Biology subjects

Maecker, H.

Publications and source records attributed to Maecker, H..

15 recordsLinked to original sources

bioRxiv2026

Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) Signature Predicts Cardiovascular Risk in Elderly Patients

Despite advances in clinical care, cardiovascular disease (CVD) remains the leading cause of disability and mortality worldwide. While age alone is a primary risk factor for CVD, accumulating evidence suggests the immune system influences the initiation and progression of CVD pathophysiology, particularly in heart failure with preserved ejection fraction (HFpEF) and atherosclerotic CVD (ASCVD). Here, using two independent cohorts of older adults, we develop a thirty-protein signature of age based on serum immune proteomics, which correlates with HFpEF and ASCVD risk and mortality (Immuno-Proteomic Age of Cardiovascular Etiology, iPACE). We find aging-related circulating immune proteins associated with ASCVD and HFpEF-specific resilience and susceptibility that may be used as potential prognostic, diagnostic, or therapeutic targets.

immunology↗

bioRxiv2026

Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease

AbstractNeuroinflammation, along with amyloid beta (A{beta}) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimers disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in nai ve T killer cells and phospho-PLC{gamma}2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-nai ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/716122v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@f5060corg.highwire.dtl.DTLVardef@600ba7org.highwire.dtl.DTLVardef@19d281dorg.highwire.dtl.DTLVardef@b4a36a_HPS_FORMAT_FIGEXP M_FIG Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimers disease. C_FIG

neuroscience↗

bioRxiv2025

Serum cytokines during acute respiratory infection and relationship to age

Influenza and other seasonal respiratory viruses affect millions annually. While age is generally known to be correlated with risk and outcome, the mechanisms underlying these differences, especially in the infected, have been poorly defined. Previous studies have focused primarily on cell-subset shifts in older adults, leaving a gap in understanding of how cytokine responses vary across the full age spectrum. Cytokine data from Luminex assays were compiled from Stanford clinical studies and after batch control filtering, the dataset included 181 healthy individuals (ages 4-97) and 27 symptomatic individuals (mostly confirmed influenza, ages 14-77). Ordinary least squares regression was applied to assess cytokine differences due to infection status, age, and their interaction, with statistical significance defined as p < 0.05. The results illustrated that pro-inflammatory cytokines were found to be significantly elevated in infected individuals, with a trend of stronger effects in the young supported by comparison of intercepts between the regressions for the healthy and infected cohorts. The concept of inflammaging was also seen through several biomarkers with significant non-zero slopes in healthy cohorts that were not well-established in prior research. Our findings reveal both expected and novel cytokine behavior in influenza infection across a wide range of ages. By incorporating younger individuals and including age as a continuous variable, the study makes progress towards a deeper understanding of the changes in the immune system and its response to influenza across the lifespan.

immunology↗

bioRxiv2025

Comprehensive Analysis of Multi-Omics Vaccine Response Data Using MOFA and Stabl Algorithms

FluPRINT is a multi-omics dataset that measures donors protein expression and cell counts across various assays. Donors were also assigned a binary value (0 or 1), being labeled as high responders (1) if they had a fold change [≥] 4 of the antibody titer for hemagglutinin inhibition (HAI) from day 0 to day 28, and low responders otherwise (0). In this project, we used the MOFA and Stabl algorithms to analyze FluPRINT, estimate the population structure from the data, and identify the most important features for predicting response to the vaccine. The preprocessing of the dataset included removing repeat features, scaling by assay, and removing outliers. Since Stabl does not directly address missing values, features with high amounts of missing values were removed and the remaining were ignored. MOFA identified the top feature in structure extraction as IL neg 2 CD4 pos CD45RA neg pSTAT5. MOFA explains well the variance of the data while also choosing features that have good significance, as illustrated by their significant p-values (p < 0.05). Stabl found the top feature for explaining the outcome to be CD33- CD3+ CD4+ CD25hiCD127low CD161+ CD45RA+ Tregs, which matched the top result of previously published analysis. MOFAs features achieved an AUROC of 0.616 (95% CI of 0.426-0.806), and Stabls achieved an AUROC of 0.634 (95% CI of 0.432-0.823). Our research addresses a key knowledge gap: understanding how these fundamentally different analytical approaches perform when analyzing the same complex dataset. Our exploration evaluates their respective strengths, limitations, and biological insights and provides guidance on using MOFA and Stabl to find the best predictive cell subsets and features for understanding large immunological multi-omics data. The code for this project can be found at https://github.com/aanya21gupta/fluprint.

immunology↗

bioRxiv2025

Cytokine Regulation of Human Antibody Responses to Influenza Vaccines

Studies show that human vaccine responses widely vary. Here, we analyzed data measuring 66 cytokines from 4 different inactivated influenza vaccine (IIV) cohorts over 5 seasons (N=581) and identified a significant correlation between baseline/day 0 serum IL-18 and IFN-{beta} concentrations and the vaccine-specific antibody response on day 28, suggesting these factors may have an adjuvant-like effect. To investigate this further, we tested the impact of 19 cytokines on the development of anti-influenza antibody response when administered together with the IIV vaccine in human tonsil and spleen organoids. We found that Type I IFNs (IFN-{beta} and others), IL-21, IL-12, IL-10, but not IL-18 or IFN-{gamma}, enhanced the antibody response. The live attenuated influenza vaccine (LAIV) induced a stronger antibody response than the inactivated one in organoids. Adding a single cytokine, IFN-{beta}, to IIV stimulation recapitulated most of the live vaccine-specific cytokine activation program. It increased the antibody response of the inactivated vaccine to that of the LAIV. Two other antibody-boosting cytokines, IL-12 and IL-21, were induced by LAIV but not by Type I IFNs, indicating different cytokines can affect different pathways leading to a robust antibody response. We then generated cytokine mRNA lipid nanoparticles (LNPs) to test the effect of cytokines on IIV response in a mouse model of immunization. We found that IL-21-LNPs augmented the quantity and breadth of the antibody responses, while IFN-{beta} LNPs enhanced durability. These findings identified parallel cytokine pathways regulating human vaccine responses and provide a rationale for using cytokines as adjuvants to mimic the effectiveness of live-attenuated vaccines without the risk of viral replication.

immunology↗

bioRxiv2023

Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

immunology↗

bioRxiv2023

Age-Associated Weaker Immunity to Coronaviruses is Characteristic of Children that Develop Multisystem Inflammatory Syndrome following SARS-CoV-2 Infection

We analyzed the antibody and cytokine responses of twenty-three patients with multisystem inflammatory syndrome of children (MIS-C) that appeared with a three-to-six-week delay following a mild or asymptomatic SARS-CoV-2 infection. These responses were compared to healthy convalescent pediatric COVID-19 patients approximately twenty-eight days after the onset of symptoms. Both groups had strong IgG responses to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, but the MIS-C patients had weaker antibody responses to certain epitopes in the SARS-CoV-2 S and N proteins and to the S and N proteins of endemic human coronaviruses (HCoV) compared to pediatric convalescent COVID patients. HCoV antibody reactivity was correlated with age. In contrast, MIS-C patients had elevated serum levels of several proinflammatory cytokines compared to convalescent COVID patients, including interleukins IL-6, IL-8, IL-18 and chemokines CCL2, CCL8, CXCL5, CXCL9 and CXCL10 as well as tumor necrosis factor alpha and interferon gamma. Moreover, many cytokine responses of MIS-C patients were positively correlated with antibody responses to the SARS-CoV-2 S, N, membrane and ORF3a proteins while pediatric convalescent COVID patient cytokine responses were more often negatively correlated with antibody responses to the S, N and ORF3a proteins of SARS-CoV-2.

immunology↗

bioRxiv2023

Disease Tolerance Acquired Through Repeated Plasmodium Infection Involves Epigenetic Reprogramming of Innate Immune Cells

The regulation of inflammation is a critical aspect of disease tolerance and naturally acquired immunity to malaria. Here, we demonstrate using RNA sequencing and epigenetic landscape profiling by cytometry by Time-Of-Flight (EpiTOF), that the regulation of inflammatory pathways during asymptomatic parasitemia occurs downstream of pathogen sensing--at the epigenetic level. The abundance of certain epigenetic markers (methylation of H3K27 and dimethylation of arginine residues) and decreased prevalence of histone variant H3.3 correlated with suppressed cytokine responses among monocytes of Ugandan children. Such an epigenetic signature was observed across diverse immune cell populations and not only characterized active asymptomatic parasitemia but also predicted long-term future disease tolerance when observed in uninfected children. This broad methylated signature likely develops gradually and was associated with age and recent parasite exposure. Our data support a model whereby exposure to Plasmodium falciparum induces epigenetic changes that regulate excessive inflammation and contribute to naturally acquired immunity to malaria.

immunology↗

bioRxiv2023

Extending the dynamic range of biomarker quantification through molecular equalization

Precision medicine requires highly scalable methods of multiplexed biomarker quantification that can accurately describe patient physiology. Unfortunately, contemporary molecular detection methods are generally limited to a dynamic range of sensitivity spanning just 3-4 orders of magnitude, whereas the actual physiological dynamic range of the human plasma proteome spans more than 10 orders of magnitude. Current methods rely on sample splitting and differential dilution to compensate for this mismatch, but such measures greatly limit the reproducibility and scalability that can be achieved--in particular, the effects of non-linear dilution can greatly confound the analysis of multiplexed assays. We describe here a two- pronged strategy for equalizing the signal generated by each analyte in a multiplexed panel, thereby enabling simultaneous quantification of targets spanning a wide range of concentrations. We apply our EVROS strategy to a proximity ligation assay and demonstrate simultaneous quantification of four analytes present at concentrations spanning from low femtomolar to mid-nanomolar levels. In this initial demonstration, we achieve a dynamic range spanning seven orders of magnitude in a single 5 {micro}l sample of undiluted human serum, highlighting the opportunity to achieve sensitive, accurate detection of diverse analytes in a highly multiplexed fashion.

bioengineering↗

bioRxiv2023

Enkurin: A novel marker for myeloproliferative neoplasms from platelet, megakaryocyte, and whole blood specimens.

Impaired protein homeostasis, though well established in age-related disorders, has been linked in recent research with the pathogenesis of myeloproliferative neoplasms (MPNs). As yet, however, little is known about MPN-specific modulators of proteostasis, thus impeding our ability for increased mechanistic understanding and discovery of additional therapeutic targets. Loss of proteostasis, in itself, is traced to dysregulated mechanisms in protein folding and intracellular calcium signaling at the endoplasmic reticulum (ER). Here, using ex vivo and in vitro systems (including CD34+ cultures from patient bone marrow, and healthy cord/peripheral blood specimens), we extend our prior data from MPN patient platelet RNA sequencing, and discover select proteostasis-associated markers at RNA and/or protein levels in each of platelets, parent megakaryocytes, and whole blood specimens. Importantly, we identify a novel role in MPNs for enkurin (ENKUR), a calcium mediator protein, implicated originally only in spermatogenesis. Our data reveal consistent ENKUR downregulation at both RNA and protein levels across MPN patient specimens and experimental models, with a concomitant upregulation of a cell cycle marker, CDC20. Silencing of ENKUR by shRNA in CD34+ derived megakaryocytes further confirm this association with CDC20 at both RNA and protein levels; and indicate a likely role for the PI3K/Akt pathway. The inverse association of ENKUR and CDC20 expression was further confirmed upon treatment with thapsigargin (an agent that causes protein misfolding in the ER by selective loss of calcium) in both megakaryocyte and platelet fractions at RNA and protein levels. Together, our work sheds light on enkurin as a novel marker of MPN pathogenesis beyond the genetic alterations; and indicates further mechanistic investigation into a role for dysregulated calcium homeostasis, and ER and protein folding stress in MPN transformation. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/523111v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@80834corg.highwire.dtl.DTLVardef@12c033forg.highwire.dtl.DTLVardef@8948c8org.highwire.dtl.DTLVardef@1096184_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIEnkurin, a calcium adaptor protein, is identified as a novel marker of pathogenesis in MPNs. C_LIO_LIMPN megakaryocyte and platelet expression of enkurin at RNA and protein levels is inversely associated with a cell differentiation cycle gene, CDC20. C_LIO_LILikely role for dysregulated calcium homeostasis, and ER and protein folding stress in MPN transformation. C_LI

cancer biology↗

bioRxiv2022

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics

Approximately five million dengue virus-infected patients, particularly children, progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16+ monocytes, and high expression of the Fc{gamma}R, CD64 on myeloid cells, yet diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage vs. enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.

immunology↗

bioRxiv2022

Community assessment of methods to deconvolve cellular composition from bulk gene expression

We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

bioinformatics↗

bioRxiv2021

Progressive and predictive markers of disease evolution: platelet transcriptome in chronic myeloproliferative neoplasms

Predicting disease progression remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs) as a model, we identify the blood platelet transcriptome as a proxy for highly sensitive progression biomarkers that also enables prediction of advanced disease via machine learning algorithms. Using RNA sequencing (RNA-seq), we derive disease-relevant gene expression in purified platelets from 120 peripheral blood samples constituting two time-separated cohorts of patients diagnosed with one of three MPN subtypes at sample acquisition - essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), and healthy donors (n=21). The MPN platelet transcriptome reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy and discriminates each clinical phenotype. Leveraging this dataset that shows a characteristic progressive expression gradient across MPN, we develop a machine learning model (Lasso-penalized regression) and predict advanced subtype MF at high accuracy and under two conditions of external validation: i) temporal: our two Stanford cohorts, AUC-ROC of 0.96; and ii) geographical: independently published data of an additional n=25 MF and n=46 healthy donors, AUC-ROC of 0.97). Lasso-derived signatures offer a robust core set of < 5 MPN transcriptome markers that are progressive in expression. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis-associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs demonstrates a proof of principle for disease risk stratification and progression beyond genetic data alone, with potential utility in other progressive disorders. HighlightsLeveraging two independent and mutually validating MPN patient cohorts, we identify progressive transcriptomic markers that also enable externally validated prediction in MPNs. Our platelet RNA-Seq data identifies impaired protein homeostasis as prominent in MPN progression and offers putative targets of therapy. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=135 HEIGHT=200 SRC="FIGDIR/small/435190v3_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@72dc16org.highwire.dtl.DTLVardef@cf5096org.highwire.dtl.DTLVardef@b3d460org.highwire.dtl.DTLVardef@3c0ddc_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2019

An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans

While many diseases of aging have been linked to the immunological system, immune metrics with which to identify the most at-risk individuals are lacking. Here, we studied the blood immunome of 1001 individuals age 8-96 and derived an inflammatory clock of aging (iAge), which tracked with multi-morbidity and immunosenescence. In centenarians, iAge was on average, 40 years lower than their corresponding chronological age. The strongest contributor to this metric was the chemokine CXCL9, which was involved in cardiac aging, affected vascular function, and down-regulated Sirtuin-3, a longevity-associated molecule. Thus, our results identify an important link between inflammatory molecules and pathways known to govern lifespan.

immunology↗

bioRxiv2018

MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies

The MYC oncogene drives T and B lymphoid malignancies, including Burkitts lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Using CyTOF, we demonstrate a systemic reduction in natural killer (NK) cell-mediated surveillance in SR-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas, due to an arrest in NK cell maturation. Inactivation of lymphoma-intrinsic MYC releases the brakes on NK maturation restoring NK homeostasis. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.\n\nAbbreviations

cancer biology↗