Publications by authors named "Miriam Merad"

247 Publications

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

bioRxiv 2022 Jan 12. Epub 2022 Jan 12.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMΦ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.
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http://dx.doi.org/10.1101/2022.01.11.475918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764718PMC
January 2022

Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

Sci Transl Med 2022 Jan 18:eabm7853. Epub 2022 Jan 18.

Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, 94305, USA.

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcγR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.
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http://dx.doi.org/10.1126/scitranslmed.abm7853DOI Listing
January 2022

Expanding dendritic cell nomenclature in the single-cell era.

Nat Rev Immunol 2022 Jan 13. Epub 2022 Jan 13.

Precision Immunology Institute, Human Immune Monitoring Center, Department of Oncological Sciences Tisch Cancer Institute, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-022-00675-7DOI Listing
January 2022

Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy.

Nat Med 2021 Dec 10;27(12):2099-2103. Epub 2021 Dec 10.

Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial ( NCT03548207 ) and who developed a progressive movement disorder with features of parkinsonism approximately 3 months after ciltacabtagene autoleucel BCMA-targeted CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We show BCMA expression on neurons and astrocytes in the patient's basal ganglia. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting that this might be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade 3 or higher parkinsonism on the phase 2 ciltacabtagene autoleucel trial and of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.
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http://dx.doi.org/10.1038/s41591-021-01564-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678323PMC
December 2021

Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.

Cancer Cell 2021 12 11;39(12):1594-1609.e12. Epub 2021 Nov 11.

The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1CXCL13 activated T cells, IgG plasma cells, and SPP1 macrophages, referred to as the lung cancer activation module (LCAM). We confirmed LCAM enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAM lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2021.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728963PMC
December 2021

From mRNA sensing to vaccines.

Immunity 2021 12 4;54(12):2676-2680. Epub 2021 Nov 4.

The 2005 Immunity paper by Karikó et al. has been hailed as a cornerstone insight that directly led to the design and delivery of the mRNA vaccines against COVID-19. We asked experts in pathogen sensing, vaccine development, and public health to provide their perspective on the study and its implications.
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http://dx.doi.org/10.1016/j.immuni.2021.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567413PMC
December 2021

Variable cellular responses to SARS-CoV-2 in fully vaccinated patients with multiple myeloma.

Cancer Cell 2021 11 19;39(11):1442-1444. Epub 2021 Oct 19.

Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ccell.2021.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523488PMC
November 2021

Quantitative chest CT combined with plasma cytokines predict outcomes in COVID-19 patients.

medRxiv 2021 Oct 14. Epub 2021 Oct 14.

Despite extraordinary international efforts to dampen the spread and understand the mechanisms behind SARS-CoV-2 infections, accessible predictive biomarkers directly applicable in the clinic are yet to be discovered. Recent studies have revealed that diverse types of assays bear limited predictive power for COVID-19 outcomes. Here, we harness the predictive power of chest CT in combination with plasma cytokines using a machine learning approach for predicting death during hospitalization and maximum severity degree in COVID-19 patients. Patients (n=152) from the Mount Sinai Health System in New York with plasma cytokine assessment and a chest CT within 5 days from admission were included. Demographics, clinical, and laboratory variables, including plasma cytokines (IL-6, IL-8, and TNF-α) were collected from the electronic medical record. We found that chest CT combined with plasma cytokines were good predictors of death (AUC 0.78) and maximum severity (AUC 0.82), whereas CT quantitative was better at predicting severity (AUC 0.81 vs 0.70) while cytokine measurements better predicted death (AUC 0.70 vs 0.66). Finally, we provide a simple scoring system using plasma IL-6, IL-8, TNF-α, GGO to aerated lung ratio and age as novel metrics that may be used to monitor patients upon hospitalization and help physicians make critical decisions and considerations for patients at high risk of death for COVID-19.
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http://dx.doi.org/10.1101/2021.10.11.21264709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528085PMC
October 2021

Acute COVID-19 gene-expression profiles show multiple etiologies of long-term sequelae.

medRxiv 2021 Oct 5. Epub 2021 Oct 5.

Two years into the SARS-CoV-2 pandemic, the post-acute sequelae of infection are compounding the global health crisis. Often debilitating, these sequelae are clinically heterogeneous and of unknown molecular etiology. Here, a transcriptome-wide investigation of this new condition was performed in a large cohort of acutely infected patients followed clinically into the post-acute period. Gene expression signatures of post-acute sequelae were already present in whole blood during the acute phase of infection, with both innate and adaptive immune cells involved. Plasma cells stood out as driving at least two distinct clusters of sequelae, one largely dependent on circulating antibodies against the SARS-CoV-2 spike protein and the other antibody-independent. Altogether, multiple etiologies of post-acute sequelae were found concomitant with SARS-CoV-2 infection, directly linking the emergence of these sequelae with the host response to the virus.
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http://dx.doi.org/10.1101/2021.10.04.21264434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509101PMC
October 2021

Histiocytic disorders.

Nat Rev Dis Primers 2021 10 7;7(1):73. Epub 2021 Oct 7.

Texas Children's Cancer Center, Department of Paediatrics, Baylor College of Medicine, Houston, TX, USA.

The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207 antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.
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http://dx.doi.org/10.1038/s41572-021-00307-9DOI Listing
October 2021

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Nat Commun 2021 08 11;12(1):4854. Epub 2021 Aug 11.

Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56CD57 natural killer (NK) cells and exhausted CD8 T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8 T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.
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http://dx.doi.org/10.1038/s41467-021-24981-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357784PMC
August 2021

An aberrant inflammatory response in severe COVID-19.

Cell Host Microbe 2021 07;29(7):1043-1047

Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address:

Severe COVID-19 arises from the convergence of inadequate pre-existing immunity and a host response that damages, rather than repairs, tissues. We outline clinical presentations of COVID-19 that are likely driven by dysregulated host immunity, discuss potential mechanisms underlying pathological responses, and highlight important areas for basic research on this topic.
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http://dx.doi.org/10.1016/j.chom.2021.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279571PMC
July 2021

Children and SARS-CoV-2.

Cell Host Microbe 2021 07;29(7):1040-1042

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological science, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

A previously immune-naive world population is experiencing natural infection with SARS-CoV-2. Severe COVID-19 predominantly impacts adults, yet multisystem inflammatory disorder primarily impacts children. Herein, we discuss known clinical and biological features of SARS-CoV-2 in children and reflect on currently identified immune features and discuss what remains unknown.
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http://dx.doi.org/10.1016/j.chom.2021.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279573PMC
July 2021

Limited intestinal inflammation despite diarrhea, fecal viral RNA and SARS-CoV-2-specific IgA in patients with acute COVID-19.

Sci Rep 2021 06 25;11(1):13308. Epub 2021 Jun 25.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Gastrointestinal symptoms are common in COVID-19 patients but the nature of the gut immune response to SARS-CoV-2 remains poorly characterized, partly due to the difficulty of obtaining biopsy specimens from infected individuals. In lieu of tissue samples, we measured cytokines, inflammatory markers, viral RNA, microbiome composition, and antibody responses in stool samples from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.
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http://dx.doi.org/10.1038/s41598-021-92740-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233421PMC
June 2021

Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.

Nature 2021 07 16;595(7868):578-584. Epub 2021 Jun 16.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8 T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
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http://dx.doi.org/10.1038/s41586-021-03651-8DOI Listing
July 2021

IL10RB as a key regulator of COVID-19 host susceptibility and severity.

medRxiv 2021 Jun 2. Epub 2021 Jun 2.

Background: Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step.

Methods: We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence.

Results: We identify as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of and higher expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19.

Conclusions: We establish an integrative data-driven approach for gene target prioritization. We identify and validate as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.
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http://dx.doi.org/10.1101/2021.05.31.21254851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183086PMC
June 2021

A microRNA expression and regulatory element activity atlas of the mouse immune system.

Nat Immunol 2021 07 7;22(7):914-927. Epub 2021 Jun 7.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

To better define the control of immune system regulation, we generated an atlas of microRNA (miRNA) expression from 63 mouse immune cell populations and connected these signatures with assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq) and nascent RNA profiles to establish a map of miRNA promoter and enhancer usage in immune cells. miRNA complexity was relatively low, with >90% of the miRNA compartment of each population comprising <75 miRNAs; however, each cell type had a unique miRNA signature. Integration of miRNA expression with chromatin accessibility revealed putative regulatory elements for differentially expressed miRNAs, including miR-21a, miR-146a and miR-223. The integrated maps suggest that many miRNAs utilize multiple promoters to reach high abundance and identified dominant and divergent miRNA regulatory elements between lineages and during development that may be used by clustered miRNAs, such as miR-99a/let-7c/miR-125b, to achieve distinct expression. These studies, with web-accessible data, help delineate the cis-regulatory elements controlling miRNA signatures of the immune system.
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http://dx.doi.org/10.1038/s41590-021-00944-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480231PMC
July 2021

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response.

bioRxiv 2021 Dec 27. Epub 2021 Dec 27.

A damaging inflammatory response is strongly implicated in the pathogenesis of severe COVID-19 but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated, anti-SARS-CoV-2 IgG predicted progression from mild, to more severe COVID-19. In contrast to the antibody structures that predicted disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were low in Fc afucosylation and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an model which revealed that human IgG-FcγR interactions can regulate inflammation in the lung. Afucosylated IgG immune complexes induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine elicited IgG did not promote an inflammatory lung response. Here, we show that IgG-FcγR interactions can regulate inflammation in the lung and define distinct lung activities associated with the IgG that predict severe COVID-19 and protection against SARS-CoV-2.

One Sentence Summary: Divergent early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response and are functionally distinct .
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http://dx.doi.org/10.1101/2021.05.25.445649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168384PMC
December 2021

MMP2 and TLRs modulate immune responses in the tumor microenvironment.

JCI Insight 2021 06 22;6(12). Epub 2021 Jun 22.

Tisch Cancer Institute.

The presence of an immunosuppressive tumor microenvironment is a major obstacle in the success of cancer immunotherapies. Because extracellular matrix components can shape the microenvironment, we investigated the role of matrix metalloproteinase 2 (MMP2) in melanoma tumorigenesis. We found that MMP2 signals proinflammatory pathways on antigen presenting cells, and this requires both TLR2 and TLR4. B16 melanoma cells that express MMP2 at baseline have slower kinetics in Tlr2-/- Tlr4-/- mice, implicating MMP2 in promoting tumor growth. Indeed, Mmp2 overexpression in B16 cells potentiated rapid tumor growth, which was accompanied by reduced intratumoral cytolytic cells and increased M2 macrophages. In contrast, knockdown of Mmp2 slowed tumor growth and enhanced T cell proliferation and NK cell recruitment. Finally, we found that these effects of MMP2 are mediated through dysfunctional DC-T cell cross-talk as they are lost in Batf3-/- and Rag2-/- mice. These findings provide insights into the detrimental role of endogenous alarmins like MMP2 in modulating immune responses in the tumor microenvironment.
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http://dx.doi.org/10.1172/jci.insight.144913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262464PMC
June 2021

Cooperation between the alveolar epithelium and lung-resident basophils shapes alveolar macrophages.

Nat Rev Immunol 2021 Jun;21(6):344

OxMS Preprint Journal Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-021-00561-8DOI Listing
June 2021

MDSC: Markers, development, states, and unaddressed complexity.

Immunity 2021 05;54(5):875-884

The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has evolved, MDSCs most commonly describe cells arising during chronic inflammation, especially late-stage cancers, and are defined by their T cell immunosuppressive functions. This MDSC concept has helped explain myeloid phenomena associated with disease outcome, but currently lacks clear definitions and a unifying framework across pathologies. Here, we propose such a framework to classify MDSCs as discrete cell states based on activation signals in myeloid populations leading to suppressive modes characterized by specific, measurable effects. Developing this level of knowledge of myeloid states across pathological conditions may ultimately transform how disparate diseases are grouped and treated.
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http://dx.doi.org/10.1016/j.immuni.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709560PMC
May 2021

BRAF-induced senescence drives Langerhans cell histiocytosis pathophysiology.

Nat Med 2021 05 6;27(5):851-861. Epub 2021 May 6.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAF. We recently discovered that the BRAF mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAF mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.
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http://dx.doi.org/10.1038/s41591-021-01304-xDOI Listing
May 2021

Publisher Correction: Innate IL-13 licenses dermal type 2 dendritic cells for efficient T helper 2 cell responses.

Nat Rev Immunol 2021 May;21(5):336

OxMS Preprint Journal Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-021-00555-6DOI Listing
May 2021

Innate IL-13 licenses dermal type 2 dendritic cells for efficient T helper 2 cell responses.

Nat Rev Immunol 2021 05;21(5):275

OxMS Preprint Journal Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-021-00552-9DOI Listing
May 2021

Highlights from a year in a pandemic.

J Exp Med 2021 05;218(5)

Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

COVID-19 has emerged as one of the worst pandemics in recent history and has exposed the weaknesses of healthcare systems worldwide. Here, we reflect on the lessons learned from a year in a pandemic. We discuss the extraordinary scientific advances made in our understanding of a new disease, the failed and successful attempts to halt its progression, and the impact of the pandemic on the scientific discourse within the global community.
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http://dx.doi.org/10.1084/jem.20210220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042610PMC
May 2021

High-dimensional analysis defines multicytokine T-cell subsets and supports a role for IL-21 in atopic dermatitis.

Allergy 2021 10 25;76(10):3080-3093. Epub 2021 Apr 25.

Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Flow cytometry is a well-accepted approach for immune profiling; however, its value is restricted by the limited number of markers that can be analyzed simultaneously. Mass cytometry/CyTOF offers broad-scale immune characterization integrating large number of parameters. While partial blood phenotyping was reported in atopic dermatitis (AD), patients' comprehensive profiling, critical for leveraging new targeted treatments, is not available. IL-21 may be involved in inflammatory skin diseases but its role in AD is not well established.

Methods: We studied T-cell polarization in the blood of 20 moderate-to-severe AD and 15 controls. Using CyTOF and an unsupervised analysis, we measured the frequencies and mean metal intensities of activated polar CD4 /CD8 T-cell subsets. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to analyze skin samples.

Results: Examining 24 surface, intracellular markers, and transcription factors, we identified six CD4 and five CD8 T-cell metaclusters. A CD4 skin-homing IL-13 monocytokine and a novel IL-13 IL-21 multicytokine metaclusters were increased in AD vs. controls (p < .01). While IL-13 signature characterized both clusters, levels were significantly higher in the IL-21 group. Both clusters correlated with AD severity (r = 0.49, p = .029). Manual gating corroborated these results and identified additional multicytokine subsets in AD. Immunohistochemistry and immunofluorescence, validated by mRNA expression, displayed significantly increasedIL-21 counts and colocalization with IL-13/IL-4R in AD skin.

Conclusion: A multicytokine signature characterizes moderate-to-severe AD, possibly explaining partial therapeutic responses to one cytokine targeting, particularly in severe patients. Prominent IL-21 signature in blood and skin hints for a potential pathogenic role of IL-21 in AD.
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http://dx.doi.org/10.1111/all.14845DOI Listing
October 2021

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Mod Pathol 2021 08 1;34(8):1456-1467. Epub 2021 Apr 1.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41379-021-00793-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015313PMC
August 2021

A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease.

Nature 2021 05 31;593(7858):275-281. Epub 2021 Mar 31.

The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD2, which increase the risk of stricturing. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14 peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease-potentially as a complement to anti-TNF therapy.
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http://dx.doi.org/10.1038/s41586-021-03484-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284870PMC
May 2021

Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms.

Gastroenterology 2021 06 4;160(7):2435-2450.e34. Epub 2021 Mar 4.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

Background & Aims: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance.

Methods: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions.

Results: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms.

Conclusions: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
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http://dx.doi.org/10.1053/j.gastro.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931673PMC
June 2021

A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses.

medRxiv 2021 Feb 2. Epub 2021 Feb 2.

The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.
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http://dx.doi.org/10.1101/2021.01.29.21250755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872387PMC
February 2021
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