Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

AIM: Elderly adults are at higher risk for severe COVID-19 infection. This multicenter, prospective cohort study assessed immunogenicity after COVID-19 vaccinations in elderly residents compared with staff in geriatric intermediate care facilities. Predictors of lower antibody titers were also examined. METHODS: Fifty-four residents and 117 staff who had received three doses of the COVID-19 mRNA vaccine between March 2021 and September 2022 were included. Anti-receptor binding domain antibody titers were measured 3-4 weeks and 6 months after the vaccinations. Adjusted geometric mean titers (GMT) were calculated using multivariable linear mixed effects models. RESULTS: After the first dose, residents had a significantly lower adjusted GMT than did staff (115 vs. 267 AU/mL, P < 0.01), whereas the adjusted GMT of residents was comparable to that of staff after the third dose (14 178 vs. 12 159 AU/mL, P = 0.63). However, 6 months later, the adjusted GMT of residents was less than half that of staff (1645 vs. 4302 AU/mL, P < 0.01). In residents, steroid users had a significantly lower adjusted GMT than did steroid nonusers. CONCLUSIONS: The third dose of mRNA vaccine boosted the immune response of elderly residents. However, their antibody titers, particularly in steroid users, were highly attenuated 6 months after the last vaccination. For this population, attention should be focused on additional vaccinations. Geriatr Gerontol Int 2025; 25: 588-597.

DOI： 10.1111/ggi.70028

PubMed

シャーガス病はラテンアメリカで重要な顧みられない熱帯病であり、感染経路としてサシガメ(Triatoma dimidiate)が広く知られている。本研究では、エルサルバドル全域14県で2018年12月～2019年9月に採取されたサシガメ1376匹を対象に、T.cruzi感染の有無と吸血源を調査した。PCRと顕微鏡検査で陽性と判定された135匹(9.8%)を解析対象とし、DNAを抽出後、NGSを用いた12S rRNA解析で吸血源を同定した。その結果、13種の脊椎動物が血液供給源として明らかになり、ヒト、イヌ、ニワトリ、ドブネズミなどが主要な吸血源であった。特にヒト由来DNAは135匹中90匹(67%)から検出され、地域ごとの検出率は33～83%であった。1匹あたり平均2.4種類の宿主血液が検出され、複数の吸血源を保持していた。低感染性宿主(ニワトリ、カエル、ハトなど)の割合が高い家庭では、T.cruzi感染率が低く(<33%)、高感染家庭(≧33%)と比較し有意に感染率が抑制されていた。ヒトとイヌ血液の共検出が多く、両者の間で感染伝播が頻繁に生じている可能性が示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe illness and mortality in patients with immunodeficiency. Although vaccination has been recommended, the induction of protective antibodies by immunization, and thus the disease-preventive effect, has proven insufficient in immunodeficient patients, especially in those with predominantly antibody deficiency. A monoclonal antibody combination of tixagevimab and cilgavimab (TIX/CIL) was developed as a pre-exposure prophylaxis (PrEP). In this study, we investigated the post-PrEP increase in antiviral antibody titers and detailed the breakthrough infections that occurred despite PrEP in Japanese immunodeficient patients who had received TIX/CIL. METHODS: Blood samples were collected before and after TIX/CIL administration between November 2022 and August 2023. Antibody titers against the S-protein of SARS-CoV-2 were measured to evaluate TIX/CIL-induced protection. Information regarding breakthrough infection, as evidenced by positive antigen and/or PCR tests, was collected. RESULTS: A significant increase in the anti-S antibody titer was observed in all 89 immunodeficient patients who had received TIX/CIL. However, 14 (16 %) patients experienced breakthrough SARS-CoV-2 infections, of which one died of respiratory failure. CONCLUSION: The shift in the SARS-CoV-2 circulating strain might have reduced the efficacy of TIX/CIL, leading to an increased number of breakthrough infections.

DOI： 10.1016/j.jiac.2024.12.006

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Background: Current influenza A vaccines primarily induce neutralizing antibodies targeting the variable hemagglutinin (HA) head domain, limiting their effectiveness against diverse or emerging influenza A virus (IAV) subtypes. The conserved HA stem domain, particularly the long α-helix (LAH) epitope, is a focus of universal vaccine research due to its cross-protective potential. Additionally, Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are recognized as important protective immune mechanisms. This study evaluated IgG responses to the HA head, stem, and LAH regions and assessed cross-reactive potential through neutralization, ADCC, and ADCP assays. Methods: IgG responses to the HA head, stem, and LAH regions were measured in vaccinated individuals. Functional assays were conducted for neutralization, ADCC, and ADCP to evaluate the association between antibody levels and immune function. Results: The results showed that HA head-specific IgG increased significantly after vaccination in 50 individuals, whereas stem-specific IgG increased by 72% and LAH-specific IgG by 12-14%. Among the induced antibody subclasses, IgG1 was predominantly increased. Neutralization titers were detected in viruses of the same strain as the vaccine strain, but not in classical or pandemic strains (H5N1, H7N9). HA stem-specific IgG1 antibody titers showed a significant correlation with ADCC/ADCP activity breadth, but no correlation was observed with neutralization breadth. Conclusions: These findings suggest that although current influenza vaccines can induce HA stem-targeted cross-reactive antibodies, their quantity may be insufficient for broad cross-protection, underscoring the need for improved vaccine strategies.

DOI： 10.3390/vaccines13020140

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Adults infected with Plasmodium spp. in endemic areas need to be re-evaluated in light of global malaria elimination goals. They potentially undermine malaria interventions but remain an overlooked aspect of public health strategies. METHODS: This study aimed to estimate the prevalence of Plasmodium spp. infections, to identify underlying parasite species, and to assess predicting factors among adults residing in an endemic area from the Democratic Republic of Congo (DRC). A community-based cross-sectional survey in subjects aged 18 years and above was therefore carried out. Study participants were interviewed using a standard questionnaire and tested for Plasmodium spp. using a rapid diagnostic test and a nested polymerase chain reaction assay. Logistic regression models were fitted to assess the effect of potential predictive factors for infections with different Plasmodium spp. RESULTS: Overall, 420 adults with an estimated prevalence of Plasmodium spp. infections of 60.2% [95% CI 55.5; 64.8] were included. Non-falciparum species infected 26.2% [95% CI 22.2; 30.5] of the study population. Among infected participants, three parasite species were identified, including Plasmodium falciparum (88.5%), Plasmodium malariae (39.9%), and Plasmodium ovale (7.5%) but no Plasmodium vivax. Mixed species accounted for 42.3% of infections while single-species infections predominated with P. falciparum (56.5%) among infected participants. All infected participants were asymptomatic at the time of the survey. Adults belonging to the "most economically disadvantaged" households had increased risks of infections with any Plasmodium spp. (adjusted odds ratio, aOR = 2.87 [95% CI 1.66, 20.07]; p < 0.001), compared to those from the "less economically disadvantaged" households. Conversely, each 1 year increase in age reduced the risk of infections with any Plasmodium spp. (aOR = 0.99 [95% CI 0.97, 0.99]; p = 0.048). Specifically for non-falciparum spp., males had increased risks of infection than females (aOR = 1.83 [95% CI 1.13, 2.96]; p = 0.014). CONCLUSION: Adults infected with malaria constitute a potentially important latent reservoir for the transmission of the disease in the study setting. They should specifically be taken into account in public health measures and translational research.

DOI： 10.1186/s12936-024-04881-7

PubMed

COVID-19に感染後60日以上の残存症状(long COVID)を認め、2021年1月18日～2023年2月13日に外来クリニックを受診した798例を対象に後ろ向き横断研究を行い、症状と合併症の関連性を評価した。COVID-19後に発生した合併症を特定し、既存疾患の増悪は除外した。対象患者は男性371例、女性427例で、年齢中央値は42歳であった。初診時の主な症状は、疲労(523例)、不安(349例)、意欲欠如(344例)であった(重複回答あり)。452例(57%)で合併症を認め、主なものは体位性頻脈症候群(115例)、頻脈のない体位性症候群(65例)、気分障害(60例)であった。緊急入院および手術を要した合併症は、肺血栓塞栓症、化膿性肩関節炎、小脳橋角部腫瘍、重症筋無力症、頸椎症性脊髄症であった。COVID-19後に発生した症状すべてをlong COVIDとして治療する必要はないことが示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: Evidence for the pathogenesis and treatment of postacute coronavirus disease 2019 (COVID-19) (long COVID) is lacking. As long COVID symptoms are predicted to have an impact on the global economy, clarification of the pathogenesis is urgently needed. Our experiences indicated that some symptoms were complicated by diseases established before the COVID-19 pandemic. METHODS: Using a retrospective, cross-sectional study, we aimed to evaluate the diseases complicating long COVID. Using the medical records of patients with confirmed COVID-19 exhibiting residual symptoms lasting ≥60 days postinfection who visited our clinic in January 2021-February 2023, we investigated the symptoms and diseases observed. We identified diseases that occurred after COVID-19 and excluded those that were exacerbations of existing diseases. RESULTS: During the first visit, the most common symptoms reported in a total of 798 patients were fatigue (523 patients), anxiety (349 patients), and lack of motivation (344 patients). Complicating diseases were observed in 452 patients (57%). There were 115, 65, and 60 patients with postural tachycardia syndrome, postural syndrome without tachycardia, and mood disorders, respectively. Some diseases requiring immediate treatment included pulmonary thromboembolism, purulent shoulder arthritis, cerebellopontine angle tumors, myasthenia gravis, and cervical myelopathy. CONCLUSION: Not all symptoms that occur after COVID-19 should be treated as long COVID. Similar to normal medical treatment, a list of differential diagnoses should be maintained based on symptoms to obtain definitive diagnoses.

DOI： 10.1002/jgf2.716

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: The challenges in culturing Treponema pallidum have hindered molecular-biological analysis. This study aims to establish a molecular epidemiological analysis of syphilis among Japanese men who have sex with men (MSM) and to investigate the relationship between bacteremia and associated pathophysiology. METHODS: We used whole blood specimens from syphilis-diagnosed individuals in Tokyo, collected between February 2019 and June 2022. All individuals were MSM, and most were people with HIV (97.2%). We used a multi-locus sequence typing (MLST) scheme for epidemiological analysis. Sequences for MLST (TP0136, TP0548, and TP0705) were obtained. RESULTS: Out of 71 whole blood samples, 26 samples (36.6%) were positive for TP0136, and we sequenced three loci for MLST in 22 samples (31.0%). The most frequently detected sequence type (ST) was ST3 (n = 9), followed by ST6 (n = 6). Phylogenetic analysis revealed that 12 samples belonged to the SS14-like group (60%), and 8 samples belonged to the Nichols-like group (40%). Treponema pallidum subsp. endemicum (TEN), the cause of bejel was detected in three samples (12%). There was a significant association between TP0136 detection rate and C- reactive protein (CRP) (77.0% at a cut-off:0.5 mg/dL). CONCLUSION: Both SS14-like and Nichols-like strains were circulating concurrently, and TEN could have been sexually transmitted among MSM with HIV. Elevated CRP may indicate the presence of the pathogen in the blood.

DOI： 10.1186/s12981-024-00663-y

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.

DOI： 10.1002/ehf2.14896

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.cmicom.2024.105042

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVE: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of SLE, though the underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients. METHODS: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, ELISA, immunoblotting and epitope mapping. RESULTS: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B-cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera. CONCLUSION: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis.

DOI： 10.1093/rheumatology/keae476

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Two SARS-CoV-2 XBB sub-variants, FL.1 and GE.1, have been increasing in prevalence worldwide, but limited information is available about their ability to evade the immune system. FL.1 and GE.1 are emerging Omicron XBB variants possessing additional mutations in the spike RBD raising concerns of increased neutralization escape. In this study, we assessed the neutralizing ability of eleven FDA-approved monoclonal antibody combinations against different Omicron variants, including BA.2.75, BA.2.76, BA.4/5, XBB.1.5, and CH.1.1. Among the eleven antibodies, Sotrovimab was the only antibody to show broad neutralization ability against XBB.1.5. However, Sotrovimab showed attenuated neutralization efficiency against recently emerging XBB sub-lineages EG.5, FL.1, and GE.1 compared to XBB.1.5. Additionally, XBB.1.5 seropositive convalescent sera displayed lower neutralization activity against EG.5, FL.1, and GE.1. Overall, our findings present enhanced immune evasion capacity of emerging XBB variants and emphasize the importance of continued monitoring of novel variants.

DOI： 10.1016/j.virol.2024.110067

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

To evaluate the antibody response following the initial four doses of mRNA vaccines (BNT162b2 or mRNA-1273) in SARS-CoV-2-naïve healthy adults and investigate factors influencing antibody titer increases, this prospective cohort study was conducted in Japan from March 2021. The study included participants who received either the 1st and 2nd doses (n = 467), 3rd dose (n = 157), or 4th dose (n = 89). Blood samples were collected before and up to 6 months after each dose, and anti-receptor-binding domain antibody levels were measured. Multivariate analysis (usin multiple linear regression or linear mixed models) revealed several factors significantly associated with higher post-vaccination antibody levels, including mRNA-1273 vaccine (after the 1st and 2nd dose), male gender (after the 3rd and 4th doses), younger age (after the 1st and 2nd dose), non-smoking status (after the 2nd dose), non-use of immunosuppressive agents (after the 1st dose), higher pre-vaccination antibody titers (after the 2nd, 3rd, and 4th doses), and higher post-vaccination fever (after the 2nd and 4th doses). Furthermore, longer intervals since the last dose were significantly associated with higher antibody levels after the 3rd and 4th doses. These findings provide valuable insights for optimizing vaccination strategies.

DOI： 10.1038/s41598-024-57931-0

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: Coronavirus disease 2019 (COVID-19) sequelae, also known as long COVID, can present with various symptoms. Among these symptoms, autonomic dysregulation, particularly postural orthostatic tachycardia syndrome (POTS), should be evaluated. However, previous studies on the treatment of POTS complicated by COVID-19 are lacking. Therefore, this study aimed to investigate the treatment course of long COVID complicated by POTS. METHODS: The medical records of patients who complained of fatigue and met the criteria for POTS diagnosis were reviewed. We evaluated the treatment days, methods and changes in fatigue score, changes in heart rate on the Schellong test, and social situation at the first and last visits. RESULTS: Thirty-two patients with long COVID complicated by POTS were followed up (16 males; median age: 28 years). The follow-up period was 159 days, and the interval between COVID-19 onset and initial hospital attendance was 97 days. Some patients responded to β-blocker therapy. Many patients had psychiatric symptoms that required psychiatric intervention and selective serotonin reuptake inhibitor prescription. Changes in heart rate, performance status, and employment/education status improved from the first to the last visit. These outcomes were believed to be because of the effects of various treatment interventions and spontaneous improvements. CONCLUSIONS: Our study suggests that the condition of 94% of patients with POTS complicated by long COVID will improve within 159 days. Therefore, POTS evaluation should be considered when patients with long COVID complain of fatigue, and attention should be paid to psychological symptoms and the social context.

DOI： 10.1002/jgf2.670

PubMed

起立性頻拍症候群(POTS)を合併したCOVID-19罹患後症状(後遺症)の治療経過を評価した。2021年1月～2022年5月に当外来クリニックを受診した15歳以上の患者のうち、COVID-19発症から2ヵ月以上疲労が続き、POTSの診断基準を満たした患者の診療録を調べた。治療日数、治療法、疲労スコアの変化、Schellong testの心拍数の変化、初回および最終来院時の社会的状況を評価した。POTS診断基準を満たした34例のうち追跡できた32例(中央値28歳、うち男性16例)を解析した。追跡期間は中央値159日で、COVID-19発症から初回来院時まで中央値97日であった。一部の患者はβ遮断薬治療に反応した。多くの患者は精神科の介入と選択的セロトニン再取り込み阻害薬の処方を要する精神症状を有した。初回来院時と比べて、最終来院時の心拍数、パフォーマンスステータス、勤務や登校状況には改善がみられた。以上より、COVID-19後に長期にわたり疲労を訴える患者ではPOTSの評価が必要であることが示唆された。

<p>RAS/mitogen activated protein kinase (MAPK) pathway dysregulation, triggered by germline mutations in the involved genes, leads to a congenital syndrome termed “RASopathy.” Each form of RASopathy expresses a unique clinical phenotype; however, they share a series of functional and morphological organ abnormalities, including cardiac malformations, specific facial features, skeletal abnormalities, and intellectual disabilities. Secondary hypertrophic cardiomyopathy is the characteristic cardiac phenotype of RASopathy; its presence is strongly associated with heart failure-related mortality and sudden death. Therefore, RASopathy-associated hypertrophic cardiomyopathy (RAS-CMP) is a disease of priority in pediatric cardiology. However, the complete picture of its pathogenesis remains to be elucidated. Along with the development of novel molecular therapeutics, improving the quality of RASopathy care through collaborations between basic research and clinical practice is significantly needed. This review aimed to introduce the current evidence surrounding RAS-CMP and outline the knowledge gaps that should be addressed. Moreover, from the viewpoint of biological analogies between RAS/MAPK-related cancers and RASopathies, we deepen our discussion of recently emerging clues for exploring novel therapeutic approaches to RASopathy care.</p>

DOI： 10.24509/jpccs.24-015

CiNii Research

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Age-associated differences in the effect of repetitive vaccination, particularly on memory T-cell and B-cell responses, remain unclear. While older adults (aged ≥65 years) exhibited enhanced IgG responses following COVID-19 mRNA booster vaccination, they produced fewer spike-specific circulating follicular helper T cells-1 than younger adults. Similarly, the cytotoxic CD8+ T-cell response remained diminished with reduced PD-1 expression even after booster vaccination compared with that in younger adults, suggesting impaired memory T-cell activation in older adults. In contrast, although B-cell responses in older adults were weaker than those in younger adults in the primary response, the responses were significantly enhanced upon booster vaccination, reaching levels comparable with that observed in younger adults. Therefore, while booster vaccination ameliorates impaired humoral immunity in older adults by efficiently stimulating memory B-cell responses, it may less effectively enhance T-cell-mediated cellular immunity. Our study provides insights for the development of effective therapeutic and vaccine strategies for the most vulnerable older population.

DOI： 10.3389/fimmu.2024.1455334

PubMed

Publishing type：Research paper (scientific journal)  

Abstract

Background

Chagas disease can lead to life-threatening cardiac manifestations. Regional factors, including genetic characteristics of circulating Trypanosoma cruzi (T. cruzi), have attracted attention as likely determinants of Chagas disease phenotypic expression and Chagas cardiomyopathy (CCM) progression. Our objective was to elucidate the differential transcriptomic signatures of cardiomyocytes resulting from infection with genetically discrete T. cruzi strains and explore their relationships with CCM pathogenesis and progression.

Methods

HL-1 rodent cardiomyocytes were infected with T. cruzi trypomastigotes of the Colombian, Y, or Tulahuen strain. RNA was serially isolated post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change ≥ 2 or ≤ 0.5) highlighted over-represented biological pathways. Intracellular levels of reactive oxygen species (ROS) were compared between T. cruzi-infected and non-infected HL-1 cardiomyocytes.

Results

We found that oxidative stress-related gene ontology terms (GO terms), ‘Hypertrophy model’, ‘Apoptosis’, and ‘MAPK signaling’ pathways (all with P &lt; 0.01) were upregulated. ‘Glutathione and one-carbon metabolism’ pathway, and ‘Cellular nitrogen compound metabolic process’ GO term (all with P &lt; 0.001) were upregulated exclusively in the cardiomyocytes infected with the Colombian/Y strains. Mean intracellular levels of ROS were significantly higher in the T. cruzi-infected cardiomyocytes compared to the non-infected (P &lt; 0.0001).

Conclusions

The upregulation of oxidative stress-related and hypertrophic pathways constitutes the universal hallmarks of the cardiomyocyte response elicited by T. cruzi infection. Nitrogen metabolism upregulation and glutathione metabolism imbalance may implicate a relationship between nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of Chagas cardiomyopathy.

DOI： 10.1186/s41182-023-00552-6

PubMed

Other URL： https://link.springer.com/article/10.1186/s41182-023-00552-6/fulltext.html

DOI： 10.1186/s41182-023-00551-7

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jvacx.2023.100412

PubMed

DOI： 10.1038/s41467-023-44266-z

PubMed

DOI： 10.1016/j.vaccine.2023.08.076

PubMed

DOI： 10.1089/ars.2021.0279

PubMed

DOI： 10.1016/j.jiac.2022.10.020

PubMed

DOI： 10.3389/fimmu.2023.1087473

PubMed

DOI： 10.1016/j.jiac.2022.09.018

PubMed

B細胞標的治療を受けたリンパ球系腫瘍患者におけるSARS-CoV-2ワクチンの免疫原性を前向きに監視した。2回目のBNT162b2 mRNAワクチン接種を受けた参加者から血清を採取し、抗スパイクIgGとIgAの抗体陽転率と抗体保有率を調べた。リンパ腫/白血病の患者12例中11例はリツキシマブを含むレジメン(RTX)、1例はブルトン型チロシンキナーゼ阻害薬(BTKi)によるB細胞標的療法を受けた。RTX/BTKi治療群は他のリンパ球系腫瘍患者(他群、n=5)と比べて有意に減弱した抗スパイク抗体を示した。RTX/BTKi群と他群の間の幾何平均抗スパイクIgG抗体価には280倍の差があった。RTX/BTKi群のIgG抗体陽転率33%(4/12)は他群の100%(5/5)より有意に低かった。更に、他群のIgG抗体保有率が20%(1/5)であったのに対してRTX/BTKi群では0%(0/12)であった。RTX/BTKi群のIgA抗体陽転率が8%(1/12)まで減少したことから、RTX/BTKi曝露患者におけるIgGからIgAへのクラススイッチ異常が示唆された。直近のRTX/BTKi投与からワクチン接種までの期間中央値は5.3ヵ月であった。ワクチン接種時にRTX/BTKi群で推奨リンパ球数を超えたのは抗体陽転者が75%(3/4)、非抗体陽転者は63%(5/8)であった。

DOI： 10.5334/gh.1207

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Cross-neutralizing capacity of antibodies against SARS-CoV-2 variants is important in mitigating (re-)exposures. Role of antibody maturation, the process whereby selection of higher affinity antibodies augments host immunity, to determine SARS-CoV-2 neutralizing capacity was investigated. METHODS: Sera from SARS-CoV-2 convalescents at 2-, 6-, or 10-months post-recovery, and BNT162b2 vaccine recipients at 3- or 25-weeks post-vaccination, were analyzed. Anti-spike IgG avidity was measured on urea-treated ELISAs. Neutralizing capacity was assessed by surrogate neutralization assays. Fold change between variant and wild-type neutralization inferred the breadth of neutralizing capacity. RESULTS: Compared with early-convalescence, avidity indices of late-convalescent sera were significantly higher (median 37.7 (interquartile range 28.4-45.1) vs. 64.9 (57.5-71.5), p < 0.0001). Urea-resistant, high-avidity IgG best predicted neutralizing capacity (Spearman's r = 0.49 vs. 0.67 (wild-type); 0.18-0.52 vs. 0.48-0.83 (variants)). Higher-avidity convalescent sera better cross-neutralized SARS-CoV-2 variants (p < 0.001 (Alpha); p < 0.01 (Delta and Omicron)). Vaccinees only experienced meaningful avidity maturation following the booster dose, exhibiting rather limited cross-neutralizing capacity at week-25. CONCLUSIONS: Avidity maturation was progressive beyond acute recovery from infection, or became apparent after the booster vaccine dose, granting broader anti-SARS-CoV-2 neutralizing capacity. Understanding the maturation kinetics of the two building blocks of anti-SARS-CoV-2 humoral immunity is crucial.

DOI： 10.1093/infdis/jiac492

PubMed

DOI： 10.1186/s40249-022-01008-5

PubMed

健康人の唾液蛋白質(SP)がアンジオテンシン変換酵素2(ACE2)に結合する能力を評価し、新型コロナウイルス(SARS-CoV-2)スパイク蛋白質S1(S1)受容体結合ドメインとACE2の間の結合に及ぼすSPの影響を測定した。SPはACE2に結合し、S1のACE2への結合を妨害し、S1-ACE2相互作用を阻害するカチオン性ヒストンH2Aと好中球エラスターゼを含む4種類のACE2結合性SPを同定した。ウシ胸腺ヒストン(CTH)もH2Aと同じく効果的に結合を阻害した。CTHはACE2発現宿主細胞へのSARS-CoV-2偽ウイルス性侵入を抑制した。ε-ポリ-L-リジンなどの合成ポリペプチドもS1-ACE2結合を妨害し、ACE2結合におけるSPの重要性が示された。以上より、正荷電のSPはACE2の負荷電表面をクローキングしてSARS-CoV-2の侵入に対する障壁になり、カチオン性ポリペプチドは新型コロナウイルス感染症に対する予防的・治療的手法になり得ると考えられた。

新型コロナウイルス(SARS-CoV-2)に対するmRNA COVID-19ワクチン接種後に自己免疫性血球減少を発症することが知られているが,成熟B細胞腫瘍患者のワクチン接種が腫瘍随伴症状へ与える影響を調べた報告はない。症例は71歳男性。数年前に成熟B細胞腫瘍を疑う症状があったが自然軽快し経過観察されていた。BNT162b2 mRNA COVID-19ワクチン2回目接種10日後に温式自己免疫性溶血性貧血を発症した。貧血はステロイドで改善したが,脾腫,IgM-M蛋白血症,腎障害が増悪した。診断・治療目的に脾臓摘出術を施行し,脾辺縁帯リンパ腫と診断され,M蛋白血症,腎障害は改善した。本症例でSARS-CoV-2特異的抗体の獲得は障害されていた。ワクチン接種後の非特異的な免疫賦活が,成熟B細胞腫瘍の腫瘍随伴症状を増悪させる可能性が示唆されたが,病態解明のためにさらなる症例集積が必要である。(著者抄録)

DOI： 10.1016/j.vaccine.2022.08.018

PubMed

DOI： 10.11477/mf.1542203069

CiNii Research

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an important determinant of protection from reinfection and of postvaccine immune responses. Herein, we conducted a follow-up analysis of health care workers previously infected with coronavirus disease 2019 (COVID-19) with the aim of evaluating different immunoassays for their capability in detecting the waning anti-SARS-CoV-2 immune responses and accuracy in documenting past SARS-CoV-2 infections. We evaluated serum antinucleocapsid antibody levels in convalescent individuals following a 1.5-year interval from SARS-CoV-2 infection. Three different commercial immunoassays that qualitatively measure serum antibodies targeting the SARS-CoV-2 nucleocapsid protein, namely, the Abbott Architect SARS-CoV-2 IgG, the Euroimmun anti-SARS-CoV-2 NCP enzyme-linked immunosorbent assay (ELISA) IgG, and the Roche Elecsys anti-SARS-CoV-2, were tested for comparison of detectability. A total of 38 individuals consented to participating in this follow-up analysis. From assay to assay, seropositivity rate at 18 months from infection varied from lowest at 42% to highest at 92%. The Roche Elecsys immunoassay, dependent on the dual-antigen antibody detection method and tuned for the detection of high avidity antibodies, was most capable of accurately documenting past SARS-CoV-2 infections. Different immunoassays showed variable capability of determining previous infection status under waning antibody concentrations. Immunoassays with lower detection limits are to be selected, and adjusted thresholds are to be considered in order to maximize the tests' performance. IMPORTANCE Past SARS-CoV-2 infection is an important determinant of protection from reinfection and of postvaccine immune responses. Our results show that different immunoassays, by design, harbor variable capability of tracking SARS-CoV-2 infection under waning antibody concentrations. With each recovered patient standing at a unique time point along the decline curve of antibodies, precise estimation of COVID-19 cumulative incidence remains a challenge. Since future surveillance studies will be targeting more than ever heterogenous cohorts, selecting the appropriate immunoassay is crucial in order to assure reliable decisions about an individual's previous infection status.

DOI： 10.1128/spectrum.00986-22

PubMed

DOI： 10.1093/jb/mvac054

PubMed

International / domestic magazine：International journal  

DOI： 10.1016/j.cmi.2022.06.020

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Recently, immune response to coronavirus disease (COVID-19) has attracted attention where an association between higher antibody titer and worsening disease severity has been reported. However, our experiences with severe COVID-19 patients with low antibody titers led to hypothesizing that suppressed humoral immune response may be associated with poorer prognosis in severe COVID19. In this study, antibody titers in severe COVID19 patients were measured at 7, 10, 12, and 14 days after onset. Patients were divided into survivors and non-survivors. SARS-CoV-2 IgM in survivors and non-survivors were 0.06 AU and 0.02 AU (P = 0.048) at 10 days, 0.1 AU and 0.03 AU (P = 0.02) at 12 days, and 0.17 AU and 0.06 AU (P = 0.02) at 14 days. IgG in survivors and non-survivors were 0.01 AU and 0.01 AU (P = 0.04) at 7 days, 0.42 AU and 0.01 AU (P = 0.04) at 12 days, and 0.42 AU and 0.01 AU (P = 0.02) at 14 days. Multivariate analysis showed better survival among patients with IgM positivity at 12 days (P = 0.04), IgG positivity at 12 days (P = 0.04), IgM positivity at 14 days (P = 0.008), and IgG positivity at 14 days (P = 0.005). In severe COVID-19, low antibody titers on days 12 and 14 after onset were associated with poorer prognosis.

DOI： 10.1038/s41598-022-12834-w

PubMed

DOI： 10.21203/rs.3.rs-1430985/v1

PubMed

DOI： 10.1002/ehf2.13771

PubMed

DOI： 10.1007/s10875-022-01308-3

PubMed

DOI： 10.2491/jjsth.33.338

CiNii Research

DOI： 10.1080/21645515.2022.2140549

PubMed

<p>There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient’s symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient’s serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.</p>

DOI： 10.11406/rinketsu.63.1379

PubMed

CiNii Research

DOI： 10.1253/circj.cj-21-0802

PubMed

CiNii Research

International / domestic magazine：International journal  

Serial antibody measurements using an array of SARS-CoV-2 immunoassays have demonstrated differing kinetics among assay platforms (1).….

DOI： 10.1128/JCM.02262-21

PubMed

<p>A 73-year-old man previously treated with rituximab for his mucosa-associated lymphoid tissue lymphoma suffered a suboptimal humoral immune response against an acquired SARS-CoV-2 infection. A detailed serological description revealed discrepant antigen-specific humoral immune responses. The titer of spike-targeting, "viral-neutralizing" antibodies remained below the detection level, in contrast to the anti-nucleocapsid, "binding" antibody response, which was comparable in both magnitude and kinetics. Accordingly, viral neutralizability and clearance was delayed, leading to prolonged RNAemia and persistent pneumonia. The present case highlights the need to closely monitor this unique population of recipients of B-cell-targeted therapies for their neutralizing antibody responses against SARS-CoV-2. </p>

DOI： 10.2169/internalmedicine.7884-21

PubMed

CiNii Research

DOI： 10.1128/Spectrum.00965-21

PubMed

症例は73歳男性で、食道の粘膜関連リンパ組織リンパ腫と診断され、リツキシマブを8回投与後、局所照射を行った。最終リツキシマブ投与の12週後、発熱と呼吸症状が出現し、SARS-CoV-2陽性が判明した。呼吸検体だけでなく血清もSARS-CoV-2陽性であったことから、SARS-CoV-2播種によるRNA血症が示唆された。胸部CT所見から、新型コロナウイルス感染症(COVID-19)H型が示唆された。重度呼吸障害のために機械的換気を行い、ファビピラビルとクロロキンによる併用療法を行ったが、明らかな有効性は得られなかった。高用量メチルプレドニゾロンにより換気パラメータが軽度に改善したが、一過性であった。イベルメクチン単回投与を行ったが、発症24日目の喀痰PCRは、依然としてSARS-CoV-2陽性であった。発症25日目の血清SARS-CoV-2特異的抗体検査では矛盾した結果が得られ、スパイク標的ウイルス中和抗体は検出レベル未満であったが、抗ヌクレオカプシド結合抗体の程度と動態は他の免疫正常重度COVID-19患者と同等であった。発症29日目、酸素化不良により死亡した。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

We describe the results of testing health care workers, from a tertiary care hospital in Japan that had experienced a coronavirus disease 2019 (COVID-19) outbreak during the first peak of the pandemic, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody seroconversion. Using two chemiluminescent immunoassays and a confirmatory surrogate virus neutralization test, serological testing revealed that a surprising 42% of overlooked COVID-19 diagnoses (27/64 cases) occurred when case detection relied solely on SARS-CoV-2 nucleic acid amplification testing (NAAT). Our results suggest that the NAAT-positive population is only the tip of the iceberg and the portion left undetected might potentially have led to silent transmissions and triggered the spread. A questionnaire-based risk assessment was further indicative of exposures to specific aerosol-generating procedures (i.e., noninvasive ventilation and airway suctioning) having mediated transmission and served as the origins of the outbreak. Our observations are supportive of a multitiered testing approach, including the use of serological diagnostics, in order to accomplish exhaustive case detection along the whole COVID-19 spectrum. IMPORTANCE We describe the results of testing frontline health care workers, from a hospital in Japan that had experienced a COVID-19 outbreak, for SARS-CoV-2-specific antibodies. Antibody testing revealed that a surprising 42% of overlooked COVID-19 diagnoses occurred when case detection relied solely on PCR-based viral detection. COVID-19 clusters have been continuously striking the health care system around the globe. Our findings illustrate that such clusters are lined with hidden infections eluding detection with diagnostic PCR and that the cluster burden in total is more immense than actually recognized. The mainstays of diagnosing infectious diseases, including COVID-19, generally consist of two approaches, one aiming to detect molecular fragments of the invading pathogen and the other to measure immune responses of the host. Considering antibody testing as one trustworthy option to test our way through the pandemic can aid in the exhaustive case detection of COVID-19 patients with variable presentations.

DOI： 10.1128/Spectrum.01082-21

PubMed

DOI： 10.1016/j.jiph.2021.08.023

PubMed

DOI： 10.1126/sciimmunol.abl4340

DOI： 10.1126/sciimmunol.abl4348

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: The gold standard for coronavirus disease (COVID-19) diagnosis has been the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA by nucleic acid amplification testing (NAAT). On the other hand, serological testing for COVID-19 may offer advantages in detecting possibly overlooked infections by NAAT. METHODS: To evaluate seroconversion of NAAT-negative pneumonia patients, immunoglobulin M (IgM) and IgG targeting the spike protein of SARS-CoV-2 were semiquantified by an immunofluorescence assay. Seroconversion was confirmed by another serological method, targeting the nucleocapsid protein. RESULTS: Eight suspected but unconfirmed COVID-19 pneumonia patients (median age, 39 years; range, 21-55) were included. The median period between symptom onset and NAAT sample collection was 6 days (2-27 days). None of them had tested positive for SARS-CoV-2 by NAAT. In contrast, all eight patients revealed seropositivity with the two serological methods, indicating actual seroconversion against SARS-CoV-2. The median period between onset and blood sampling was 26.5 days (7-51 days). CONCLUSION: Eight patients with COVID-19 pneumonia, initially tested negative for SARS-CoV-2 by NAAT, were finally confirmed of the diagnosis by serological testing. To cover the whole spectrum of this heterogenous infectious disease, serology testing should be implemented to the multitiered diagnostic algorithm for COVID-19.

DOI： 10.1002/jmv.26949

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>Recessive mutations in the Myosin regulatory light chain 2 (<i>MYL2</i>) gene are the cause of an infantile-onset myopathy, associated with fatal myocardial disease of variable macromorphology. We here present the first Japanese family affected with recessive <i>MYL2</i> myopathy. Affected siblings manifested typical features and the proband's autopsy findings were compatible with the diagnosis of noncompaction cardiomyopathy. The rapidly progressive clinical course of this recessive <i>MYL2</i> cardiomyopathy highlights the crucial role of c-terminal tails in MYL2 protein in maintaining cardiac morphology and function.</p>

DOI： 10.1536/ihj.20-639

PubMed

CiNii Research

症例は生後4ヵ月の女児で、ミオパチーの疑いで精査を目的に当院へ紹介された。生後1ヵ月に不規則な不随意運動が間歇的に出現し、神経学的検査で筋緊張低下を示唆するスカーフ徴候と踵耳徴候が陽性を呈した。顔面筋に異常はなかった。深部腱反射消失と定頸の遅れを認めた。臨床検査または骨格筋画像で異常は見られなかった。1ヵ月後の臨床検査で脳性ナトリウム利尿ペプチド(BNP)は149.2pg/mLであった。心エコー検査で左室駆出率は49%で、拡張不全を認めた。心電図で右脚ブロックを認めた。生後11ヵ月でBNPは5186pg/mLに増加し、左室駆出率は27%に低下した。心不全の増悪に対して集中治療管理を施行したが、治療の甲斐なく1ヵ月後に死亡した。遺伝学的検査でMYL2遺伝子の劣性変異(c.431_432del:p.P144Rfs*57)を認め、MYL2ミオパチーと診断した。姉も同様の遺伝子変異を有しており、生後8ヵ月で拡張型心筋症のため死亡していた。剖検で骨格筋にMYL2ミオパチーに典型的な所見を認めた。心臓は乳頭筋の形成が不明瞭で、肉柱層(NC)に比べて緻密層(C)が菲薄化しており、NC/Cは1.6であった。

International / domestic magazine：International journal  

DOI： 10.1016/j.jmii.2020.09.005

PubMed

International / domestic magazine：International journal  

DOI： 10.1002/jmv.26495

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

We used 2 commercially available antibody tests to estimate seroprevalence of severe acute respiratory syndrome coronavirus 2 infection in Japan during June 2020. Of 7,950 samples, 8 were positive by both assays. Using 2 reliable antibody tests in conjunction is an effective method for estimating seroprevalence in low prevalence settings.

DOI： 10.3201/eid2702.204088

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Variants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking. METHODS: By CRISPR-Cas9 genome editing, we generated lztr1-mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome. RESULTS: A frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss-of-function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome-associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue. CONCLUSION: Our novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss-of-function mechanism of disease-causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow-up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.

DOI： 10.1002/mgg3.1107

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Concomitant heart failure is associated with poor clinical outcome in dialysis patients. The arteriovenous shunt, created as vascular access for hemodialysis, increases ventricular volume-overload, predisposing patients to developing cardiac dysfunction. The integral function of mitochondrial respiration is critically important for the heart to cope with hemodynamic overload. The involvement, however, of mitochondrial activity or reactive oxygen species (ROS) in the pathogenesis of ventricular-overload-induced heart failure has not been fully elucidated. We herein report that disorganization of mitochondrial respiration increases mitochondrial ROS production in the volume-overloaded heart, leading to ventricular dysfunction. We adopted the murine arteriovenous fistula (AVF) model, which replicates the cardinal features of volume-overload-induced ventricular dysfunction. Enzymatic assays of cardiac mitochondria revealed that the activities of citrate synthase and NADH-quinone reductase (complex Ⅰ) were preserved in the AVF heart. In contrast, the activity of NADH oxidase supercomplex was significantly compromised, resulting in elevated ROS production. Importantly, the antioxidant N-acetylcysteine prevented the development of ventricular dilatation and cardiac dysfunction, suggesting a pathogenic role for ROS in dialysis-related cardiomyopathy. A cardioprotective effect was also observed in metformin-treated mice, illuminating its potential use in the management of heart failure complicating diabetic patients on dialysis.

DOI： 10.1016/j.jphs.2019.09.005

PubMed

Volume overloadによる心室機能不全モデルを用いて、ミトコンドリア活性酸素種(ROS)産生の分子メカニズムとROSの機能について検討した。VOL誘発性心室機能障害の基本的特徴を再現した動静脈瘻(AVF)マウスモデルを用いた。心臓ミトコンドリアの酵素アッセイにて、クエン酸シンターゼ-NADH-キノンレダクターゼ(complex I)の活性がAVF心臓内では維持されていた。一方、NADHオキシダーゼ超複合体の活性は顕著に障害され、ROS産生が増加していた。また、抗酸化物質のN-アセチルシステインは心室拡張と心機能障害を予防したことから、透析関連心筋症におけるROSの役割が示唆された。心保護効果はメトフォルミン(MET)処置マウスでも観察され、透析糖尿病患者の複合的心不全の管理におけるMETの有用性が示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>Myocardial infarction (MI) occurs when the heart muscle is severely damaged due to a decrease in blood flow from the coronary arteries. During recovery from an MI, cardiac fibroblasts become activated and produce extracellular matrices, contributing to the wound healing process in the damaged heart. Inappropriate activation of the fibroblasts leads to excessive fibrosis in the heart. However, the molecular pathways by which cardiac fibroblasts are activated have not yet been fully elucidated.</p><p>Here we show that serum deprivation, which recapitulates the cellular microenvironment of the MI area, strikingly induces collagen production in C3H/10T1/2 cells. Based on transcriptomic and pharmacological studies, we found that cell cycle perturbation is directly linked to collagen production in fibroblasts. Importantly, collagen synthesis is increased independently of the transcriptional levels of type I collagen genes. These results reveal a novel mode of fibroblast activation in the ischemic area, which will allow us to gain insights into the molecular mechanisms underlying cardiac fibrosis and establish a basis for anti-fibrotic therapy.</p>

DOI： 10.1536/ihj.18-710

PubMed

CiNii Research

心臓線維芽細胞活性化の分子機序について検討した。マウス線維芽細胞系C3H/10T1/2を、心筋梗塞(MI)後の細胞微小環境を再現した血清枯渇下で培養し、細胞外マトリックス産生に影響する成長因子または栄養素欠乏の影響について検討した。血清枯渇状態では、当該細胞におけるコラーゲン産生が顕著に促進され、血清枯渇線維芽細胞上澄みのコラーゲン含量はTGF-βで刺激した線維芽細胞よりも多かった。また当該細胞の遺伝子発現プロファイルにおよぼす血清枯渇の役割を、トランスクリプトーム解析と遺伝子発現解析により検討した結果、血清枯渇環境では709遺伝子の転写物レベルが減少し、260遺伝子の転写物レベルが情報制御されていた。またサイクリンA2、B2、ゲミニン遺伝子を含む細胞周期関連遺伝子の転写物レベルは、血清枯渇環境で有意に減少していた。さらに当該細胞の細胞周期阻害によるコラーゲン産生の検討から、細胞周期の攪乱は線維芽細胞のコラーゲン産生に直接関連し、特にコラーゲン合成はI型コラーゲン遺伝子の転写レベルとは無関係に増加していることが示された。虚血領域における線維芽細胞活性化の新たな様式が明らかとなった。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.

DOI： 10.1038/s41467-019-10859-w

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.1212/NXG.0000000000000319

PubMed

DOI： 10.1007/s10238-023-01057-6

PubMed

＜文献概要＞Point　●ワクチンと免疫学的検査は両者が表裏一体となって,感染症に対するpharmaceuticalな(医薬品を用いた)対策の一翼を担う.●ワクチン接種後に獲得免疫の検査を行う目的は,ワクチンが目指すところの防御レベル抗体価が適正に構築されたかを評価することにある.●臨床検査室における免疫学的検査法が多様化するなか,測定結果の標準化(ハーモナイゼーション)はますます重要な課題となっている.

DOI： 10.1186/s13054-021-03768-2

PubMed

J-GLOBAL

Presentation type：Oral presentation (general)  

Venue：Orlando  

Presentation type：Oral presentation (invited, special)