ABSTRACT
The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.
Subject(s)
Fungi , Gastrointestinal Microbiome , Mycobiome , Animals , Humans , Male , Mice , Feces/microbiology , Fungi/genetics , Fungi/classification , Fungi/isolation & purification , Genome, Fungal/genetics , Genomics , Inflammatory Bowel Diseases/microbiology , Inflammatory Bowel Diseases/genetics , Metagenome , Phylogeny , Female , Adult , Middle AgedABSTRACT
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
Subject(s)
Clonal Hematopoiesis , DNA (Cytosine-5-)-Methyltransferases , DNA Methyltransferase 3A , Periodontitis , Animals , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA (Cytosine-5-)-Methyltransferases/genetics , Mice , Clonal Hematopoiesis/genetics , Humans , Periodontitis/genetics , Periodontitis/pathology , Mutation , Male , Female , Inflammation/genetics , Inflammation/pathology , Osteoclasts/metabolism , Mice, Inbred C57BL , Adult , Interleukin-17/metabolism , Interleukin-17/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Hematopoiesis/genetics , Osteogenesis/genetics , Hematopoietic Stem Cells/metabolism , Bone Resorption/genetics , Bone Resorption/pathology , Middle AgedABSTRACT
Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.
Subject(s)
COVID-19 Drug Treatment , COVID-19 , Dexamethasone , Monocytes , SARS-CoV-2 , Single-Cell Analysis , Humans , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Monocytes/metabolism , Monocytes/drug effects , SARS-CoV-2/drug effects , Male , Female , Transcriptome , Middle Aged , Aged , Glucocorticoids/therapeutic use , Glucocorticoids/pharmacology , Lung/pathology , AdultABSTRACT
Menopause is the cessation of ovarian function, with loss of reproductive hormone production and irreversible loss of fertility. It is a natural part of reproductive aging. The physiology of the menopause is complex and incompletely understood. Globally, menopause occurs around the age of 49 years, with geographic and ethnic variation. The hormonal changes of the menopause transition may result in both symptoms and long-term systemic effects, predominantly adverse effects on cardiometabolic and musculoskeletal health. The most effective treatment for bothersome menopausal symptoms is evidence-based, menopausal hormone therapy (MHT), which reduces bone loss and may have cardiometabolic benefits. Evidence-based non-hormonal interventions are also available for symptom relief. Treatment should be individualized with shared decision-making. Most MHT regimens are not regulator approved for perimenopausal women. Studies that include perimenopausal women are needed to determine the efficacy and safety of treatment options. Further research is crucial to improve menopause care, along with research to guide policy and clinical practice.
Subject(s)
Cardiovascular Diseases , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Middle Aged , Menopause , Aging , BiologyABSTRACT
Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Neurodegenerative Diseases , Humans , Middle Aged , Aged , Aged, 80 and over , Ligands , Brain , Aging , Lipids , BiomarkersABSTRACT
Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.
Subject(s)
Dermatoglyphics , Fingers/growth & development , Organogenesis/genetics , Polymorphism, Single Nucleotide , Toes/growth & development , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Asian People/genetics , Body Patterning/genetics , Child , Cohort Studies , Female , Forelimb/growth & development , Genetic Loci , Genome-Wide Association Study , Humans , MDS1 and EVI1 Complex Locus Protein/genetics , Male , Mice , Middle Aged , Young AdultABSTRACT
Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.
Subject(s)
Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Cell Differentiation , Cohort Studies , Disease Progression , Epithelial Cells/pathology , Epithelium/pathology , Extracellular Matrix/metabolism , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/pathology , Phenotype , Single-Cell Analysis , Stromal Cells/pathology , Tumor MicroenvironmentABSTRACT
Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.
Subject(s)
COVID-19/immunology , COVID-19/pathology , Complement Activation , Proteome , SARS-CoV-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Transcriptome , Adult , Aged , Aged, 80 and over , COVID-19/virology , Chemotactic Factors/metabolism , Cytotoxicity, Immunologic , Endothelial Cells/virology , Female , Humans , Lymphocyte Activation , Male , Microvessels/virology , Middle Aged , Monocytes/metabolism , Neutrophils/metabolism , Receptors, IgG/metabolism , Single-Cell Analysis , Young AdultABSTRACT
HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.
Subject(s)
HIV-1/genetics , Proviruses/genetics , Transcription, Genetic , Aged , Base Sequence , Biological Evolution , Chromatin/metabolism , Clone Cells , DNA, Viral/genetics , Epigenesis, Genetic/drug effects , Female , Humans , Ionomycin/pharmacology , Male , Middle Aged , Phylogeny , Proviruses/drug effects , RNA, Viral/genetics , Tetradecanoylphorbol Acetate/pharmacology , Transcription, Genetic/drug effects , Virus Integration/genetics , Virus Latency/drug effects , Virus Latency/geneticsABSTRACT
Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.
Subject(s)
Brain Neoplasms/pathology , Brain Neoplasms/secondary , Adult , Aged , Animals , Biomarkers, Tumor/metabolism , Brain Neoplasms/blood , Brain Neoplasms/immunology , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Female , Genetic Variation , Humans , Immune Evasion , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Models, Biological , Myeloid Cells/pathology , Principal Component Analysis , RNA-Seq , Single-Cell Analysis , T-Lymphocytes/immunologyABSTRACT
SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.
Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity/immunology , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Vaccination , Vaccines, Synthetic/immunology , mRNA Vaccines/immunology , Adult , B-Lymphocytes/immunology , BNT162 Vaccine/immunology , COVID-19/blood , Clone Cells , Cohort Studies , Cytokines/metabolism , Female , Germinal Center/immunology , HLA-DP beta-Chains/immunology , Humans , Immunodominant Epitopes/immunology , Jurkat Cells , Lymph Nodes/metabolism , Male , Middle Aged , Peptides/chemistry , Peptides/metabolism , Protein Multimerization , Receptors, Antigen, T-Cell/metabolismABSTRACT
An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.
Subject(s)
COVID-19/epidemiology , COVID-19/immunology , COVID-19/transmission , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/virology , Child , Child, Preschool , Contact Tracing/methods , Disease Outbreaks , Female , Genome, Viral , Humans , Infant , Infant, Newborn , Male , Massachusetts/epidemiology , Middle Aged , Molecular Epidemiology , Phylogeny , SARS-CoV-2/classification , Vaccination , Whole Genome Sequencing , Young AdultABSTRACT
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
Subject(s)
COVID-19/complications , COVID-19/diagnosis , Convalescence , Adaptive Immunity/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Autoantibodies/blood , Biomarkers/metabolism , Blood Proteins/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Disease Progression , Female , Humans , Immunity, Innate/genetics , Longitudinal Studies , Male , Middle Aged , Risk Factors , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult , Post-Acute COVID-19 SyndromeABSTRACT
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.
Subject(s)
Biomarkers/blood , COVID-19/pathology , Proteome/analysis , Adult , Blood Proteins/metabolism , COVID-19/blood , COVID-19/virology , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Female , Humans , Influenza, Human/blood , Influenza, Human/pathology , Lymphocytes/immunology , Lymphocytes/metabolism , Machine Learning , Male , Middle Aged , Mitogen-Activated Protein Kinase 14/genetics , Mitogen-Activated Protein Kinase 14/metabolism , Monocytes/immunology , Monocytes/metabolism , Principal Component Analysis , SARS-CoV-2/isolation & purification , Sepsis/blood , Sepsis/pathology , Severity of Illness Index , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolismABSTRACT
Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.
Subject(s)
Macrophages , Neoplasms , Sepsis , Humans , Sepsis/immunology , Macrophages/immunology , Female , Neoplasms/immunology , Neoplasms/therapy , Male , Receptors, CXCR6/metabolism , Animals , T-Lymphocytes/immunology , Receptors, CCR2/metabolism , Middle Aged , Mice , Aged , Chemokines/metabolism , AdultABSTRACT
To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.
Subject(s)
Colitis, Ulcerative , Hepatocyte Nuclear Factor 1-alpha , Colitis, Ulcerative/immunology , Colitis, Ulcerative/pathology , Humans , Animals , Mice , Hepatocyte Nuclear Factor 1-alpha/metabolism , Hepatocyte Nuclear Factor 1-alpha/genetics , CD8-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Proto-Oncogene Proteins c-bcl-6/metabolism , Proto-Oncogene Proteins c-bcl-6/genetics , Stem Cells/immunology , Stem Cells/metabolism , Female , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Mice, Knockout , Colon/immunology , Colon/pathology , Male , Mice, Inbred C57BL , Adoptive Transfer , Disease Models, Animal , Adult , Middle AgedABSTRACT
Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.
Subject(s)
Celiac Disease , Diet, Gluten-Free , GTP-Binding Proteins , Gene Expression Profiling , Glutens , Intestinal Mucosa , Protein Glutamine gamma Glutamyltransferase 2 , Transglutaminases , Celiac Disease/immunology , Humans , Glutens/immunology , Transglutaminases/metabolism , Transglutaminases/antagonists & inhibitors , GTP-Binding Proteins/metabolism , GTP-Binding Proteins/antagonists & inhibitors , GTP-Binding Proteins/genetics , Intestinal Mucosa/pathology , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/drug effects , Female , Male , Adult , Transcriptome , Duodenum/pathology , Duodenum/immunology , Duodenum/metabolism , Interferon-gamma/metabolism , Middle Aged , HLA-DQ Antigens/genetics , HLA-DQ Antigens/immunology , Young Adult , Adaptive Immunity/drug effectsABSTRACT
Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/metabolism , Tumor Microenvironment , Adult , Aged , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Single-Cell AnalysisABSTRACT
Endometriosis is a common condition associated with infertility that causes chronic pain in many, but not all, women. It is defined by the presence of endometrial-like tissue outside the uterus. Although the cause and natural history of the disorder remain uncertain, hormonal, neurological, and immunological factors are all implicated in the mechanisms contributing to development of symptoms. Because definitive diagnosis requires surgery, there is often a long diagnostic delay after onset of symptoms. Current interventions for endometriosis have limited efficacy and unacceptable side effects/risks and are associated with high rates of symptom recurrence. Here, we review recent advances in our understanding of the etiology of endometriosis, discuss current diagnostic and treatment strategies, highlight current clinical trials, and consider how recent results offer new avenues for the identification of endometriosis biomarkers and the development of effective non-surgical therapies that are fertility-sparing.
Subject(s)
Endometriosis/etiology , Endometriosis/pathology , Endometriosis/therapy , Adult , Delayed Diagnosis , Endometrium/pathology , Female , Hormones/therapeutic use , Humans , Inflammation/pathology , Middle Aged , Pelvic Pain/physiopathology , Pelvic Pain/therapy , Surgical Procedures, Operative/methods , Tissue Adhesions/surgery , Uterus/pathologyABSTRACT
Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.