteins. Among the antigens, nucleoporin 107 (NUP107) was isolated most frequently (5 of 41 clones). The second most frequently isolated antigen was coded for by C21orf58 (4 of 41 clones). During serological analysis of selected antigens based on their reactivity to sera from normal individuals and lung cancer patients, none of the antigens showed a cancer-restricted recognition pattern. However, five genes including NUP107 showed higher expression when we examined the changes in gene expression in five different adenocarcinoma cell lines, including those used in SEREX, compared with their levels in normal lung tissues by cDNA microarray analysis. On the other hand, the expression levels of five genes including C21orf58 were down regulated in all adenocarcinoma cell lines. This SEREX study combining comprehensive gene expression assays has added to the growing list of lung cancer antigens, which may aid the development of diagnostic and immunotherapeutic reagents for patients with lung cancer

免疫抑制剤投与中に急性呼吸促迫症候群を合併した粟粒結核の１例

症例は75歳，女性．MPO-ANCA 関連血管炎に対して半年間，ステロイド薬が投与されていた．４日前から発熱，呼吸困難が出現，意識障害も伴ってきたため，当院を受診した．画像上，両側肺にびまん性の中枢側に有意な浸潤影とすりガラス陰影を認め，急性呼吸促迫症候群（ARDS）の合併を疑われた．人工呼吸管理となり，挿管中に採取した喀痰抗酸菌検査で塗抹陽性，結核菌PCR陽性の結果が得られ，血液や尿からも結核菌が検出され，粟粒結核によるARDS と診断した．治療は入院後の第３病日からINH ＋ RFP ＋ EB による抗結核療法を開始し，人工呼吸管理および血液透析をしながら経過観察をしていたが，播種性血管内凝固症候群も併発し，第14病日に死亡した．ARDS を合併する粟粒結核の症例も散見されることから，鑑別診断に粟粒結核も念頭におきながら診療することが重要と思われた．A 75-year-old woman, who was treated with corticosteroid therapy for six months for MPO-ANCA related vasculitis, visited to our hospital with fever, dyspnea and consciousness disturbance four days ago. She was diagnosed with acute respiratory distress syndrome (ARDS) from radiological findings such as diffuse bilateral hilar dominant infiltration shadow and ground-glass opacity. She was admitted to the intensive care unit (ICU) and put on mechanical ventilation for acute respiratory failure. The aspiration sputum after incubation turned out to be positive for acid-fast bacilli, which were identified as Mycobacterium tuberculosis (MTB) using a polymerase chain reaction test. As the same results in the clinical specimens of peripheral blood and urine were obtained, we made final diagnosis of miliary tuberculosis complicated with ARDS. Although we initiated the anti-tuberculosis treatment using INH, RFP, EB with mechanical ventilation and hemodialysis treatment, she died of multiple organ failure complicated with disseminated intravascular coagulation (DIC). Due to the fact, that we have encountered few cases of miliary tuberculosis complicated with ARDS, it is important that we suspect severe miliary tuberculosis in patients with immunosuppressive treatment

急速に増大する腫瘤影を呈した肺Mycobacterium avium症の1例

症例は66歳,男性.慢性閉塞性肺疾患とい草塵肺で経過観察をしていた.6カ月前の胸部CTでは明らかな異常を認めなかったが,新たに左上葉の気腫性病変周囲に腫瘤性病変を認めた.気管支鏡検査にて,局所検体からM.avium が検出されたものの生検で肉芽腫病変を認めなかったため,CTガイド下肺生検を実施した結果,肺MAC症と最終診断した.近年,孤立性腫瘤形成型肺MAC症の症例を散見するようになってきているが,本症例のごとく短期間で急速に増大することもあることから,抗酸菌を含めた肺感染症に対する積極的な検査が必要と思われる.A 66-year-old man was admitted to our hospital for follow-up on chronic obstructive pulmonary disease with a recent-showing abnormal chest shadow. He had received a periodic chest computed tomography (CT) six months prior due to a past history of COPD and Igusa pneumoconiosis. Although there was no mass shadow on the chest CT six months ago, a solitary tumorous shadow appeared surrounding the emphysematous lesions in the left upper lobe. M. avium was detected from local specimens viabronchoscopic examination, but because a granulomatous lesion was not observed, we performed a CT-guided lung biopsy and made a final diagnosis of pulmonary MAC disease. We recently observed that pulmonary MAC disease presents as a solitary tumorous shadow. However, as there are cases of pulmonary MAC disease presenting as a rapidly growing tumorous shadow within a short time, it is necessary to perform aggressive examinations for infectious diseases including an acid-fast bacilli examination