A5027728617- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- vaccines and immunoinformatics approaches
- Single-cell and spatial transcriptomics
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Peripheral Neuropathies and Disorders
- Asthma and respiratory diseases
- Systemic Sclerosis and Related Diseases
- Myasthenia Gravis and Thymoma
- Pancreatic function and diabetes
- Immune cells in cancer
- Connective Tissue Growth Factor Research
- Diabetes Management and Research
- COVID-19 Clinical Research Studies
- Cell Image Analysis Techniques
- Diabetes and associated disorders
- Chronic Lymphocytic Leukemia Research
- Multiple Sclerosis Research Studies
- Sarcoidosis and Beryllium Toxicity Research
- Proteoglycans and glycosaminoglycans research
- Ion Channels and Receptors
- Inflammation biomarkers and pathways
- Respiratory Support and Mechanisms
Yale University
2013-2019
Bar-Ilan University
2014
Hofstra University
2014
Abstract Summary: Advances in high-throughput sequencing technologies now allow for large-scale characterization of B cell immunoglobulin (Ig) repertoires. The high germline and somatic diversity the Ig repertoire presents challenges biologically meaningful analysis, which requires specialized computational methods. We have developed a suite utilities, Change-O, provides tools advanced analyses data. Change-O includes determining complete set variable region gene segment alleles carried by...
Abstract Summary: Driven by dramatic technological improvements, large-scale characterization of lymphocyte receptor repertoires via high-throughput sequencing is now feasible. Although promising, the high germline and somatic diversity, especially B-cell immunoglobulin repertoires, presents challenges for analysis requiring development specialized computational pipelines. We developed REpertoire Sequencing TOolkit (pRESTO) processing reads from studies. pRESTO processes raw sequences to...
In multiple sclerosis patients, B cells mature in the draining cervical lymph nodes before trafficking across blood-brain barrier.
Analyses of somatic hypermutation (SHM) patterns in B cell immunoglobulin (Ig) sequences contribute to our basic understanding adaptive immunity, and have broad applications not only for the immune response pathogens, but also determining role SHM autoimmunity cancers. Although stochastic, displays intrinsic biases that can confound statistical analysis, especially when combined with particular codon usage base composition Ig sequences. Analysis clonal expansion, diversification, selection...
Significance The immune system must constantly adapt to combat infections and other challenges. This is accomplished by continuously evolving the antibody repertoire, maintaining memory of prior By using next-generation DNA sequencing technology, we have examined shear amount made individuals during a flu vaccination trial. We demonstrate one first characterizations fast dynamics through time in multiple responding an challenge.
CD4+ follicular regulatory T (Tfr) cells suppress B cell responses through modulation of helper (Tfh) and germinal center (GC) development. We found that Tfr can also promote the GC response provision interleukin-10 (IL-10) after acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing IL-10 by was necessary for optimal development response. formed in absence Treg cell-derived displayed an altered dark zone state decreased expression transcription factor Forkhead box protein 1...
The adaptive immune system's capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, influence of individual genetic and epigenetic differences on these repertoires is not typically measured. By leveraging unique characteristics B, CD4(+) T CD8(+) T-lymphocyte subsets from monozygotic twins, we quantify impact heritable factors both V(D)J recombination process thymic selection. We show that resulting biases in usage N/P addition lengths,...
Abstract Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20–50 people per 100,000. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). are pathogenic, but their generation associated with broader defects in cell repertoire unknown. To address this question, we performed deep sequencing BCR AChR-MG, MuSK-MG,...
Despite the development of effective therapies, a substantial proportion asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, rodents, TRPA1 is involved induction airway inflammation hyperreactivity. Here, discovery early clinical GDC-0334, highly potent, selective, orally bioavailable antagonist, described. GDC-0334 inhibited function on smooth...
In order to produce effective antibodies, B cells undergo rapid somatic hypermutation (SHM) and selection for binding affinity antigen via a process called maturation. The similarities between this evolution by natural have led many groups use phylogenetic methods characterize the development of immunological memory, vaccination, other processes that depend on However, these applications are limited fact most models designed be applied individual lineages comprising genetically diverse...
High-throughput sequencing (HTS) of immunoglobulin (B-cell receptor, antibody) and T-cell receptor repertoires has increased dramatically since the technique was introduced in 2009 [1-3]. This experimental approach explores maturation adaptive immune system its response to antigens, pathogens disease conditions exquisite detail. It holds significant promise for diagnostic therapy-guiding applications. New technology often spreads rapidly, sometimes more rapidly than understanding how make...
Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions embryonic development; however, the postnatal pathological roles activation mechanisms TGFβ2 TGFβ3 not been well characterized. Here, we show that latent forms can be activated by integrin-independent lower thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 TGFB3 expression increased human lung liver fibrotic tissues healthy control tissues....
Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote fibroblast migration partly via osteopontin (OPN) secretion, which amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk single-cell RNA sequencing elevated OPN expression SSc tissue enriched macrophages, partially overlapping...
Neuromyelitis optica spectrum disorders (NMOSD) constitute rare autoimmune of the CNS that are primarily characterized by severe inflammation spinal cord and optic nerve. Approximately 75% NMOSD patients harbour circulating pathogenic autoantibodies targeting aquaporin-4 water channel (AQP4). The source these remains unclear, but parallels between other autoantibody-mediated diseases posit compromised B cell tolerance checkpoints as common underlying contributing factors. Using a well...
The adaptive immune receptor repertoire (AIRR) contains information on an individuals' past, present and potential in the form of evolving sequences that encode B cell (BCR) repertoire. AIRR sequencing (AIRR-seq) studies rely databases known BCR germline variable (V), diversity (D), joining (J) genes to detect somatic mutations AIRR-seq data via comparison best-aligning database alleles. However, it has been shown these are far from complete, leading systematic misidentification mutated...
Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity these senescent remain unclear, tools characterize context-specific human are lacking. We observed that marker p16 is predominantly localized bronchiolized structures scarred regions IPF systemic sclerosis-associated interstitial disease (SSc-ILD)...
Abstract Single-cell RNA-seq (scRNA-seq) studies have profiled over 100 million human cells across diseases, developmental stages, and perturbations to date. A singular view of this vast growing expression landscape could help reveal novel associations between cell states discover in unexpected tissue contexts, relate vivo vitro models. However, these require a common, scalable representation profiles from the body, general measure their similarity, an efficient way query data. Here, we...
Analyses of somatic hypermutation (SHM) patterns in B cell Ig sequences have important basic science and clinical applications, but they are often confounded by the intrinsic biases SHM targeting on specific DNA motifs (i.e., hot cold spots). Modeling these has been hindered difficulty identifying mutated vivo absence selection pressures, which skew observed mutation patterns. To generate a large number unselected mutations, we immunized B1-8 H chain transgenic mice with nitrophenyl to...
Bacterial-associated LPS drives oncostatin M–dependent airway inflammation and mucus hypersecretion in severe asthma.
BackgroundTransforming growth factor β (TGF-β) is implicated as a key mediator of pathological fibrosis, but its pleiotropic activity in range homeostatic functions presents challenges to safe and effective therapeutic targeting. There are three isoforms TGF-β, TGF-β1, TGF-β2, TGF-β3, which bind common receptor complex composed TGF-βR1 TGF-βR2 induce similar intracellular signals vitro. We have recently shown that the cellular expression patterns activation thresholds TGF-β2 TGF-β3 distinct...
Previous studies of immunoglobulin gene sequences in patients with allergic diseases using low-throughput Sanger sequencing have limited the analytic depth for characterization IgE repertoires.We used a high-throughput, next-generation approach to characterize heavy-chain (IGH) repertoires seasonal rhinitis (AR) aim better understanding underlying disease mechanisms.IGH matched peripheral blood and nasal biopsy specimens from nonallergic healthy control subjects (n = 3) grass pollen-related...