A5063854981- Diabetes and associated disorders
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Pancreatic function and diabetes
- Diabetes Management and Research
- Monoclonal and Polyclonal Antibodies Research
- Systemic Lupus Erythematosus Research
- Immunodeficiency and Autoimmune Disorders
- Immunotherapy and Immune Responses
- Ecology and Vegetation Dynamics Studies
- Plant and animal studies
- Genetic diversity and population structure
- Respiratory Support and Mechanisms
- Asthma and respiratory diseases
- Genomics and Phylogenetic Studies
- Brucella: diagnosis, epidemiology, treatment
- Species Distribution and Climate Change
- Immune Response and Inflammation
- Neonatal Respiratory Health Research
- Cancer Immunotherapy and Biomarkers
- Avian ecology and behavior
- CAR-T cell therapy research
- Blood disorders and treatments
- Cytokine Signaling Pathways and Interactions
- Parasite Biology and Host Interactions
Benaroya Research Institute
2018-2025
Seattle University
2023-2024
Virginia Mason Medical Center
2018-2020
University of Minnesota
2011-2015
Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss production in patients with type diabetes, but might affect clinical progression before diagnosis are needed.We conducted phase 2, randomized, placebo-controlled, double-blind trial teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives who did not were at high risk...
Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while role human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported number of circulating neutrophils reduced patients with T1D presymptomatic at-risk subjects. The aim present work was identify possible changes pancreas-residing throughout course better elucidate...
Although most patients with type 1 diabetes (T1D) retain some functional insulin-producing islet β cells at the time of diagnosis, rate further cell loss varies across individuals. It is not clear what drives this differential progression rate. CD8+ T have been implicated in autoimmune destruction cells. Here, we addressed whether phenotype and function autoreactive influence disease progression. We identified islet-specific using high-content, single-cell mass cytometry combination...
Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes autoantibodies this autoimmune disease, including the production critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) response immune complexes (ICs). We focused on IgA, which is second-most prevalent isotype serum and, along with IgG, deposited glomeruli...
Abstract The significance of islet Ag-reactive T cells found in peripheral blood type 1 diabetes (T1D) subjects is unclear, partly because similar are also healthy control (HC) subjects. We hypothesized that key disease-associated would show evidence prior Ag exposure, inferred from expanded TCR clonotypes, and essential phenotypic properties their transcriptomes. To test this, we developed single-cell RNA sequencing procedures for identifying clonotypes transcript phenotypes individual...
CCR5 is thought to play a central role in orchestrating migration of cells response inflammation. antagonists can reduce inflammatory disease processes, which has led an increased interest using wide range inflammation-driven diseases. Paradoxically, these appear function without negatively affecting host immunity at barrier sites. We reasoned that the resolution this paradox may lie CCR5+ T cell populations permanently reside tissues. used single-cell analysis approach examine human...
Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), CTLA4Ig (abatacept) results in transient stabilization insulin C-peptide, a surrogate for endogenous secretion. With the goal inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated C-peptide clinical trial blood samples from new-onset T1D subjects treated B cell-depleting drug, rituximab. RNA...
The rate of decline in insulin secretion after diagnosis with type 1 diabetes (T1D) varies substantially among individuals and age at diagnosis, but the mechanism(s) behind this heterogeneity are not well understood. We investigated loss pancreatic β cell function new-onset T1D subjects using unbiased whole blood RNA-seq verified key findings by targeted count measurements. found that patients who lost more rapidly had immune phenotypes ("immunotypes") characterized higher levels B cells...
Costimulatory interactions control T cell activation at sites of activated antigen-presenting cells, including B cells. Blockade the CD28/CD80/CD86 costimulatory axis with CTLA4Ig (abatacept) is widely used to treat certain autoimmune diseases. While transiently effective in subjects new-onset type 1 diabetes (T1D), abatacept did not induce long-lasting immune tolerance. To elucidate mechanisms limiting tolerance T1D, we performed unbiased analysis whole blood transcriptomes and targeted...
We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other manifestations, including type 1 diabetes (T1D). report here siblings, aged 10 years, neonatal-onset T1D (diagnosed the ages day 7 wk), are homozygous for a splice-site variant CD274 (encoding PD-L1). This results in exclusive expression an alternative, loss-of-function PD-L1 protein isoform overexpression experiments patients' primary...
Abstract Th2 cells must sense and adapt to the tissue milieu in order provide protective host immunity repair. Here, we examined mechanisms promoting cell differentiation function within small intestinal lamina propria. Single RNA-seq analyses of CD4 + T from propria helminth infected mice revealed high expression gene Epas1 , encoding transcription factor hypoxia-inducible 2a (HIF2α). In vitro exposure hypoxia or genetic HIF2α activation promoted differentiation, even under non-polarizing...
Abstract Dysregulated differentiation of naïve CD4+ T cells into helper 17 (Th17) is likely a key factor predisposing to many autoimmune diseases. Therefore, better understanding how Th17 regulated essential identify novel therapeutic targets and strategies individuals at high risk developing autoimmunity. Here, we extend our prior work using chemical inhibitors provide mechanistic insight regulator differentiation, the kinase dual-specificity tyrosine phosphorylation-regulated 1A (DYRK1A)....
At diagnosis, most people with type 1 diabetes (T1D) produce measurable levels of endogenous insulin, but the rate at which insulin secretion declines is heterogeneous. To explain this heterogeneity, we sought to identify a composite signature predictive secretion, using collaborative assay evaluation and analysis pipeline that incorporated multiple cellular serum measures reflecting β cell health immune system activity. The ability predict decline in would be useful for patient...
Therapeutics that inhibit IL-6 at different points in its signaling pathway are clinical use, yet whether the immunological effects of these interventions differ based on their molecular target is unknown. We performed short-term individuals with type 1 diabetes using anti-IL-6 (siltuximab) or receptor (IL-6R; tocilizumab) therapies and investigated impact this vivo blockade T cell fate function. Immune outcomes were influenced by therapeutic intervention (IL-6 versus IL-6R) peak drug...
Abstract This article documents the addition of 112 microsatellite marker loci and 24 pairs single nucleotide polymorphism (SNP) sequencing primers to Molecular Ecology Resources Database. Loci were developed for following species: Agelaius phoeniceus , Austrolittorina cincta Circus cyaneus macrourus pygargus Cryptocoryne × purpurea Ridl. nothovar. Mya arenaria Patagioenas squamosa Prochilodus mariae Scylla serrata Scytalopus speluncae . These cross‐tested on affinis ciliata cordata var...
Abstract Brucellosis is a zoonotic disease caused by Brucella bacteria, acquired humans through contact with or consumption of products from infected animals. Treatment outcomes vary widely; some patients recover, others relapse, and develop chronic symptoms despite therapy. We employed expression profiling using RNA sequencing (RNAseq) to better understand variation in investigate mechanisms. performed RNAseq analysis whole blood samples 125 51 healthy controls Macedonia. Patients were...
Abstract Autoantibodies to nuclear antigens are hallmarks of the autoimmune disease systemic lupus erythematosus (SLE) where they contribute pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes autoantibodies disease, including production critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) response immune complexes (ICs). We focused on IgA, which is second most prevalent isotype serum, and along with IgG deposited...
Geographic distributions of genetic and phenotypic characters can illuminate historical evolutionary processes. In particular, mosaic phenotypically similar populations arise from parallel evolution or irregular patterns dispersal colonization by divergent forms. Two forms the red-winged blackbird (Agelaius phoeniceus) show a distribution, with "bicolored" form occurring disjunctly in California Mexico. We analyzed relationships among these bicolored neighboring typical populations, using...
Introduction & Objective: Islet antigen reactive (IAR) T cells play an important role in pancreatic β-cell destruction type 1 diabetes (T1D) and are clonally expanded after T1D diagnosis, indicative of vivo exposure. The objective this study was to determine if clonal expansion IAR CD4 occurs prior onset is associated with risk for disease progression. Methods: included prospective blood samples collected from islet autoantibody (Aab) positive individuals enrolled the TrialNet Pathways...