JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.173489
Daniel Kirchmeier, Yun Deng, Lisa Rieble, Michelle Böni, Fabienne Läderach, Patrick Schuhmachers, Alma Delia Valencia-Camargo, Anita Murer, Nicole Caduff, Bithi Chatterjee, Obinna Chijioke, Kyra Zens, Christian Münz
{"title":"Epstein-Barr virus infection induces tissue-resident memory T cells in mucosal lymphoid tissues.","authors":"Daniel Kirchmeier, Yun Deng, Lisa Rieble, Michelle Böni, Fabienne Läderach, Patrick Schuhmachers, Alma Delia Valencia-Camargo, Anita Murer, Nicole Caduff, Bithi Chatterjee, Obinna Chijioke, Kyra Zens, Christian Münz","doi":"10.1172/jci.insight.173489","DOIUrl":"10.1172/jci.insight.173489","url":null,"abstract":"<p><p>EBV contributes to around 2% of all tumors worldwide. Simultaneously, more than 90% of healthy human adults persistently carry EBV without clinical symptoms. In most EBV carriers, it is thought that virus-induced tumorigenesis is prevented by cell-mediated immunity. Specifically, memory CD8+ T cells recognize EBV-infected cells during latent and lytic infection. Using a symptomatic primary infection model, similar to infectious mononucleosis (IM), we found EBV-induced CD8+ tissue resident memory T cells (TRMs) in mice with a humanized immune system. These human TRMs were preferentially established after intranasal EBV infection in nasal-associated lymphoid tissues (NALT), equivalent to tonsils, the primary site of EBV infection in humans. They expressed canonical TRM markers, including CD69, CD103, and BLIMP-1, as well as granzyme B, CD107a, and CCL5. Despite cytotoxic activity and cytokine production ex vivo, these TRMs demonstrated reduced CD27 expression and proliferation and failed to control EBV viral loads in the NALT during infection, although effector memory T cells (TEMs) controlled viral titers in spleen and blood. Overall, TRMs are established in mucosal lymphoid tissues by EBV infection, but primarily, systemic CD8+ T cell expansion seems to control viral loads in the context of IM-like infection.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287596","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}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.177899
Carla Gómez-Oro, Maria C Latorre, Patricia Arribas-Poza, Alexandra Ibáñez-Escribano, Katia R Baca-Cornejo, Jorge Gallego-Valle, Natalia López-Escobar, Mabel Mondéjar-Palencia, Marjorie Pion, Luis A López-Fernández, Enrique Mercader, Federico Pérez-Milán, Miguel Relloso
{"title":"Progesterone promotes CXCl2-dependent vaginal neutrophil killing by activating cervical resident macrophage-neutrophil crosstalk.","authors":"Carla Gómez-Oro, Maria C Latorre, Patricia Arribas-Poza, Alexandra Ibáñez-Escribano, Katia R Baca-Cornejo, Jorge Gallego-Valle, Natalia López-Escobar, Mabel Mondéjar-Palencia, Marjorie Pion, Luis A López-Fernández, Enrique Mercader, Federico Pérez-Milán, Miguel Relloso","doi":"10.1172/jci.insight.177899","DOIUrl":"10.1172/jci.insight.177899","url":null,"abstract":"<p><p>Vaginal infections in women of reproductive age represent a clinical dilemma with significant socioeconomic implications. The current understanding of mucosal immunity failure during early pathogenic invasions that allows the pathogen to grow and thrive is far from complete. Neutrophils infiltrate most tissues following circadian patterns as part of normal repair, regulation of microbiota, or immune surveillance and become more numerous after infection. Neutrophils are responsible for maintaining vaginal immunity. Specific to the vagina, neutrophils continuously infiltrate at high levels, although during ovulation, they retreat to avoid sperm damage and permit reproduction. Here we show that, after ovulation, progesterone promotes resident vaginal macrophage-neutrophil crosstalk by upregulating Yolk sac early fetal organs (FOLR2+) macrophage CXCl2 expression, in a TNFA-patrolling monocyte-derived macrophage-mediated (CX3CR1hiMHCIIhi-mediated) manner, to activate the neutrophils' capacity to eliminate sex-transmitted and opportunistic microorganisms. Indeed, progesterone plays an essential role in conciliating the balance between the commensal microbiota, sperm, and the threat of pathogens because progesterone not only promotes a flurry of neutrophils but also increases neutrophilic fury to restore immunity after ovulation to thwart pathogenic invasion after intercourse. Therefore, modest progesterone dysregulations could lead to a suboptimal neutrophilic response, resulting in insufficient mucosal defense and recurrent unresolved infections.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287565","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}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.183913
Sylvia Mink, Christoph H Saely, Andreas Leiherer, Patrick Reimann, Matthias Frick, Janne Cadamuro, Wolfgang Hitzl, Heinz Drexel, Peter Fraunberger
{"title":"Antibody levels versus vaccination status in the outcome of older adults with COVID-19.","authors":"Sylvia Mink, Christoph H Saely, Andreas Leiherer, Patrick Reimann, Matthias Frick, Janne Cadamuro, Wolfgang Hitzl, Heinz Drexel, Peter Fraunberger","doi":"10.1172/jci.insight.183913","DOIUrl":"10.1172/jci.insight.183913","url":null,"abstract":"<p><p>BACKGROUNDDespite the currently prevailing, milder Omicron variant of COVID-19, older adults remain at elevated risk of hospital admission, critical illness, and death. Loss of efficacy of the immune system, including reduced strength, quality, and durability of antibody responses, may render generalized recommendations on booster vaccinations inadequate. There is a lack of data on the efficacy of antibody levels in older adults and on the utility of vaccination status versus antibody levels as a correlate of protection. It is further unclear whether antibody levels may be used to guide the timing of booster vaccinations in older adults.METHODSWe conducted a prospective multicenter cohort study comprising hospitalized patients with COVID-19. Anti-SARS-CoV-2 spike antibodies were measured on hospital admission. The primary endpoint was in-hospital mortality. Patients were stratified by age, antibody levels, and vaccination status. Multiple logistic regression and Cox regression analyses were conducted.RESULTSIn total, 785 older patients (≥60 years of age [a]) and 367 controls (<60a) were included. After adjusting for confounders, risk of mortality, ICU admission, endotracheal intubation, and oxygen administration was 4.9, 2.6, 6.5, and 2.3 times higher, respectively, if antibody levels were < 1,200 BAU/mL (aOR, 4.92 [95%CI, 2.59-9.34], P < 0.0001; aOR, 2.64 [95%CI, 1.52-4.62], P = 0.0006; aOR, 6.50 [95%CI, 1.48-28.47], P = 0.013; aOR, 2.34 [95%CI, 1.60-3.343], P < 0.0001). Older adults infected with the Omicron variant were approximately 6 times more likely to die if antibody levels were < 1,200 BAU/mL (aOR, 6.3 [95% CI, 2.43-16.40], P = 0.0002).CONCLUSIONAntibody levels were a stronger predictor of in-hospital mortality than vaccination status. Monitoring antibody levels may constitute a better and more direct approach for safeguarding older adults from adverse COVID-19 outcomes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465877","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}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.179899
Anna E Kersh, Satish Sati, Jianhe Huang, Christina Murphy, Olivia Ahart, Thomas H Leung
{"title":"CXCL9, CXCL10, and CCL19 synergistically recruit T lymphocytes to skin in lichen planus.","authors":"Anna E Kersh, Satish Sati, Jianhe Huang, Christina Murphy, Olivia Ahart, Thomas H Leung","doi":"10.1172/jci.insight.179899","DOIUrl":"10.1172/jci.insight.179899","url":null,"abstract":"<p><p>Lichen planus (LP) is a chronic, debilitating, inflammatory disease of the skin and mucous membranes that affects 1%-2% of Americans. Its molecular pathogenesis remains poorly understood, and there are no FDA-approved treatments. We performed single-cell RNA sequencing on paired blood and skin samples (lesional and nonlesional tissue) from 7 patients with LP. We discovered that LP keratinocytes and fibroblasts specifically secrete a combination of CXCL9, CXCL10, and CCL19 cytokines. Using an in vitro migration assay with primary human T cells, we demonstrated that CCL19 in combination with either of the other 2 cytokines synergistically enhanced recruitment of CD8+ T cells more than any individual cytokine. Moreover, exhausted T cells in lesional LP skin secreted CXCL13, which, along with CCL19, also enhanced recruitment of T cells, suggesting a feed-forward loop in LP. Finally, LP blood revealed decreased circulating naive CD8+ T cells compared with that in healthy volunteers, consistent with recruitment to skin. Molecular analysis of LP skin and blood samples increased our understanding of disease pathogenesis and identified CCL19 as a new therapeutic target for treatment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080292","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}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.178768
Rabiat Adele, Rowaida Hussein, Erika Tavares, Kashif Ahmed, Matteo Di Scipio, Jason Charish, Minggao Liang, Simon Monis, Anupreet Tumber, Xiaoyan Chen, Tara A Paton, Nicole M Roslin, Christabel Eileen, Evgueni Ivakine, Nishanth E Sunny, Michael D Wilson, Eric Campos, Raju Vs Rajala, Jason T Maynes, Philippe P Monnier, Andrew D Paterson, Elise Héon, Ajoy Vincent
{"title":"Autosomal dominant macular dystrophy linked to a chromosome 17 tandem duplication.","authors":"Rabiat Adele, Rowaida Hussein, Erika Tavares, Kashif Ahmed, Matteo Di Scipio, Jason Charish, Minggao Liang, Simon Monis, Anupreet Tumber, Xiaoyan Chen, Tara A Paton, Nicole M Roslin, Christabel Eileen, Evgueni Ivakine, Nishanth E Sunny, Michael D Wilson, Eric Campos, Raju Vs Rajala, Jason T Maynes, Philippe P Monnier, Andrew D Paterson, Elise Héon, Ajoy Vincent","doi":"10.1172/jci.insight.178768","DOIUrl":"https://doi.org/10.1172/jci.insight.178768","url":null,"abstract":"<p><p>Hereditary Macular Dystrophies (HMDs) are a genetically diverse group of disorders that cause central vision loss due to photoreceptor and retinal pigment epithelium (RPE) damage. We investigated a family with a presumed novel autosomal dominant HMD characterized by faint, hypopigmented RPE changes involving the central retina. Genome and RNA sequencing identified the disease-causing variant to be a 560 kilobase tandem duplication on chromosome 17 [NC_000017.10 (hg19): g.4012590_4573014dup], which led to the formation of a novel ZZEF1-ALOX15 fusion gene, that upregulates ALOX15. ALOX15 encodes a lipoxygenase involved in polyunsaturated fatty acid metabolism. Functional studies showed retinal disorganization, and photoreceptor and RPE damage following electroporation of the chimera transcript in mouse retina. Photoreceptor damage also occurred following electroporation with a native ALOX15 transcript but not with a near-null ALOX15 transcript. Affected patients' lymphoblasts demonstrated lower levels of ALOX15 substrates and an accumulation of neutral lipids. We implicated the fusion gene as the cause of this family's HMD, due to mis-localization and overexpression of ALOX15, driven by the ZZEF1 promoter. To our knowledge, this is the first reported instance of a fusion gene leading to HMD or inherited retinal dystrophy, highlighting the need to prioritize duplication analysis in unsolved retinal dystrophies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.179017
Kevin D Mangum, Aaron denDekker, Qinmengge Li, Lam C Tsoi, Amrita D Joshi, William J Melvin, Sonya J Wolf, Jadie Y Moon, Christopher O Audu, James Shadiow, Andrea T Obi, Rachael Wasikowski, Emily C Barrett, Tyler M Bauer, Kylie Boyer, Zara Ahmed, Frank M Davis, Johann Gudjonsson, Katherine A Gallagher
{"title":"The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.","authors":"Kevin D Mangum, Aaron denDekker, Qinmengge Li, Lam C Tsoi, Amrita D Joshi, William J Melvin, Sonya J Wolf, Jadie Y Moon, Christopher O Audu, James Shadiow, Andrea T Obi, Rachael Wasikowski, Emily C Barrett, Tyler M Bauer, Kylie Boyer, Zara Ahmed, Frank M Davis, Johann Gudjonsson, Katherine A Gallagher","doi":"10.1172/jci.insight.179017","DOIUrl":"10.1172/jci.insight.179017","url":null,"abstract":"<p><p>Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465886","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}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.183516
Talita Z Choudhury, Sarah C Greskovich, Holly B Girard, Anupama S Rao, Yogesh Budhathoki, Emily M Cameron, Sara Conroy, Deqiang Li, Ming-Tao Zhao, Vidu Garg
{"title":"Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease.","authors":"Talita Z Choudhury, Sarah C Greskovich, Holly B Girard, Anupama S Rao, Yogesh Budhathoki, Emily M Cameron, Sara Conroy, Deqiang Li, Ming-Tao Zhao, Vidu Garg","doi":"10.1172/jci.insight.183516","DOIUrl":"https://doi.org/10.1172/jci.insight.183516","url":null,"abstract":"<p><p>Congenital heart disease (CHD) affects ~1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxE) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between Notch1 haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage specific effect of Notch1 haploinsufficiency in matDM-exposed embryos, implicating endothelial/endocardial derived tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM exposed Notch1+/- animals and show a synergistic effect of NOTCH1 haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via SOD1 overexpression did not rescue CHD in Notch1 haploinsufficient mice compared to wildtype littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition, Notch1 haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies maybe ineffective in genetically-susceptible individuals.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.181219
Lin Yuan, Qingwu Qin, Ye Yao, Long Chen, Huijun Liu, Xizi Du, Ming Ji, Xinyu Wu, Weijie Wang, Qiuyan Qin, Yang Xiang, Bei Qing, Xiangping Qu, Ming Yang, Xiaoqun Qin, Zhenkun Xia, Chi Liu
{"title":"Increased expression of Cathepsin C in airway epithelia exacerbates airway remodeling in asthma.","authors":"Lin Yuan, Qingwu Qin, Ye Yao, Long Chen, Huijun Liu, Xizi Du, Ming Ji, Xinyu Wu, Weijie Wang, Qiuyan Qin, Yang Xiang, Bei Qing, Xiangping Qu, Ming Yang, Xiaoqun Qin, Zhenkun Xia, Chi Liu","doi":"10.1172/jci.insight.181219","DOIUrl":"https://doi.org/10.1172/jci.insight.181219","url":null,"abstract":"<p><p>Airway remodeling is a critical factor determining the pathogenesis and treatment sensitivity of severe asthma (SA) or uncontrolled asthma (UA). The activation of epithelial-mesenchymal trophic units (EMTUs) regulated by airway epithelial cells (AECs) has been proven to induce airway remodeling directly. However, the triggers for EMTU activation and the underlying mechanism of airway remodeling are not fully elucidated. Here, we screened the differentially expressed gene Cathepsin C (CTSC)/dipeptidyl peptidase 1 (DPP-1) in epithelia of SA and UA patients using RNA sequencing data and further verified the increased expression of CTSC in induced sputum of asthma patients which was positively correlated with the severity and airway remodeling. Moreover, direct instillation of exogenous CTSC induced airway remodeling. Genetic inhibition of CTSC suppressed EMTU activation and airway remodeling in two asthma models with airway remodeling. Mechanistically, increased secretion of CTSC from AECs induced EMTU activation through p38-mediated pathway, further inducing airway remodeling. Meanwhile, inhibition of CTSC also reduced the infiltration of inflammatory cells and the production of inflammatory factors in the lungs of asthmatic mice. Consequently, targeting CTSC with compound AZD7986 protected against airway inflammation, EMTU activation and remodeling in asthma model. Based on the dual effects of CTSC on airway inflammation and remodeling, CTSC is a potential biomarker and therapeutic target for SA or UA.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.178373
Katsuhito Ihara, Eiichiro Satake, Parker C Wilson, Bozena Krolewski, Hiroki Kobayashi, Zaipul I Md Dom, Joseph Ricca, Jonathan Wilson, Jonathan M Dreyfuss, Monika A Niewczas, Alessandro Doria, Robert G Nelson, Marcus G Pezzolesi, Benjamin D Humphreys, Kevin Duffin, Andrzej S Krolewski
{"title":"Circulating proteins linked to apoptosis processes and fast development of end-stage kidney disease in diabetes.","authors":"Katsuhito Ihara, Eiichiro Satake, Parker C Wilson, Bozena Krolewski, Hiroki Kobayashi, Zaipul I Md Dom, Joseph Ricca, Jonathan Wilson, Jonathan M Dreyfuss, Monika A Niewczas, Alessandro Doria, Robert G Nelson, Marcus G Pezzolesi, Benjamin D Humphreys, Kevin Duffin, Andrzej S Krolewski","doi":"10.1172/jci.insight.178373","DOIUrl":"10.1172/jci.insight.178373","url":null,"abstract":"<p><p>Many circulating proteins are associated with risk of ESKD, but their source and the biological pathways/disease processes they represent are unclear. Using OLINK proteomics platform, concentrations of 455 proteins were measured in plasma specimens obtained at baseline from 399 individuals with diabetes. Elevated concentrations of 46 circulating proteins were associated (P < 1 × 10-5) with development of ESKD (n = 143) during 7-15 years of follow-up. Twenty of these proteins enriched apoptosis/TNF receptor signaling pathways. A subset of 20 proteins (5-7 proteins), summarized as an apoptosis score, together with clinical variables accurately predicted risk of ESKD. Expression of genes encoding the 46 proteins in peripheral WBCs showed no difference between cells from individuals who did or did not develop ESKD. In contrast, plasma concentration of many of the 46 proteins differed by this outcome. In single-nucleus RNA-Seq analysis of kidney biopsies, the majority of genes encoding for the 20 apoptosis/TNF receptor proteins were overexpressed in injured versus healthy proximal tubule cells. Expression of these 20 genes also correlated with the overall index of apoptosis in these cells. Elevated levels of circulating proteins flagging apoptotic processes/TNF receptor signaling pathways - and likely originating from kidney cells, including injured/apoptotic proximal tubular cells - preceded the development of ESKD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465878","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}
JCI insightPub Date : 2024-10-22DOI: 10.1172/jci.insight.176527
Shuai Dong, Cong Fu, Chang Shu, Min Xie, Yan Li, Jun Zou, Yi-Zi Meng, Peng Xu, Yan-Hong Shan, Hui-Min Tian, Jin He, Yong-Guang Yang, Zheng Hu
{"title":"Development of a humanized mouse model with functional human materno-fetal interface immunity.","authors":"Shuai Dong, Cong Fu, Chang Shu, Min Xie, Yan Li, Jun Zou, Yi-Zi Meng, Peng Xu, Yan-Hong Shan, Hui-Min Tian, Jin He, Yong-Guang Yang, Zheng Hu","doi":"10.1172/jci.insight.176527","DOIUrl":"10.1172/jci.insight.176527","url":null,"abstract":"<p><p>Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465879","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}