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Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice. 常染色体显性 LZTR1 突变导致 RAS 蛋白稳态失调,诱发小鼠出现类似努南综合征的表型。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/jci.insight.182382
Taiki Abe, Kaho Morisaki, Tetsuya Niihori, Miho Terao, Shuji Takada, Yoko Aoki

Leucine-zipper-like post translational regulator 1 (LZTR1) is a member of the BTB-Kelch superfamily, which regulates the RAS proteostasis. Autosomal dominant (AD) mutations in LZTR1 have been identified in patients with Noonan syndrome (NS), a congenital anomaly syndrome. However, it remains unclear whether LZTR1 AD mutations regulate the proteostasis of the RAS subfamily molecules or cause NS-like phenotypes in vivo. To elucidate the pathogenesis of LZTR1 mutations, we generated two novel LZTR1 mutation knock-in mice (Lztr1G245R/+ and Lztr1R409C/+), which correspond to the human p.G248R and p.R412C mutations, respectively. LZTR1-mutant male mice exhibit low birth weight, distinctive facial features, and cardiac hypertrophy. Cardiomyocyte size and the expression of RAS subfamily members, including MRAS and RIT1, were significantly increased in the left ventricles (LVs) of mutant male mice. LZTR1 AD mutants did not interact with RIT1 and functioned as dominant-negative forms of wild-type LZTR1. Multi-omics analysis revealed that the MAPK signaling pathway was activated in the LVs of mutant mice. Treatment with the MEK inhibitor trametinib ameliorated cardiac hypertrophy in mutant male mice. These results suggest that MEK/ERK pathway is a therapeutic target for NS-like phenotype resulting from dysfunction of RAS proteostasis by LZTR1 AD mutations.

亮氨酸-拉链样翻译后调节因子 1(LZTR1)是 BTB-Kelch 超家族的成员,它调节 RAS 蛋白稳态。在先天性异常综合征努南综合征(NS)患者中发现了 LZTR1 的常染色体显性(AD)突变。然而,目前仍不清楚 LZTR1 AD 突变是否会调节 RAS 亚家族分子的蛋白稳态或在体内导致类似于 NS 的表型。为了阐明LZTR1突变的发病机制,我们产生了两种新型LZTR1突变基因敲入小鼠(Lztr1G245R/+和Lztr1R409C/+),它们分别对应于人类的p.G248R和p.R412C突变。LZTR1突变雄性小鼠出生体重低、面部特征明显、心脏肥大。突变雄性小鼠左心室的心肌细胞大小和 RAS 亚家族成员(包括 MRAS 和 RIT1)的表达均显著增加。LZTR1 AD突变体不与RIT1相互作用,而是作为野生型LZTR1的显性阴性形式发挥作用。多组学分析表明,突变小鼠左心室中的MAPK信号通路被激活。用MEK抑制剂曲美替尼治疗可改善突变雄性小鼠的心肌肥厚。这些结果表明,MEK/ERK通路是LZTR1 AD突变导致的RAS蛋白稳态功能障碍所引起的NS样表型的治疗靶点。
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引用次数: 0
GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension. GCN2 激酶激活介导肺血管重塑和肺动脉高压。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1172/jci.insight.177926
Maggie M Zhu, Jingbo Dai, Zhiyu Dai, Yi Peng, You-Yang Zhao

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding general control nonderepressible 2 kinase, GCN2) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely in patients with PAH. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here, we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and patients with idiopathic PAH. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor pulmonary hypertension (PH) but inhibited hypoxia-induced PH. RNA-sequencing analysis suggested endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss-of-function mutations.

肺动脉高压(PAH)的特点是肺血管阻力进行性增加和重塑,从而导致右心衰竭。EIF2AK4基因(编码GCN2,即General control nonderepressibe 2 kinase)的隐性突变与患者的遗传性肺静脉闭塞症(PVOD)有关,但在PAH患者中却很少见(约1%)。GCN2 激酶激活在 PAH 发病机制中的作用仍不清楚。在这里,我们发现 GCN2 在缺氧小鼠、单克隆处理的大鼠和 PAH 患者的肺血管内皮细胞(ECs)中过度磷酸化和活化。意想不到的是,Eif2ak4-/-小鼠激酶结构域的遗传性破坏导致GCN2激酶活性丧失,既不会诱导PVOD,也不会诱导PH,但会抑制缺氧诱导的PH。RNA 测序分析表明,内皮素-1(Edn1)是 GCN2 的下游靶标。GCN2 通过 HIF-2α 介导缺氧诱导的人肺 EC 中 Edn1 的表达。恢复 Eif2ak4-/- 小鼠心血管细胞中 Edn1 的表达可部分逆转缺氧诱导的 PH 表型。此外,GCN2 激酶抑制剂 A-92 可减轻单克隆处理大鼠的 PAH。这些研究表明,GCN2 激酶激活至少部分通过 Edn1 介导了肺血管重塑和 PAH。因此,靶向 GCN2 激酶活化是治疗无 EIF2AK4 功能缺失突变患者 PAH 的一种很有前景的治疗策略。
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引用次数: 0
Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity. 经改造的细胞因子/抗体融合蛋白可改善 IL-2 向促炎细胞的输送,并促进抗肿瘤活性。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1172/jci.insight.173469
Elissa K Leonard, Jakub Tomala, Joseph R Gould, Michael I Leff, Jian-Xin Lin, Peng Li, Mitchell J Porter, Eric R Johansen, Ladaisha Thompson, Shanelle D Cao, Shenda Hou, Tereza Henclova, Maros Huliciak, Paul R Sargunas, Charina S Fabilane, Ondřej Vaněk, Marek Kovar, Bohdan Schneider, Giorgio Raimondi, Warren J Leonard, Jamie B Spangler

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

细胞因子工程学的进展正在克服这些蛋白质作为药物的局限性,从而推动治疗转化。白细胞介素-2(IL-2)细胞因子是一种很有希望用于癌症治疗的免疫刺激剂,但它同时激活促炎免疫效应细胞和抗炎调节性 T 细胞、大剂量时有毒性以及血清半衰期短等限制了它的作用。提高 IL-2 选择性、安全性和长效性的一种方法是与抗 IL-2 抗体复合,使细胞因子偏向于激活免疫效应细胞。虽然这种策略在临床前模型中显示出了潜力,但细胞因子/抗体复合物的临床转化因配制多蛋白药物的挑战和对复合物稳定性的担忧而变得复杂。在这里,我们引入了一种多功能方法来设计分子内组装的单药融合蛋白(免疫细胞因子,ICs),其中包括 IL-2 和一种可将细胞因子导向免疫效应细胞的偏向性抗 IL-2 抗体。我们优化了 IC 的结构,并设计了细胞因子/抗体亲和力,以改善免疫偏向性。我们证明,我们的集成电路能优先激活和扩增免疫效应细胞,从而获得比天然 IL-2 更强的抗肿瘤活性,无论是单独使用还是与免疫检查点抑制剂联合使用。此外,在观察到疗效的同时,还不会产生毒性。这项研究为细胞因子/抗体融合蛋白的设计和转化提供了路线图。
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引用次数: 0
T cell responses and clinical symptoms among infants with congenital cytomegalovirus infection. 先天性巨细胞病毒感染婴儿的 T 细胞反应和临床症状。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1172/jci.insight.171029
Alexandra K Medoro, Ravi Dhital, Pablo J Sánchez, Kaitlyn Flint, Brianna Graber, Traci Pifer, Rachelle Crisan, William C Ray, Christopher C Phelps, Jonathan R Honegger, Jing Peng, Ursula Findlen, Prashant Malhotra, Oliver Adunka, Masako Shimamura

BACKGROUNDCongenital cytomegalovirus (cCMV) infection can cause developmental impairment and sensorineural hearing loss (SNHL). To determine the relationship between immune responses to cCMV infection and neurologic sequelae, T cell responses were compared for their connection to clinical symptoms at birth and neurodevelopmental outcomes.METHODSThirty cCMV-infected and 15 uninfected infants were enrolled in a single-center prospective observational case-control study. T cell pp65-specific cytokine responses; CD57, CD28, and PD-1 expression; and memory subsets were compared.RESULTSInfected neonates (73% symptomatic at birth) lacked pp65-specific cytokine-secreting T cells, with elevated frequencies of CD57+, CD28-, and PD-1+CD8+ T cells and effector memory subsets. Though frequencies overlapped between cCMV symptom groups, asymptomatic infants had higher frequencies of CD57+PD-1+CD8+ T cells. Neonates with subsequent developmental delay lacked detectable CMV-specific T cell responses, with patterns resembling those of uninfected infants. Two children with progressive SNHL had high frequencies of PD-1+CD8+ T cells over the first year compared with children without progressive SNHL.CONCLUSIONSimilar to published reports, neonatal viral antigen-specific cytokine-secreting T cell responses were not detected, but overall patterns indicate that globally differentiated memory CD8+ T cell populations were induced by cCMV infection, with higher frequencies of terminally differentiated PD-1+CD8+ T cells potentially associated with asymptomatic infection. In this cohort, a lack of in utero T cell differentiation was associated with developmental delay, and high frequencies of PD-1+CD8+ T cells persisted only in children with progressive SNHL. Further work is needed to define the specificity of these T cells and their mechanistic connection to these outcomes.FUNDINGThis study was funded through an intramural research award at Nationwide Children's Hospital, the Pediatric Infectious Disease Society Fellowship Award funded by Stanley and Susan Plotkin and Sanofi Pasteur, the Abigail Wexner Research Institute at Nationwide Children's Hospital, and the Pichichero Family Foundation Vaccines for Children Initiative Research Award from the Pediatric Infectious Diseases Society Foundation.

背景先天性巨细胞病毒(cCMV)感染可导致发育障碍和感音神经性听力损失(SNHL)。为了确定 cCMV 感染的免疫反应与神经系统后遗症之间的关系,我们比较了 T 细胞反应与出生时临床症状和神经发育结果之间的关系。结果感染的新生儿(73% 出生时无症状)缺乏 pp65 特异性细胞因子分泌 T 细胞,CD57+、CD28- 和 PD-1+CD8+ T 细胞及效应记忆亚群的频率升高。虽然cCMV症状组之间的频率有重叠,但无症状婴儿的CD57+PD-1+CD8+ T细胞频率更高。随后出现发育迟缓的新生儿缺乏可检测到的CMV特异性T细胞反应,其模式与未感染婴儿相似。结论 与已发表的报告相似,未检测到新生儿病毒抗原特异性细胞因子分泌型 T 细胞反应,但总体模式表明 cCMV 感染诱导了全局分化的记忆性 CD8+ T 细胞群,终末分化的 PD-1+CD8+ T 细胞频率较高,可能与无症状感染有关。在该队列中,宫内 T 细胞分化的缺乏与发育迟缓有关,而高频率的 PD-1+CD8+ T 细胞仅在进展性 SNHL 患儿中持续存在。本研究由全美儿童医院的一项院内研究奖、Stanley and Susan Plotkin 和赛诺菲巴斯德资助的儿科传染病学会奖学金、全美儿童医院的 Abigail Wexner 研究所以及儿科传染病学会基金会的 Pichichero 家族基金会儿童疫苗倡议研究奖资助。
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引用次数: 0
An intranasally administered adenovirus-vectored SARS-CoV-2 vaccine induces robust mucosal secretory IgA. 鼻内注射腺病毒感染的 SARS-CoV-2 疫苗可诱导强大的粘膜分泌型 IgA。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1172/jci.insight.180784
Baoqing Sun, Qian Wang, Peiyan Zheng, Xuefeng Niu, Ying Feng, Weijie Guan, Si Chen, Jin Li, Tingting Cui, Yijun Deng, Zhangkai J Cheng, Yongmei Li, Xinke Zhou, Yi Fang, Wei Wang, Zhongfang Wang, Ling Chen, Nanshan Zhong

BACKGROUNDThe level of nasal spike-specific secretory IgA (sIgA) is inversely correlated with the risk of SARS-CoV-2 Omicron infection. This study aimed to evaluate the safety and immunogenicity of intranasal vaccination using Ad5-S-Omicron (NB2155), a replication-incompetent human type 5 adenovirus carrying Omicron BA.1 spike.METHODSAn open-label, single-center, investigator-initiated trial was carried out on 128 health care workers who had never been infected with SARS-CoV-2 and had previously received 2 or 3 injections of inactivated whole-virus vaccines, with the last dose given 3-19 months previously (median 387 days, IQR 333-404 days). Participants received 2 intranasal sprays of NB2155 at 28-day intervals between November 30 and December 30, 2022. Safety was evaluated by solicited adverse events and laboratory tests. The elevation of nasal mucosal spike-specific sIgA and serum neutralizing activities were assessed. All participants were monitored for infection by antigen tests, disease symptoms, and the elevation of nucleocapsid-specific sIgA in the nasal passage.RESULTSThe vaccine-related solicited adverse events were mild. Nasal spike-specific sIgA against 10 strains had a mean geometric mean fold increase of 4.5 after the first dose, but it increased much higher to 51.5 after the second dose. Serum neutralizing titers also increased modestly to 128.1 (95% CI 74.4-220.4) against authentic BA.1 and 76.9 (95% CI 45.4-130.2) against BA.5 at 14 days after the second dose. Due to the lifting of the zero-COVID policy in China on December 7, 2022, 57.3% of participants were infected with BA.5 between days 15 and 28 after the first dose, whereas no participants reported having any symptomatic infections between day 3 and day 90 after the second dose. The elevation of nasal nucleocapsid-specific sIgA on days 0, 14, 42, and 118 after the first dose was assessed to verify that these 2-dose participants had no asymptomatic infections.CONCLUSIONA 2-dose intranasal vaccination regimen using NB2155 was safe, was well tolerated, and could dramatically induce broad-spectrum spike-specific sIgA in the nasal passage. Preliminary data suggested that the intranasal vaccination may establish an effective mucosal immune barrier against infection and warranted further clinical studies.TRIAL REGISTRATIONChinese Clinical Trial Registry (ChiCTR2300070346).FUNDINGNatural Science Foundation of China, Guangzhou Laboratory, The First Affiliated Hospital of Guangzhou Medical University.

背景鼻穗特异性分泌 IgA(sIgA)水平与感染 SARS-CoV-2 Omicron 的风险成反比。本研究旨在评估使用 Ad5-S-Omicron (NB2155)进行鼻内接种的安全性和免疫原性。方法对 128 名从未感染过 SARS-CoV-2 并曾注射过 2 或 3 次灭活全病毒疫苗的医护人员进行了一项由研究者发起的开放标签、单中心试验,最后一次注射是在 3-19 个月前(中位数为 387 天,IQR 为 333-404 天)。参与者在 2022 年 11 月 30 日至 12 月 30 日期间接受了 2 次 NB2155 鼻内喷雾,每次间隔 28 天。安全性通过征询不良事件和实验室检测进行评估。对鼻粘膜尖峰特异性 sIgA 和血清中和活性的升高进行了评估。通过抗原检测、疾病症状和鼻腔核苷酸特异性 sIgA 的升高监测所有参与者的感染情况。针对 10 种菌株的鼻腔尖峰特异性 sIgA 在接种第一剂后的几何平均倍数平均增加了 4.5 倍,但在接种第二剂后增加到 51.5 倍。第二剂后 14 天,血清中和滴度也略有增加,对真品 BA.1 的中和滴度为 128.1(95% CI 74.4-220.4),对 BA.5 的中和滴度为 76.9(95% CI 45.4-130.2)。由于中国于2022年12月7日取消了零COVID政策,57.3%的参与者在第一剂后的第15天至第28天感染了BA.5,而在第二剂后的第3天至第90天,没有参与者报告有任何症状的感染。对第一剂后第 0、14、42 和 118 天鼻腔核苷酸特异性 sIgA 的升高进行了评估,以核实这些接种 2 剂的参与者没有出现无症状感染。初步数据表明,鼻内疫苗接种可建立有效的粘膜免疫屏障,抵御感染,值得进一步临床研究。
{"title":"An intranasally administered adenovirus-vectored SARS-CoV-2 vaccine induces robust mucosal secretory IgA.","authors":"Baoqing Sun, Qian Wang, Peiyan Zheng, Xuefeng Niu, Ying Feng, Weijie Guan, Si Chen, Jin Li, Tingting Cui, Yijun Deng, Zhangkai J Cheng, Yongmei Li, Xinke Zhou, Yi Fang, Wei Wang, Zhongfang Wang, Ling Chen, Nanshan Zhong","doi":"10.1172/jci.insight.180784","DOIUrl":"10.1172/jci.insight.180784","url":null,"abstract":"<p><p>BACKGROUNDThe level of nasal spike-specific secretory IgA (sIgA) is inversely correlated with the risk of SARS-CoV-2 Omicron infection. This study aimed to evaluate the safety and immunogenicity of intranasal vaccination using Ad5-S-Omicron (NB2155), a replication-incompetent human type 5 adenovirus carrying Omicron BA.1 spike.METHODSAn open-label, single-center, investigator-initiated trial was carried out on 128 health care workers who had never been infected with SARS-CoV-2 and had previously received 2 or 3 injections of inactivated whole-virus vaccines, with the last dose given 3-19 months previously (median 387 days, IQR 333-404 days). Participants received 2 intranasal sprays of NB2155 at 28-day intervals between November 30 and December 30, 2022. Safety was evaluated by solicited adverse events and laboratory tests. The elevation of nasal mucosal spike-specific sIgA and serum neutralizing activities were assessed. All participants were monitored for infection by antigen tests, disease symptoms, and the elevation of nucleocapsid-specific sIgA in the nasal passage.RESULTSThe vaccine-related solicited adverse events were mild. Nasal spike-specific sIgA against 10 strains had a mean geometric mean fold increase of 4.5 after the first dose, but it increased much higher to 51.5 after the second dose. Serum neutralizing titers also increased modestly to 128.1 (95% CI 74.4-220.4) against authentic BA.1 and 76.9 (95% CI 45.4-130.2) against BA.5 at 14 days after the second dose. Due to the lifting of the zero-COVID policy in China on December 7, 2022, 57.3% of participants were infected with BA.5 between days 15 and 28 after the first dose, whereas no participants reported having any symptomatic infections between day 3 and day 90 after the second dose. The elevation of nasal nucleocapsid-specific sIgA on days 0, 14, 42, and 118 after the first dose was assessed to verify that these 2-dose participants had no asymptomatic infections.CONCLUSIONA 2-dose intranasal vaccination regimen using NB2155 was safe, was well tolerated, and could dramatically induce broad-spectrum spike-specific sIgA in the nasal passage. Preliminary data suggested that the intranasal vaccination may establish an effective mucosal immune barrier against infection and warranted further clinical studies.TRIAL REGISTRATIONChinese Clinical Trial Registry (ChiCTR2300070346).FUNDINGNatural Science Foundation of China, Guangzhou Laboratory, The First Affiliated Hospital of Guangzhou Medical University.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis. 高风险肝移植受者接受先期抗病毒治疗与预防治疗后的巨细胞病毒免疫力。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1172/jci.insight.180115
Danniel Zamora, Sayan Dasgupta, Terry Stevens-Ayers, Bradley Edmison, Drew J Winston, Raymund R Razonable, Aneesh K Mehta, G Marshall Lyon, Michael Boeckh, Nina Singh, David M Koelle, Ajit P Limaye

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.

在一项随机试验中,对供体血清反应阳性/受体血清反应阴性(D+R-)的肝移植受者(LTxR)进行了巨细胞病毒(CMV)特异性T细胞、NK细胞和中和抗体(nAb)的评估,该试验是在移植后100天(干预结束)、6个月和12个月时进行的,评估的结果是采用先期抗病毒疗法(PET)与预防性抗病毒疗法(PRO)预防CMV。与PRO组相比,PET组在第100天时循环多功能T细胞、NK细胞和nAb的数量明显增加,到移植后12个月时,几个CMV免疫参数仍明显增加。在 PET 受体中,之前的 CMV 病毒感染(与之前无病毒感染相比)与第 100 天时大多数 CMV 免疫参数水平明显升高有关。在多变量考克斯回归中,第100天时较高数量的CMV特异性多功能T细胞和NKG2C+ NK细胞与CMV疾病发病率的降低有关。CMV特异性多功能CD4 T细胞、CD3negCD56dimCD57negNKG2Cpos和CD3negCD56dimCD57posNKG2Cpos NK细胞数量的增加与预防CMV疾病的关系最为密切。在预防 CMV 疾病方面,PET 优于 PRO,因为它允许低水平 CMV 复制和相关抗原暴露,而抗病毒治疗可及时控制这种低水平 CMV 复制和相关抗原暴露,并有利于增强 D+R- LTxR 的 CMV 保护性免疫。
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引用次数: 0
Clinical cell-surface targets in metastatic and primary solid cancers. 转移性和原发性实体癌中的临床细胞表面靶点。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-24 DOI: 10.1172/jci.insight.183674
Marina N Sharifi, Yue Shi, Matthew R Chrostek, S Carson Callahan, Tianfu Shang, Tracy J Berg, Kyle T Helzer, Matthew L Bootsma, Martin Sjöström, Andreas Josefsson, Felix Y Feng, Laura B Huffman, Chris Schulte, Grace C Blitzer, Quaovi H Sodji, Zachary S Morris, Vincent T Ma, Labros Meimetis, David Kosoff, Amy K Taylor, Aaron M LeBeau, Joshua M Lang, Shuang G Zhao

Therapies against cell-surface targets (CSTs) represent an emerging treatment class in solid malignancies. However, high-throughput investigations of CST expression across cancer types have been reliant on data sets of mostly primary tumors, despite therapeutic use most commonly in metastatic disease. We identified a total of 818 clinical trials of CST therapies with 78 CSTs. We assembled a data set spanning RNA-seq and microarrays in 7,927 benign samples, 16,866 primary tumor samples, and 6,124 metastatic tumor samples. We also utilized single-cell RNA-seq data from 36 benign tissues and 558 primary and metastatic tumor samples, and matched RNA versus protein expression in 29 benign tissue samples, 1,075 tumor samples, and 942 cell lines. High RNA expression accurately predicted high protein expression across CST therapies in benign tissues, tumor samples, and cell lines. We compared metastatic versus primary tumor expression, identified potential opportunities for repositioning, and matched cell lines to tumor types based on CST and global RNA expression. We evaluated single-cell heterogeneity across tumors, and identified rare normal cell subpopulations that may contribute to toxicity. Finally, we identified combinations of CST therapies for which bispecific approaches could improve tumor specificity. This study helps better define the landscape of CST expression in metastatic and primary cancers.

针对细胞表面靶点(CST)的疗法是实体恶性肿瘤的一种新兴治疗手段。然而,尽管CST通常用于治疗转移性疾病,但对不同癌症类型CST表达的高通量研究却主要依赖于原发性肿瘤的数据集。我们共发现了 818 项 CST 疗法的临床试验,涉及 78 种 CST。我们收集了 7,927 份良性样本、16,866 份原发性肿瘤样本和 6,124 份转移性肿瘤样本的 RNA 序列和微阵列数据集。我们还利用了来自 36 个良性组织、558 个原发性和转移性肿瘤样本的单细胞 RNA-seq 数据,并匹配了 29 个良性组织样本、1,075 个肿瘤样本和 942 个细胞系的 RNA 与蛋白质表达。在良性组织、肿瘤样本和细胞系中,高 RNA 表达准确预测了 CST 疗法的高蛋白表达。我们比较了转移性肿瘤和原发性肿瘤的表达,确定了重新定位的潜在机会,并根据 CST 和全局 RNA 表达将细胞系与肿瘤类型相匹配。我们评估了肿瘤中的单细胞异质性,并确定了可能导致毒性的罕见正常细胞亚群。最后,我们确定了双特异性方法可提高肿瘤特异性的 CST 治疗组合。这项研究有助于更好地界定 CST 在转移性癌症和原发性癌症中的表达情况。
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引用次数: 0
NKG2C and NKG2A Co-expression Defines a Highly Functional Antiviral NK Population in Spontaneous HIV Control. NKG2C和NKG2A共表达定义了自发HIV控制中的高功能抗病毒NK群体
IF 8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/jci.insight.182660
Nerea Sanchez-Gaona,Ana Gallego-Cortés,Antonio Astorga-Gamaza,Norma Rallón,Jose Benito,Ezequiel Ruiz-Mateos,Adrian Curran,Joaquin Burgos,Jordi Navarro,Paula Suanzes,Vicenç Falco,Meritxell Genescà,Maria J Buzon
Elite controllers (EC), a unique group of people with HIV (PWH), exhibit remarkable control of viral replication in the absence of antiretroviral therapy. In this study, we comprehensively characterized the NK cell repertoire in EC after long-term viral control. Phenotypic profiling of NK cells revealed profound differences compared with other PWH, but marked similarities to uninfected individuals, with a distinctive prevalence of NKG2C+CD57+memory-like NK cells. Functional analyses indicated that EC had limited production of functional molecules upon NK stimulation and consequently reduced natural cytotoxicity against non-HIV target cells. Importantly, EC showed an exceptional ability to kill primary HIV-infected cells by the antibody-dependent cell cytotoxicity (ADCC) adaptive mechanism, which was achieved by a specific memory-like NK population expressing CD16, NKG2A, NKG2C, CD57 and CXCR3. In-depth single-cell RNA sequencing unveiled a unique transcriptional signature in these NK cells linked to increased cell metabolism, migration, chemotaxis, effector functions, cytokine secretion, and antiviral response. Our findings underscore a pivotal role of NK cells in the immune control of HIV and identify specific NK cells as emerging targets for immunotherapies.
精英控制者(EC)是艾滋病病毒感染者(PWH)中的一个特殊群体,他们在没有抗逆转录病毒疗法的情况下也能显著控制病毒复制。在这项研究中,我们全面描述了长期病毒控制后精英控制者体内 NK 细胞的特征。NK细胞的表型分析表明,与其他PWH患者相比,EC患者的NK细胞有很大差异,但与未感染的患者有明显相似之处,其中NKG2C+CD57+记忆样NK细胞明显多见。功能分析表明,EC在受到NK刺激时产生的功能分子有限,因此降低了对非艾滋病毒靶细胞的天然细胞毒性。重要的是,通过抗体依赖性细胞细胞毒性(ADCC)适应性机制,EC表现出了杀死原代HIV感染细胞的特殊能力,这种能力是由表达CD16、NKG2A、NKG2C、CD57和CXCR3的特异性记忆样NK群体实现的。深入的单细胞 RNA 测序揭示了这些 NK 细胞的独特转录特征,它与细胞代谢、迁移、趋化、效应功能、细胞因子分泌和抗病毒反应的增强有关。我们的发现强调了 NK 细胞在 HIV 免疫控制中的关键作用,并确定了特定的 NK 细胞作为免疫疗法的新兴靶点。
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引用次数: 0
Distinct strategies for intravascular triglyceride metabolism in hearts of mammals and lower vertebrate species. 哺乳动物和低等脊椎动物心脏血管内甘油三酯代谢的不同策略
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/jci.insight.184940
Le Phuong Nguyen, Wenxin Song, Ye Yang, Anh P Tran, Thomas A Weston, Hyesoo Jung, Yiping Tu, Paul H Kim, Joonyoung R Kim, Katherine Xie, Rachel G Yu, Julia Scheithauer, Ashley M Presnell, Michael Ploug, Gabriel Birrane, Hannah Arnold, Katarzyna Koltowska, Maarja A Mäe, Christer Betsholtz, Liqun He, Jeffrey L Goodwin, Anne P Beigneux, Loren G Fong, Stephen G Young

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1-the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen-is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary.

脂蛋白脂肪酶(LPL)和 LPL 活性的多种调节因子(如 APOC2 和 ANGPTL4)存在于所有脊椎动物中,但 GPIHBP1(一种内皮细胞(EC)蛋白,用于捕捉内皮下空间中的 LPL 并将其运送到毛细血管腔内的作用部位)存在于哺乳动物中,但不存在于鸡或其他低等脊椎动物中。在哺乳动物中,GPIHBP1 缺乏会导致严重的高甘油三酯血症,但鸡尽管缺乏 GPIHBP1,却能保持较低的甘油三酯水平。为了了解低等脊椎动物血管内脂肪分解的情况,我们研究了小鼠和鸡心脏中 LPL 的表达。在这两种动物的毛细血管中,LPL的含量都很高,但Lpl转录物的分布却有显著不同。在小鼠心脏中,Lpl转录本在心肌细胞中含量极高,但在毛细血管EC中几乎检测不到。在鸡的心脏中,心肌细胞中没有 Lpl 转录本,但毛细血管 EC 中却有大量 Lpl 转录本。在斑马鱼心脏中,lpl转录本也存在于毛细血管内皮细胞中,但不存在于心肌细胞中。在小鼠和鸡的心脏中,通过免疫金电子显微镜判断,LPL 存在于毛细血管 EC 的糖萼中。因此,哺乳动物在心肌细胞中产生 LPL,并依靠 GPIHBP1 将 LPL 转运到毛细血管中,而低等脊椎动物直接在毛细血管 EC 中产生 LPL,因此不需要 LPL 转运体。
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引用次数: 0
Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease. 患者成纤维细胞的定量蛋白质组学揭示了线粒体疾病的生物标志物和诊断特征。
IF 8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-17 DOI: 10.1172/jci.insight.178645
Sandrina P Correia,Marco F Moedas,Lucie S Taylor,Karin Naess,Albert Z Lim,Robert McFarland,Zuzanna Kazior,Anastasia Rumyantseva,Rolf Wibom,Martin Engvall,Helene Bruhn,Nicole Lesko,Ákos Végvári,Lukas Käll,Matthias Trost,Charlotte L Alston,Christoph Freyer,Robert W Taylor,Anna Wedell,Anna Wredenberg
BACKGROUNDMitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1:2,000-1:5,000. They are the most common form of IEM, but despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed.METHODSWe investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups. Clinical presentations were structured using human phenotype ontology terms, and mass spectrometry-based proteomics was performed on primary fibroblasts. Additionally, we integrated six patients carrying variants of uncertain significance (VUS) to test proteomics as a diagnostic expansion.RESULTSProteomic profiles from patient samples could be classified according to their biochemical and genetic characteristics, with the expression of five proteins (GPX4, MORF4L1, MOXD1, MSRA and TMED9) correlating with the disease cohort, and thus, acting as putative biomarkers. Pathway analysis showed a deregulation of inflammatory and mitochondrial stress responses. This included the upregulation of glycosphingolipid metabolism and mitochondrial protein import, as well as the downregulation of arachidonic acid metabolism. Furthermore, we could assign pathogenicity to a VUS in MRPS23 by demonstrating the loss of associated mitochondrial ribosome subunits.CONCLUSIONWe established mass spectrometry-based proteomics on patient fibroblasts as a viable and versatile tool for diagnosing patients with mitochondrial disease.FUNDINGThe NovoNordisk Foundation, Knut and Alice Wallenberg Foundation, Wellcome Centre for Mitochondrial Research, UK Medical Research Council, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children.
背景线粒体疾病属于先天性代谢错误(IEM),发病率为 1:2000-1:5000。我们对 61 例线粒体疾病患者进行了调查,以改进诊断方法、确定生物标志物并将代谢途径与特定疾病组相关联。我们使用人类表型本体术语对临床表现进行了结构化,并对原代成纤维细胞进行了基于质谱的蛋白质组学研究。结果患者样本的蛋白质组图谱可根据其生化和遗传特征进行分类,其中五种蛋白质(GPX4、MORF4L1、MOXD1、MSRA 和 TMED9)的表达与疾病群相关,因此可作为推定的生物标记物。通路分析表明,炎症和线粒体应激反应出现了失调。这包括糖磷脂代谢和线粒体蛋白导入的上调,以及花生四烯酸代谢的下调。此外,我们还通过证明相关线粒体核糖体亚基的缺失,确定了 MRPS23 中 VUS 的致病性。资金来源诺和诺德基金会、克努特和爱丽丝-沃伦贝格基金会、惠康线粒体研究中心、英国医学研究理事会和英国国家医疗服务系统成人和儿童罕见线粒体疾病高度专业化服务机构。
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