Saiti S Halder,Michael J Rynkiewicz,Lynne Kim,Meaghan Barry,Ahmed Ga Zied,Lorenzo R Sewanan,Jonathan A Kirk,Jeffrey R Moore,William Lehman,Stuart G Campbell
Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the 'closed' regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.
肥厚型心肌病和扩张型心肌病（分别为 HCM 和 DCM）是一种遗传性疾病，可能由相同的肌浆蛋白突变引起，但临床表型却完全不同。同一基因中的点突变导致表型多样性的确切机制仍不清楚。我们的目标是对两种 TPM1 突变（E62Q（HCM）和 E54K（DCM））的不同表型做出机理解释。我们利用文献数据和表达相关 TPM1 突变的干细胞衍生心肌细胞的实验，构建了计算模拟，为每种变异引起的不同肌肉收缩能力提供了合理的解释。在 E62Q 突变体中，钙敏感性和过度收缩性增加的最准确解释是肌球蛋白有效分子刚度的降低及其与肌动蛋白细丝相互作用的改变，这种改变有利于 "封闭 "调节状态。相比之下，E54K 突变似乎是通过长程异构相互作用来增加 C 端肌钙蛋白 I 移动结构域与肌球蛋白/肌动蛋白的结合率。这些与突变相关的分子事件导致了基因表达的不同变化，这些变化可以在人体工程心脏组织中观察到。肌球蛋白活性调节剂根据预测挽救了正常的收缩行为，从而证实了我们提出的机制。
{"title":"Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants.","authors":"Saiti S Halder,Michael J Rynkiewicz,Lynne Kim,Meaghan Barry,Ahmed Ga Zied,Lorenzo R Sewanan,Jonathan A Kirk,Jeffrey R Moore,William Lehman,Stuart G Campbell","doi":"10.1172/jci179135","DOIUrl":"https://doi.org/10.1172/jci179135","url":null,"abstract":"Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the 'closed' regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"234 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ting-Yu Chang,Yan Yan,Zih-Yao Yu,Moeez Rathore,Nian-Zhe Lee,Hui-Ju Tseng,Li-Hsin Cheng,Wei-Jan Huang,Wei Zhang,Ernest R Chan,Yulan Qing,Ming-Lun Kang,Rui Wang,Kelvin K Tsai,John J Pink,William E Harte,Stanton L Gerson,Sung-Bau Lee
The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.
{"title":"Combined HDAC8 and checkpoint kinase inhibition induces tumor-selective synthetic lethality in preclinical models.","authors":"Ting-Yu Chang,Yan Yan,Zih-Yao Yu,Moeez Rathore,Nian-Zhe Lee,Hui-Ju Tseng,Li-Hsin Cheng,Wei-Jan Huang,Wei Zhang,Ernest R Chan,Yulan Qing,Ming-Lun Kang,Rui Wang,Kelvin K Tsai,John J Pink,William E Harte,Stanton L Gerson,Sung-Bau Lee","doi":"10.1172/jci165448","DOIUrl":"https://doi.org/10.1172/jci165448","url":null,"abstract":"The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antwi-Boasiako Oteng,Liu Liu,Yinghong Cui,Oksana Gavrilova,Huiyan Lu,Min Chen,Lee S Weinstein,Jonathan E Campbell,Jo E Lewis,Fiona M Gribble,Frank Reimann,Jürgen Wess
Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.
进餐后，特化的肠内分泌细胞（分别为 L 细胞和 K 细胞）会分泌胰高血糖素样肽-1（GLP1）和葡萄糖依赖性促胰岛素多肽（GIP）这两种促进胰岛素释放的主要增量素。虽然 GIP 是人体中最主要的增量蛋白，但有关其释放的详细分子机制仍有待探索。GIP 的分泌受 K 细胞表达的 G 蛋白偶联受体（GPCR）活性的调节。GPCR 与一类或多类特定的异三聚体 G 蛋白偶联。在本研究中，我们重点研究了 K 细胞 Gs 的潜在代谢作用。首先，我们建立了一个小鼠模型，可以选择性地刺激 K 细胞 Gs 信号传导。其次，我们产生了一种小鼠品系，该品系在 K 细胞中选择性地携带 Gs α-亚基编码基因 Gnas 的失活突变。代谢表型研究表明，由于 GIP 分泌增强，急性或慢性刺激 K 细胞 Gs 信号大大改善了肥胖小鼠和 2 型糖尿病小鼠模型中受损的葡萄糖稳态。相反，K 细胞特异性 Gnas 基因敲除小鼠的血浆 GIP 水平明显下降。这些数据有力地表明，旨在增强 K 细胞 Gs 信号转导的策略可能被证明有助于治疗糖尿病和相关代谢疾病。
{"title":"Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits.","authors":"Antwi-Boasiako Oteng,Liu Liu,Yinghong Cui,Oksana Gavrilova,Huiyan Lu,Min Chen,Lee S Weinstein,Jonathan E Campbell,Jo E Lewis,Fiona M Gribble,Frank Reimann,Jürgen Wess","doi":"10.1172/jci182325","DOIUrl":"https://doi.org/10.1172/jci182325","url":null,"abstract":"Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maegan R Manning,Jana Blazkova,Jesse S Justement,Victoria Shi,Brooke D Kennedy,M Ali Rai,Catherine A Seamon,Kathleen Gittens,Michael C Sneller,Susan Moir,Tae-Wook Chun
{"title":"Timing of antiretroviral therapy initiation affects intact HIV reservoirs following analytical treatment interruption.","authors":"Maegan R Manning,Jana Blazkova,Jesse S Justement,Victoria Shi,Brooke D Kennedy,M Ali Rai,Catherine A Seamon,Kathleen Gittens,Michael C Sneller,Susan Moir,Tae-Wook Chun","doi":"10.1172/jci181632","DOIUrl":"https://doi.org/10.1172/jci181632","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"124 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly up-regulated in sepsis patients and correlated with the severity of sepsis. Knock out of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2 knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit Bruton tyrosine kinas (BTK)-mediated FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO, which may provide a promising target for the clinical treatment of sepsis.
{"title":"TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis.","authors":"Siqi Ming,Xingyu Li,Qiang Xiao,Siying Qu,Qiaohua Wang,Qiongyan Fang,Pingping Liang,Yating Xu,Jingwen Yang,Yongqiang Yang,Xi Huang,Yongjian Wu","doi":"10.1172/jci159400","DOIUrl":"https://doi.org/10.1172/jci159400","url":null,"abstract":"Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly up-regulated in sepsis patients and correlated with the severity of sepsis. Knock out of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2 knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit Bruton tyrosine kinas (BTK)-mediated FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO, which may provide a promising target for the clinical treatment of sepsis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaofang Tang,Wei Wei,Yuqing Sun,Timothy E Weaver,Ernesto S Nakayasu,Geremy Clair,John M Snowball,Cheng-Lun Na,Karen S Apsley,Emily P Martin,Darrell N Kotton,Konstantinos-Dionysios Alysandratos,Jiuzhou Huo,Jeffery D Molkentin,William A Gower,Xinhua Lin,Jeffrey A Whitsett
The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.
{"title":"EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease.","authors":"Xiaofang Tang,Wei Wei,Yuqing Sun,Timothy E Weaver,Ernesto S Nakayasu,Geremy Clair,John M Snowball,Cheng-Lun Na,Karen S Apsley,Emily P Martin,Darrell N Kotton,Konstantinos-Dionysios Alysandratos,Jiuzhou Huo,Jeffery D Molkentin,William A Gower,Xinhua Lin,Jeffrey A Whitsett","doi":"10.1172/jci173861","DOIUrl":"https://doi.org/10.1172/jci173861","url":null,"abstract":"The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The precise conditions by which cytokines drive cancer is relevant to improving immune checkpoint inhibition (ICI) responses while decreasing toxicity. In this issue of the JCI, Kao et al. investigated T helper cell pathways in patients with solid tumors receiving ICI. The authors evaluated T cell populations, cytokine signatures, immune related adverse events (irAEs), and survival outcomes. Patients with a history of autoimmune disorders were more likely to develop irAEs. Notably, blood samples from patients on treatment showed that elevations in IL-5, IL-6, IL-17f, and TNF-α were associated with an increased risk for grade 2 or higher irAEs. Moreover, IL-6 was associated with decreased objective response rate and worse cancer-specific and all-cause mortality. These findings may help guide decisions for optimizing ICI efficacy while minimizing toxicity and suggest that IL-6 blockade may improve response and decrease toxicity in solid tumors.
{"title":"Distinguishing between help and harm: Helper T cell subsets and immune-related adverse events.","authors":"Alexandra M Haugh,Adil I Daud","doi":"10.1172/jci184310","DOIUrl":"https://doi.org/10.1172/jci184310","url":null,"abstract":"The precise conditions by which cytokines drive cancer is relevant to improving immune checkpoint inhibition (ICI) responses while decreasing toxicity. In this issue of the JCI, Kao et al. investigated T helper cell pathways in patients with solid tumors receiving ICI. The authors evaluated T cell populations, cytokine signatures, immune related adverse events (irAEs), and survival outcomes. Patients with a history of autoimmune disorders were more likely to develop irAEs. Notably, blood samples from patients on treatment showed that elevations in IL-5, IL-6, IL-17f, and TNF-α were associated with an increased risk for grade 2 or higher irAEs. Moreover, IL-6 was associated with decreased objective response rate and worse cancer-specific and all-cause mortality. These findings may help guide decisions for optimizing ICI efficacy while minimizing toxicity and suggest that IL-6 blockade may improve response and decrease toxicity in solid tumors.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonathan Bohlen,Ivan Bagarić,Taja Vatovec,Masato Ogishi,Syed F Ahmed,Axel Cederholm,Lori Buetow,Steicy Sobrino,Corentin Le Floc'h,Carlos A Arango-Franco,Luis Seabra,Marine Michelet,Federica Barzaghi,Davide Leardini,Francesco Saettini,Francesca Vendemini,Francesco Baccelli,Albert Catala,Eleonora Gambineri,Marinella Veltroni,Yurena Aguilar de la Red,Gillian I Rice,Filippo Consonni,Laureline Berteloot,Laetitia Largeaud,Francesca Conti,Cécile Roullion,Cécile Masson,Boris Bessot,Yoann Seeleuthner,Tom Le Voyer,Darawan Rinchai,Jérémie Rosain,Anna-Lena Neehus,Lucia Erazo-Borrás,Hailun Li,Zarah Janda,En-Jui Cho,Edoardo Muratore,Camille Soudée,Candice Lainé,Eric Delabesse,Claire Goulvestre,Cindy S Ma,Anne Puel,Stuart G Tangye,Isabelle André,Christine Bole-Feysot,Laurent Abel,Miriam Erlacher,Shen-Ying Zhang,Vivien Béziat,Chantal Lagresle-Peyrou,Emmanuelle Six,Marlène Pasquet,Laia Alsina,Alessandro Aiuti,Peng Zhang,Yanick J Crow,Nils Landegren,Riccardo Masetti,Danny T Huang,Jean-Laurent Casanova,Jacinta Bustamante
Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.
{"title":"Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.","authors":"Jonathan Bohlen,Ivan Bagarić,Taja Vatovec,Masato Ogishi,Syed F Ahmed,Axel Cederholm,Lori Buetow,Steicy Sobrino,Corentin Le Floc'h,Carlos A Arango-Franco,Luis Seabra,Marine Michelet,Federica Barzaghi,Davide Leardini,Francesco Saettini,Francesca Vendemini,Francesco Baccelli,Albert Catala,Eleonora Gambineri,Marinella Veltroni,Yurena Aguilar de la Red,Gillian I Rice,Filippo Consonni,Laureline Berteloot,Laetitia Largeaud,Francesca Conti,Cécile Roullion,Cécile Masson,Boris Bessot,Yoann Seeleuthner,Tom Le Voyer,Darawan Rinchai,Jérémie Rosain,Anna-Lena Neehus,Lucia Erazo-Borrás,Hailun Li,Zarah Janda,En-Jui Cho,Edoardo Muratore,Camille Soudée,Candice Lainé,Eric Delabesse,Claire Goulvestre,Cindy S Ma,Anne Puel,Stuart G Tangye,Isabelle André,Christine Bole-Feysot,Laurent Abel,Miriam Erlacher,Shen-Ying Zhang,Vivien Béziat,Chantal Lagresle-Peyrou,Emmanuelle Six,Marlène Pasquet,Laia Alsina,Alessandro Aiuti,Peng Zhang,Yanick J Crow,Nils Landegren,Riccardo Masetti,Danny T Huang,Jean-Laurent Casanova,Jacinta Bustamante","doi":"10.1172/jci181604","DOIUrl":"https://doi.org/10.1172/jci181604","url":null,"abstract":"Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"208 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kidney transplantation from donors with HIV to recipients with HIV (HIV D+/R+) is an emerging practice that has shown substantial clinical benefit. Sustained HIV superinfection, whereby a transplant recipient acquires a new strain of HIV from their organ donor, is a theoretical risk, which might increase chances of viral failure. In this issue of the JCI, Travieso, Stadtler, and colleagues present phylogenetic analysis of HIV from kidney tissue, urine, plasma, and cells from 12 HIV D+/R+ kidney transplants out to five years of follow-up. Early after transplant, donor HIV was transiently detected in five of 12 recipients, primarily from donors with untreated HIV and high-level viremia, consistent with a viral inoculum. Long-term, donor HIV was not detected in any recipients, demonstrating no sustained HIV superinfection. These reassuring data support earlier findings from South Africa and the United States and further confirm the safety of HIV D+/R+ transplantation.
由感染 HIV 的供体向感染 HIV 的受体（HIV D+/R+）进行肾移植是一种新兴的做法，已显示出巨大的临床益处。持续的 HIV 超级感染，即移植受者从器官捐献者那里获得新的 HIV 菌株，是一种理论上的风险，可能会增加病毒失败的几率。在本期 JCI 杂志上，Travieso、Stadtler 及其同事介绍了对 12 例 HIV D+/R+ 肾移植随访五年的肾组织、尿液、血浆和细胞中 HIV 的系统发育分析。移植后早期，12 例受者中有 5 例短暂检测到供体艾滋病病毒，主要来自未治疗艾滋病病毒和高水平病毒血症的供体，与病毒接种体一致。长期来看，没有在任何受者体内检测到供体艾滋病病毒，表明没有持续的艾滋病病毒超级感染。这些令人欣慰的数据支持了南非和美国早前的研究结果，并进一步证实了 HIV D+/R+ 移植的安全性。
{"title":"HOPE springs eternal: lack of HIV superinfection in HIV Organ Policy Equity Act kidney transplants.","authors":"Christine M Durand,Andrew D Redd","doi":"10.1172/jci184326","DOIUrl":"https://doi.org/10.1172/jci184326","url":null,"abstract":"Kidney transplantation from donors with HIV to recipients with HIV (HIV D+/R+) is an emerging practice that has shown substantial clinical benefit. Sustained HIV superinfection, whereby a transplant recipient acquires a new strain of HIV from their organ donor, is a theoretical risk, which might increase chances of viral failure. In this issue of the JCI, Travieso, Stadtler, and colleagues present phylogenetic analysis of HIV from kidney tissue, urine, plasma, and cells from 12 HIV D+/R+ kidney transplants out to five years of follow-up. Early after transplant, donor HIV was transiently detected in five of 12 recipients, primarily from donors with untreated HIV and high-level viremia, consistent with a viral inoculum. Long-term, donor HIV was not detected in any recipients, demonstrating no sustained HIV superinfection. These reassuring data support earlier findings from South Africa and the United States and further confirm the safety of HIV D+/R+ transplantation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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