Integrated histopathology of the human pancreas throughout stages of type 1 diabetes progression.

Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation and progression yet an integrated perspective onto pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases.

Empiric Azithromycin in COVID-19 Impacts the Respiratory Microbiome and Antimicrobial Resistome without Anti-inflammatory Benefit.

Azithromycin is often prescribed unnecessarily for respiratory infections, many of which are viral. During the COVID-19 pandemic, its use was widespread, in part due to alleged therapeutic benefits, which have since been disproven. Here, we sought to understand the impact of azithromycin exposure on the respiratory microbiome, antimicrobial resistome, and host immune response in a prospective multicenter cohort of 1164 patients hospitalized for SARS-CoV-2 infection.

Immunization with full-length TprC variants induces a broad response to surface-exposed epitopes of the Treponema pallidum repeat protein family and is partially protective in the rabbit model of syphilis.

An effective vaccine against syphilis could aid current control measures to reduce the incidence of infection. Protective immunity from the syphilis agent, Treponema pallidum subsp. pallidum (T.

A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.

Here, we describe the use of a homologous knockin mouse model to further decipher the mechanism(s) of a novel human homozygous IL2RB hypomorphic mutation. Our model recapitulates the human immune dysregulation phenotype, showing decreased mutant interleukin-2Rβ (IL-2Rβ) cell-surface expression, impaired IL-2/15-dependent STAT5 signaling, elevated serum IL-2/15 levels, expanded effector memory CD8 T cells, and severely reduced regulatory T cells (Tregs). Using mixed bone marrow chimeras (BMCs) and wild-type (WT) Treg transfers, we distinguish receptor-intrinsic from receptor-extrinsic immunopathogenesis.

Identification of immunogenic commensal antigens using phage display.

Humoral immunity plays a major role in the establishment and maintenance of host-microbiota commensalism and immunity to pathogenic microorganisms. However, identification of antigens eliciting adaptive immune responses within barrier and systemic tissues represents a significant hurdle to further understanding this host-microbe dialogue. Here, we provide a protocol to identify immunogenic protein antigens expressed by commensal and pathogenic microbes by using bacteriophage (phage) display-mediated antibody/antigen biopanning.

A haplotype-resolved view of human gene regulation.

Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq Inferred Regulatory Elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously known and unknown biases afflicting our existing regulatory element catalog. FIRE provides a comprehensive genome-wide map of haplotype-selective chromatin accessibility (HSCA), exposing novel imprinted elements that lack underlying parent-of-origin CpG methylation differences, common and rare genetic variants that disrupt gene regulatory patterns, gene regulatory modules that enable genes to escape X chromosome inactivation, and autosomal mitotically stable somatic epimutations.

T cell and autoantibody recognition of nucleus-associated islet autoantigens in individuals with type 1 diabetes.

Aims/hypothesis: There is a progressive loss of self-tolerance in type 1 diabetes, manifested by the appearance of various autoantibodies. Array-based screening identified antibodies that recognise nucleus-associated proteins in individuals with type 1 diabetes, but the role of these antigens in the disease is poorly understood. Antibodies against MutL homologue 1 (MLH1) and nucleoporin 50 (NUP50) are enriched in DR4-positive and DR3-positive individuals, respectively.

Prevalence and severity of chronic kidney disease in a population with type 1 diabetes from a United States health system: a real-world cohort study.

Background: A contemporary description and estimates for rates of chronic kidney disease (CKD) in type 1 diabetes are needed to inform risk reduction strategies. The study aim was to assess prevalence and severity of CKD based on a population with type 1 diabetes receiving care at a large United States health system.

Methods: Type 1 diabetes was identified through the Providence health system electronic health records during 2013-2022.

Minimalistic Transcriptomic Signatures Permit Accurate Early Prediction of COVID-19 Mortality.

Background: Predicting mortality risk in patients with COVID-19 remains challenging, and accurate prognostic assays represent a persistent unmet clinical need. We aimed to identify and validate parsimonious transcriptomic signatures that accurately predict fatal outcomes within 48 hours of hospitalization.

Methods: We studied 894 patients hospitalized for COVID-19 across 20 US hospitals and enrolled in the prospective Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) with peripheral blood mononuclear cells (PBMC) and nasal swabs collected within 48 hours of admission.

Longitudinally stable T cell function and innate immune activation distinguish healthy adult immunotypes.

Understanding the variability of immune cell composition and responsiveness in health is critical to define changes that predict and explain immune-associated diseases like autoimmunity and cancer. Here, we comprehensively phenotyped a cohort of 100 healthy adults aged 25 to 35 and 55 to 65 years who were longitudinally followed for 10 visits over 2 years. Using mass cytometry, we identified four stable immunotypes derived from cell populations that remained stable within, but differed between, individuals.

Latent EBV enhances the efficacy of anti-CD3 mAb in Type 1 diabetes.

Teplizumab is approved for delaying the diagnosis of type 1 diabetes by modulating progression of disease. Compared to EBV-seronegative patients, those who are EBV-seropositive prior to treatment have a more robust response to teplizumab in two clinical trials. Here we compare the phenotypes, transcriptomes and development of peripheral blood cells before and after teplizumab treatment in participants.

Population Risk Predictors of Major Adverse Kidney Events in Patients with Focal Segmental Glomerulosclerosis from the CURE-CKD Registry.

Background: Predictors of major adverse kidney events (MAKE) in focal segmental glomerulosclerosis (FSGS) have not been previously explored within large, real-world populations. The study aim was to evaluate population-level predictors of MAKE for patients with FSGS from health system data.

Methods: The study population was derived from electronic health records from Providence and University of California Los Angeles Health.

Open Access Online Calculator Predicts Peanut-Allergic Reactions With High Accuracy.

Background: The Peanut Allergy Prediction Web Tool is a newly developed online aid, which calculates the probability of an individual's allergic reaction based on their skin prick test (SPT), Arachis hypogaea 2-specific IgE (Ara h 2-sIgE), and/or basophil activation test (BAT) results.

Objective: To validate the diagnostic performance of the online tool and assess its ability to discriminate between peanut-allergic (PA) and peanut-sensitized tolerant (PST) cases.

Methods: Demographic data, clinical history, results for SPT, Ara h 2-sIgE, BAT, and oral food challenge (OFC) outcomes were collected for pediatric cases with a confirmed peanut allergy status (PA or PST).

A systematic evaluation of the therapeutic potential of endogenous-ADAR editors in cancer prevention and treatment.

Adenosine deaminases acting on RNA (ADAR) enzymes constitute a natural cellular mechanism that induces A-to-I(G) editing, introducing genetic changes at the RNA level. Recently, interest in the endogenous-ADAR editor has emerged for correcting genetic mutations, consisting of a programmed oligonucleotide that attracts the native ADAR, thereby offering opportunities for medical therapy. Here, we systematically chart the scope of cancer mutations that endogenous-ADAR can correct.

Functional dissection of noncoding variants associated with rheumatoid arthritis.

Objectives: Noncoding variants are critical to our understanding of the genetic basis of diseases and disorders such as rheumatoid arthritis (RA). While genome-wide association studies have identified regions of the genome associated with disease, functional studies are still lagging that can identify potentially causative variants.

Methods: In order to functionally fine-map RA-associated variants, we identified variants at enhancers marked in primary activated T helper cells and conducted massively parallel reporter assay in these cells.

Ara h 2-Specific TH2A Cells Drive Peanut Allergy in DRB1*15:01 Individuals: A Detailed Epitope Analysis.

Background: The IgE-mediated CD4 T-cell response to peanut (Arachis hypogaea) is heterogeneous, yet TH2 cells remain central drivers of pathology. This study aimed to dissect this complexity at the epitope level by focusing on the HLA-DRB1*15:01-DRB5*01:01 haplotype. Specifically, we examined how distinct epitope-specific T-cell subsets shape the immunological landscape of peanut allergy in peanut-allergic (PA) versus non-peanut-allergic (NPA) individuals.

A ventilated perfused lung model platform to dissect the response of the lungs to viral infection.

In this study, we developed a 3D lung model that incorporated alveolar and vascular components, allowing for the investigation of lung physiology and responses to infection. We investigated the role of ventilation in formation of the alveolar epithelial layer and its response to viral infections. We subjected our perfused model to a continuous respiratory cycle at the air-liquid interface (ALI) for up to 10 days.

Type 1 Diabetes TrialNet: Leading the Charge in Disease Prediction, Prevention, and Immunotherapeutic Mechanistic Understanding.

Established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2001, Type 1 Diabetes TrialNet (TrialNet) is an international consortium of clinical research centers that studies the development of type 1 diabetes and performs clinical studies aimed at delaying or preventing the disease. In recognition of NIDDK's 75th anniversary, this review will summarize the major findings, accomplishments, and future opportunities of its long-running program TrialNet. More than 20 intervention, observational, and mechanism-directed clinical studies have been conducted in collaboration with thousands of people living with type 1 diabetes and their families.

A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection.

Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8 T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion.

Mapping the developmental profile of ventricular zone-derived neurons in the human cerebellum.

The cerebellar ventricular zone (VZ) is the primary source of progenitors that generate cerebellar GABAergic neurons, including Purkinje cells (PCs) and interneurons (INs). This study provides detailed characterization of human cerebellar GABAergic neurogenesis using transcriptomic and histopathological analyses and reveals conserved and unique features compared to rodents. We show that the sequential progression of neurogenesis is conserved and occurs before 8 postconception weeks.

Pancreatic enzyme replacement therapy in advanced adenocarcinoma of the pancreas improved overall survival: a retrospective, single institution study.

Background: Weight loss and exocrine pancreatic insufficiency are common in advanced pancreatic ductal adenocarcinoma (PDAC) and are associated with adverse outcomes. However, there is limited evidence on the impact of pancreatic enzyme replacement therapy (PERT) in patients with advanced PDAC.

Patients And Methods: We retrospectively studied 501 patients with advanced PDAC and exocrine pancreatic insufficiency from the Virginia Mason Pancreas Cancer Program Data Resource treated between 2010 and 2019 with first-line chemotherapy.

T Cells Promote Distinct Transcriptional Programs of Cutaneous Inflammatory Disease in Keratinocytes and Dermal Fibroblasts.

T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside altered structural cell frequencies and transcriptional states, but to what extent different T cells promote disease-associated changes remains unclear. We show that functionally diverse circulating and skin-resident CD4CLA T-cell populations promote distinct transcriptional outcomes in human keratinocytes and fibroblasts associated with inflamed or healthy tissue.