Defining a novel DYRK1A-gp130/IL-6R-pSTAT axis that regulates Th17 differentiation.

Dysregulated differentiation of naïve CD4+ T cells into T helper 17 (Th17) cells is likely a key factor predisposing to many autoimmune diseases. Therefore, better understanding how Th17 differentiation is regulated is essential to identify novel therapeutic targets and strategies to identify individuals at high risk of developing autoimmunity. Here, we extend our prior work using chemical inhibitors to provide mechanistic insight into a novel regulator of Th17 differentiation, the kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A).

Novel T Cell reactivities to Hybrid Insulin Peptides in Islet Autoantibody-Positive At-Risk Subjects.

Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 T cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in T cell-mediated beta-cell destruction. We have shown that HIPs form in human islets between fragments of the C-peptide and cleavage products of secretory granule proteins.

Evaluation of Intestinal Permeability Using Serum Biomarkers in Learning Early About Peanut Allergy Trial.

Background: Intestinal barrier dysfunction may lead to a break in tolerance and development of food allergy (FA). There is contradictory evidence on whether intestinal permeability (IP) is altered in IgE-mediated FA. Thus, we sought to determine whether IP differed between children with eczema who did (FA group) or did not (atopic controls, ACs) develop FA and whether peanut sensitization, allergy, and early introduction impacted IP using serum biomarkers zonulin, soluble CD14, and Intestinal Fatty Acid Binding Protein among randomly selected participants enrolled in the Learning Early About Peanut allergy trial.

Antigen-specific immunotherapies for autoimmune disease.

Antigen-specific therapies have a long history in the treatment of allergy but have not been successful in autoimmunity. However, in the past 20 years, advances in the definition of the self-antigens that promote autoimmunity and the growing understanding of the mechanisms that maintain tolerance in health but fail in autoimmunity have led to antigen-specific approaches being considered for the treatment of autoimmune diseases. The core goal of each antigen-specific treatment approach is to remove the immune response that promotes autoimmunity whilst sparing protective responses.

Efficacy and Safety of Dupilumab in Children With Peanut Allergy: A Multicenter, Open-Label, Phase II Study.

Background: Peanut allergy is a potentially life-threatening food allergy in children. This study explored whether dupilumab, a human monoclonal immunoglobulin (Ig)G4 antibody that blocks the activity of interleukin (IL)-4/IL-13, improved safety and desensitization to peanut exposure in children with peanut allergy.

Methods: A Phase II, 24-week, multicenter, single-arm, open-label, proof-of-concept study was conducted in the USA and Canada (NCT03793608).

ISPAD Clinical Practice Consensus Guidelines 2024: Screening, Staging, and Strategies to Preserve Beta-Cell Function in Children and Adolescents with Type 1 Diabetes.

The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive set of clinical recommendations for children, adolescents, and young adults living with diabetes worldwide. This guideline serves as an update to the 2022 ISPAD consensus guideline on staging for type 1 diabetes (T1D). Key additions include an evidence-based summary of recommendations for screening for risk of T1D and monitoring those with early-stage T1D.

Cytokine signatures in post-endoscopic retrograde cholangiopancreatography pancreatitis: a pilot study.

Background: Following endoscopic retrograde cholangiopancreatography (ERCP), post-ERCP pancreatitis (PEP) is the most common complication. The host's innate immune response to periprocedural pancreatic injury is the hallmark of its pathogenesis. Investigating cytokine signatures associated with PEP and its risk factors can guide understanding of PEP immunopathogenesis.

Arthritis progressors have a decreased frequency of circulating autoreactive T cells during the at-risk phase of rheumatoid arthritis.

Objectives: The aim of this study was to combine deep T cell phenotyping with assessment of citrulline-reactive CD4+T cells in the pre-rheumatoid arthritis (RA) phase.

Methods: 20 anti-CCP2 positive individuals () presenting musculoskeletal complaints without clinical or ultrasound signs of synovitis; 10 arthritis progressors and 10 matched non-arthritis progressors were included. Longitudinal samples (1-3 time points) of peripheral blood mononuclear cells were assessed using HLA-class II tetramers with 12 different citrullinated candidate autoantigens combined in a >20-colour spectral flow cytometry panel.

Antigen-specific T-cell frequency and phenotype mirrors disease activity in DRB1*04:04+ rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is associated with high-risk HLA class II alleles known as the "RA shared epitope." Among prevalent shared epitope alleles, study of DRB1*04:04 has been limited. To define relevant epitopes, we identified citrullinated peptide sequences from synovial antigens that were predicted to bind to HLA-DRB1*04:04 and utilized a systematic approach to confirm their binding and assess their recognition by CD4 T cells.

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults.

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination.

Dynamic chromatin architecture identifies new autoimmune-associated enhancers for and novel genes regulating CD4+ T cell activation.

Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact -regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk.

Peanut-specific IgG subclasses as biomarkers of peanut allergy in LEAP study participants.

Antigen-specific IgG2 and IgG3 are rarely measured in food allergy clinical trials despite known function in preventing mast cell and basophil activation. Our objective was to determine whether measuring peanut-specific IgG2 and IgG3 levels would correlate with peanut allergy status. Peanut-specific IgG subclasses were measured via ELISA assays in Learning Early About Peanut allergy (LEAP) trial participants at 5 years of age and were correlated with peanut allergy vs peanut sensitization vs non-peanut allergic and peanut consumption vs peanut avoidance.

cytoKernel: Robust kernel embeddings for assessing differential expression of single cell data.

High-throughput sequencing of single-cell data can be used to rigorously evlauate cell specification and enable intricate variations between groups or conditions. Many popular existing methods for differential expression target differences in aggregate measurements (mean, median, sum) and limit their approaches to detect only global differential changes. We present a robust method for differential expression of single-cell data using a kernel-based score test, cytoKernel.

Response to retention hypothesis as a source of targets for arterial wall-directed therapies to prevent atherosclerosis: A critical review.

The subendothelial retention of circulating lipoproteins on extracellular matrix proteins and proteoglycans is one of the earliest events in the development of atherosclerosis. Multiple factors, including the size, type, composition, surrounding pH, and chemical modifications to lipoproteins, influence the electrostatic interactions between relevant moieties of the apolipoproteins on lipoproteins and the glycosaminoglycans of proteoglycans. The length and chemical composition of glycosaminoglycan chains attached to proteoglycan core proteins determine the extent of initial lipoprotein binding and retention in the artery wall.

Immune markers of severe acute pancreatitis.

Purpose Of Review: Acute pancreatitis is a common acute inflammatory disorder of the pancreas, and its incidence has been increasing worldwide. Approximately 10% of acute pancreatitis progresses to severe acute pancreatitis (SAP), which carries significant morbidity and mortality. Disordered immune response to pancreatic injury is regarded as a key event that mediates systemic injury in SAP.

Identification of functional enhancer variants associated with type I diabetes in CD4+ T cells.

Type I diabetes is an autoimmune disease mediated by T-cell destruction of β cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes.

Germline-like TCR-α chains shared between autoreactive T cells in blood and pancreas.

Human type 1 diabetes (T1D) is caused by autoimmune attack on the insulin-producing pancreatic beta cells by islet antigen-reactive T cells. How human islet antigen-reactive (IAR) CD4+ memory T cells from peripheral blood affect T1D progression in the pancreas is poorly understood. Here, we aim to determine if IAR T cells in blood could be detected in pancreas.

Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention.

Background: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption.

Abatacept increases T cell exhaustion in early RA individuals who carry HLA risk alleles.

Exhausted CD8 T cells (T) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGITKLRG1 T with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGITKLRG1 T is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGITKLRG1 CD8 T population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive , together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells.

Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity.

Plasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models.