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Publication Keywords
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Moore AR, Zheng H, Ganesan A, Hasin-Brumshtein Y, Maddali MV, Levitt JE, van der Poll T, Lu J, Bouma HR, Scicluna BP, Giamarellos-Bourboulis EJ, Kotsaki A, Martin-Loeches I, Garduno A, Rothman RE, Sevransky J, Wright DW, Atreya MR, Moldawer LL, Efron PA, Kralovcova M, Karvunidis T, Giannini HM, Meyer NJ, Sweeney TE, ...
Nature medicine
2025-09-30
PMID: 41028543
HIPC 3 (2022)
Stanford
Abstract:
Critical care syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and trauma continue to have unacceptably high morbidity and mortality, with progress limited by the inherent heterogeneity within syndromic illnesses. Although numerous immune endotypes have been proposed for sepsis and critical care, the similarities and differences between these endotypes remain unclear, hindering clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine in critical care through the sharing of transcriptomic data. Here, evaluating the overlap of existing immune endotypes in sepsis across >7,074 samples from 37 independent cohorts, we developed cell-type-specific gene expression signatures to quantify dysregulation within immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. Importantly, this dysregulation was also observed in patients with ARDS, trauma and burns, suggesting a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation are associated with differential mortality in patients treated with anakinra in the SAVE-MORE trial (n = 452) and corticosteroids in the VICTAS (n = 89) and VANISH (n = 117) trials, underscoring their prognostic and therapeutic implications. In conclusion, our proposed immunology-based framework for quantifying cellular compartment dysregulation offers a potentially valuable tool for understanding immune dysregulation in critical illness with prognostic and therapeutic significance.
Saglimbeni J, Esteva E, Canales J, Perez OA, Eichinger A, Huntley W, Khanna KM, Dolgalev I, Klar N, Adams S, Reizis B
Proceedings of the National Academy of Sciences of the United States of America
2025-09-23
PMID: 40953260
Animals
Breast Neoplasms
Columbia University
Eosinophils
Female
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Interleukin-33
Macrophages
Mammary Neoplasms, Experimental
Mice
T-Lymphocytes, Regulatory
Tumor-Associated Macrophages
Tumor Microenvironment
Abstract:
Breast tumors harbor dynamic microenvironments, with multiple immune cell types playing opposing roles during tumor progression and/or response to therapy. Tumor-associated macrophages promote mammary tumorigenesis, whereas the role of mammary tissue macrophages (MTMs) remains incompletely understood. High-dimensional immunostaining of murine mammary tumor progression revealed that MTMs were localized in the peritumoral stroma and associated with eosinophils, which were previously shown to facilitate antitumor T cell responses. The depletion of MTMs accelerated tumorigenesis in both spontaneous and orthotopically transplanted mammary tumor models. Upon induction of a productive antitumor response via the depletion of regulatory T cells, MTMs assumed an alternatively activated state and expressed eotaxins, thereby attracting eosinophils to peritumoral regions. MTMs expressed the receptor for the alarmin IL-33, which induced both MTM activation and eosinophil recruitment. These results suggest that MTMs can sense IL-33 and recruit eosinophils to facilitate antitumor immunity, a mechanism that may operate during tumor progression and be further enhanced during productive antitumor responses.
Gervais A, Trespidi F, Ferrari A, Rovida F, Marchal A, Croce S, Cassaniti I, Moratti M, Uhrlaub JL, Florian DM, Stiasny K, Burdino E, Angelini M, Bizien L, Lilleri D, Codullo V, Freund T, Paran Y, Gadoth A, Biran R, Mancon A, Lucca C, Vogiatzis S, Pacenti M, Aubart M, ...
medRxiv : the preprint server for health sciences
2025-09-04
PMID: 40950468
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Yale University
Abstract:
Mosquito-borne West Nile virus (WNV) infection is a growing global health problem. About 0.5% of infected individuals develop encephalitis. We previously showed that 40% of patients in six cohorts had WNV encephalitis because of circulating auto-antibodies (auto-Abs) neutralizing type I IFNs. In seven new cohorts, we found that the prevalence of auto-Abs was highest (40% [17-44%]) in patients with encephalitis, and very low in a small sample of individuals with asymptomatic or mild infection. In the 13 European, Middle-Eastern and American cohorts available, odds ratios for WNV encephalitis in individuals with these auto-Abs relative to those without them in a large sample of the general population untested for WNV infection range from ~20 (OR=17.7; 95% CI: 13.8-22.8, p<10-16) for auto-Abs neutralizing only 100 pg/mL IFN-α2 and/or IFN-ω to >2000 (OR=2218.4; 95% CI: 125.1-39337.7, p<10-16) for auto-Abs neutralizing high concentrations of IFN-α2 and high or low concentrations of IFN-ω. Pre-existing autoantibodies neutralizing type I IFNs are therefore causal for WNV encephalitis in about 40% of patients.
Carrillo FAB, Ojeda S, Sanchez N, Plazaola M, Collado D, Miranda T, Saborio S, Mercado BL, Monterrey JC, Arguello S, Campredon L, Chu Z, Carlson CJ, Gordon A, Balmaseda A, Kuan G, Harris E
The Lancet. Child & adolescent health
2025-09-01
PMID: 40774783
Adolescent
Chikungunya Fever
Child
Child, Preschool
Dengue
Female
HIPC 2 (2015)
Humans
Male
Nicaragua
Prospective Studies
Zika Virus Infection
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis of these three diseases is complicated in children and adolescents due to overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared these three diseases. We aimed to use 18 years of primary care observations from a paediatric cohort to characterise the distinguishing features of dengue, chikungunya, and Zika.'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'This single-centre prospective cohort study was based on the ongoing Pediatric Dengue Cohort Study (PDCS), which started on Aug 30, 2004, in District II of Managua, Nicaragua. The PDCS was initiated to study dengue virus infections in children who attended the Health Center Sócrates Flores Vivas (HCSFV) for their medical needs; over the years, the PDCS expanded the age range (2 to <10 years expanded to 2 to <18 years). The PDCS also expanded eligibility criteria to include chikungunya virus and Zika virus before they entered the geographical study area in August, 2014 and January, 2016, respectively. For this study, we included laboratory confirmed cases of dengue, chikungunya, and Zika enrolled in the PDCS between Jan 19, 2006, and Dec 31, 2023, and evaluated at the HCSFV. We assessed clinical features (clinical records and laboratory results) during the first 10 days of illness using generalised additive models, day-specific and disease-specific prevalence estimates, and machine learning models.'}, {'@Label': 'FINDINGS', '@NlmCategory': 'RESULTS', '#text': 'We characterised 1405 dengue, 517 chikungunya, and 522 Zika cases. The median age was 10·0 years (IQR 7·0-12·7); 1165 (47·7%) cases were male and 1279 (52·3%) were female. The prevalence of many clinical features shown by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. The presence of basophilia (prevalence difference 42·3% [95% CI 37·4 to 47·0]), monocytopenia (13·0% [10·0 to 16·4]), abdominal pain (19·1% [15·7 to 22·9]), and leukopenia (41·1% [36·2 to 45·6]) best distinguished dengue; the presence of arthralgia (60·5% [56·3 to 64·2]) and absence of papular rash (-14·9% [-17·2 to -12·7]), leukopenia (-32·0% [-36·7 to -27·1]), and conjunctival injection (-4·9% [-6·6 to -3·3]) best distinguished chikungunya; and the presence of generalised rash (35·0% [30·1 to 39·7]) and absence of fever (-37·3% [-41·7 to -33·0]), headache (-36·2% [-41·1 to -31·2]), myalgia (-30·1% [-33·9 to -26·2]), and lymphocytopenia (-41·9% [-46·6 to -37·1]) best distinguished Zika. Dengue and chikungunya cases showed similar temperature dynamics during acute illness, and their mean temperatures were higher than Zika cases. 62 laboratory confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented most similarly to afebrile Zika cases, but five (8·1%) had warning signs of dengue disease severity. Based on boosted regression tree models, the presence of arthralgia and absence of basophilia and leukopenia most distinguished chikungunya, the presence of basophilia and leukopenia most distinguished dengue, and the absence of fever most distinguished Zika.'}, {'@Label': 'INTERPRETATIONS', '@NlmCategory': 'CONCLUSIONS', '#text': 'These findings substantially update the understanding of dengue, chikungunya, and Zika in a paediatric population and identify various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current guidance.'}, {'@Label': 'FUNDING', '@NlmCategory': 'BACKGROUND', '#text': 'US National Institutes of Health.'}, {'@Label': 'TRANSLATION', '@NlmCategory': 'UNASSIGNED', '#text': 'For the Spanish translation of the abstract see Supplementary Materials section.'}]
Wells SB, Rainbow DB, Mark M, Szabo PA, Ergen C, Caron DP, Maceiras AR, Rahmani E, Benuck E, Valiollah Pour Amiri V, Chen D, Wagner A, Howlett SK, Jarvis LB, Ellis KL, Kubota M, Matsumoto R, Mahbubani K, Saeb-Parsy K, Conde CD, Richardson L, Xu C, Li S, Mamanova L, Bolt L, ...
Nature immunology
2025-09-01
PMID: 40804529
Adult
Aged
Aging
B-Lymphocytes
Cell Lineage
Columbia University
Female
Gene Expression Profiling
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Killer Cells, Natural
Lymphoid Tissue
Macrophages
Male
Middle Aged
Organ Specificity
T-Lymphocytes
Transcriptome
Young Adult
Abstract:
The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.
Johnson MM, Kaushik A, Kline OA, Smith EM, Zhou X, Pat Y, Buergi L, Aguilera J, Alkotob S, Simonin EM, Favaro A, Couto M, Bennett O, Chinthrajah RS, Parsons E, Shamji M, Burke M, Bondy M, Akdis M, Akdis CA, Nadeau KC
Nature medicine
2025-09-01
PMID: 40571754
Adult
Biomarkers
Case-Control Studies
DNA Methylation
Environmental Exposure
Female
Fires
HIPC 3 (2022)
Humans
Male
Middle Aged
Smoke
Stanford
Abstract:
Exposure to fire smoke has become a global health concern and is associated with increased morbidity and mortality. There is a lack of understanding of the specific immune mechanisms involved in smoke exposure, with preventive and targeted interventions needed. After exposure to fire smoke, which includes PM2.5, toxic metals and perfluoroalkyl and polyfluoroalkyl substances, epidemiology-based studies have demonstrated increases in respiratory (for example, asthma exacerbation), cardiac (for example, myocardial infarction, arrhythmias), neurological (for example, stroke) and pregnancy-related (for example, low birthweight, premature birth) outcomes. However, mechanistic studies exploring how smoke exposure disrupts cellular homeostasis are lacking. Therefore, we collected blood from smoke-exposed individuals (n = 31) and age-matched and sex-matched non-smoke-exposed controls (n = 29), and investigated these complex interactions using a single-cell exposomic approach based on both methylation and mass cytometry. Overall, our data demonstrated a strong association between smoke exposure and methylation at 133 disease-relevant gene loci, while immunophenotyping showed increased homing and activation biomarkers. We developed an application of mass cytometry to analyze single-cell/metal binding and found, for example, increased levels of mercury in dead cells and cadmium in the live and dead cell populations. Moreover, mercury levels were associated with years of smoke exposure. Several epigenetic sites across multiple chromosomes were associated with individual toxic metal isotopes in single immune cells. Our methods for detecting the effect of smoke exposure at the single-cell level and the study results may help to determine the timing of exposure and identify specific molecular targets that could be modified to prevent and manage exposure to smoke.
Rao VN, Sapse IA, Cohn H, Yoo DK, Tong P, Clark JJ, Bozarth B, Chen Y, Srivastava K, Singh G, Krammer F, Simon V, Wesemann DR, Bajic G, Coelho CH
Cell reports
2025-08-26
PMID: 40803328
Antibodies, Viral
Antibody Affinity
Epitopes
HIPC 3 (2022)
Humans
Icahn School of Medicine at Mount Sinai
Somatic Hypermutation, Immunoglobulin
Abstract:
Investigating public antibodies that recognize conserved epitopes is critical for vaccine development. Identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public antibodies is key to guiding vaccine design for better protection against pathogens. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes but with different epitope specificities. Using M15, a human IGHV4-59/IGKV3-20 public antibody as a model, we compare SHM signatures in antibodies that use the same V genes but recognize other epitopes. We identified clonotype-enriched mutations in the light chain of M15 and showed that, in combination, these SHMs enhance binding to a previously uncharacterized Sarbecovirus epitope, with antibody responses to it increasing after sequential vaccination. Our findings identify convergence and clonotype enrichment as features of affinity-enhancing SHMs in public antibodies, which can help guide vaccine design aimed at eliciting such antibodies.
Pickering H, Alipanah-Lechner N, Chen E, Duchen D, Maecker HT, Kim-Schulze S, Montgomery RR, Cotsapas C, Steen H, Krammer F, Langelier CR, Levy O, Baden LR, Melamed E, Ehrlich LI, McComsey GA, Sekaly RP, Cairns CB, Haddad EK, Shaw AC, Hafler DA, Corry DB, Kheradmand F, Atkinson MA, Brakenridge SC, ...
JCI insight
2025-08-08
PMID: 40608426
Acute Lung Injury
Adult
Aged
Alleles
COVID-19
Female
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Histocompatibility Antigens Class I
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Respiration, Artificial
SARS-CoV-2
Yale University
Abstract:
MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from IMPACC. Associations between MICBG406A and outcomes were determined by linear regression or Cox proportional hazards models. We also measured immune profiles of peripheral blood and the upper and lower airway. We identified 560 major allele homozygous patients, and 426 and 50 with 1 or 2 copies of the variant allele, respectively. MICBG406A conferred reduced odds of severe COVID-19. MICBG406A homozygous participants demonstrated 34% reduced cumulative odds for mechanical ventilation or death and 43% reduced risk for mortality. Patients with MICBG406A variant alleles had reduced soluble inflammatory mediators and differential regulation of multiple immune pathways. These findings demonstrate a potentially novel association between increasing MICBG406A variant allele copies and reduced COVID-19 severity, independent of SARS-CoV-2 viral burden and humoral immunity, suggesting the NKG2D-ligand pathway as an intervention target.
Fantin RF, Clark JJ, Cohn H, Jaiswal D, Bozarth B, Rao V, Civljak A, Lobo I, Nardulli JR, Srivastava K, Yong JS, Andreata-Santos R, Bushfield K, Lee ES, Singh G, Kleinstein SH, Krammer F, Simon V, Bajic G, Coelho CH
The Lancet. Microbe
2025-08-01
PMID: 40456237
Adult
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
B-Lymphocytes
BNT162 Vaccine
COVID-19
COVID-19 Vaccines
Female
HIPC 3 (2022)
Humans
Icahn School of Medicine at Mount Sinai
Immunization, Secondary
Male
Middle Aged
SARS-CoV-2
Spike Glycoprotein, Coronavirus
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'The rapid emergence of highly transmissible and immune-evasive SARS-CoV-2 variants has required the reformulation of COVID-19 vaccines to target these evolving threats. Although previous infections and booster vaccinations can boost variant neutralisation, it remains uncertain whether monovalent vaccines-delivered via mRNA or protein-based platforms-can trigger novel B-cell responses specific to omicron XBB.1.5 variants. We sought to address this uncertainty by characterising the antibody repertoire of individuals receiving a monovalent booster vaccine.'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'In this observational study, we analysed the genetic antibody repertoire of 603 individual plasmablasts from five individuals (recruited at the Icahn School of Medicine at Mount Sinai, New York, NY, USA, from STUDY-16-01215/IRB-16-00971 and STUDY-20-00442/IRB-20-03374) vaccinated with a monovalent XBB.1.5 vaccine, either through mRNA (Moderna or Pfizer-BioNTech; participants 1, 2, and 3) or adjuvanted protein (Novavax; participants 4 and 5) platforms. Before XBB.1.5 booster vaccination, all participants received mRNA-based priming and booster vaccine with ancestral SARS-CoV-2 and four of the five participants had a breakthrough omicron variant infection. We expressed 100 human monoclonal antibodies (mAbs; 50 from participants 1, 2, and 3, and 50 from participants 4 and 5) and evaluated their binding and neutralisation against various SARS-CoV-2 variants, including JN.1. We then selected four mAbs for in-vivo protection experiments by passive immunisation and viral challenge, and cryo-electron microscopy with two selected mAbs complexed with the XBB.1.5 spike (S) protein to determine their structures and binding interactions.'}, {'@Label': 'FINDINGS', '@NlmCategory': 'RESULTS', '#text': 'Between October and November, 2023, we enrolled three male and two female participants (mean age 46 years) all of whom were White. We identified 21 binding mAbs and tested their neutralisation capacity against ancestral SARS-CoV-2, XBB.1.5, and JN.1. From the six neutralising mAbs we characterised, we selected three (M2, M27, and M39) for in-vivo protection studies, along with one broadly binding antibody (M15), finding that three neutralising mAbs offered full protection against morbidity from XBB.1.5. M27 also displayed robust protection against the ancestral and JN.1 strains, and M39 offered partial protection from JN.1. Among these, we identified two standout antibodies: M2 and M39. M2 was uniquely specific to XBB.1.5, and M39 demonstrated the ability to bind and neutralise both XBB.1.5 and JN.1 strains. Using high-resolution cryo-electron microscopy, we mapped the binding sites of M2 and M39 on the XBB.1.5 S glycoprotein, uncovering the precise molecular interactions that dictate their specificity.'}, {'@Label': 'INTERPRETATION', '@NlmCategory': 'CONCLUSIONS', '#text': 'Our findings offer key molecular insights into whether strain-specific boosters elicit sufficient protection against SARS-CoV-2 emerging variants. This knowledge can inform decisions on booster design and strategies to enhance preparedness to evolving viral threats.'}, {'@Label': 'FUNDING', '@NlmCategory': 'BACKGROUND', '#text': 'Icahn School of Medicine at Mount Sinai; National Institutes of Health (NIH) FIRST; Laura and Isaac Perlmutter Cancer Center Support Grant; National Institute of Allergy and Infectious Diseases; Human Immunology Project Consortium by NIH; the São Paulo Research Foundation; the National Heart, Lung, and Blood Institute of the NIH; Irma T Hirschl and Monique Weill-Caulier Trust; and the Collaborative Influenza Vaccine Innovation Centers.'}]
Tsuji I, Dominguez D, Hernandez J, Kpamegan E, Zambrana JV, Balmaseda A, Dean H, Sharma M, Harris E
The Journal of infectious diseases
2025-07-30
PMID: 40179248
Adolescent
Antibodies, Viral
Antibody Affinity
Child
Child, Preschool
Cohort Studies
Dengue
Dengue Virus
Female
HIPC 2 (2015)
Humans
Male
Nicaragua
Abstract:
Antibody avidity is indicative of antibody affinity maturation following virus infection or vaccination. To determine correlation between preexisting anti-dengue virus (DENV) antibody avidity and secondary DENV exposure outcomes, we assessed anti-DENV antibody avidity, represented as avidity index (antibody response/dissociation rate) in sera of Nicaraguan Pediatric Dengue Cohort Study participants prior to symptomatic or inapparent secondary DENV infections. The avidity index was significantly higher in participants who subsequently developed inapparent versus symptomatic infections. Risk factor analysis suggested that odds of inapparent DENV infection increase as avidity index increases. Antibody avidity index is an important parameter for characterizing protective DENV immune responses.
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