A5026508289- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- vaccines and immunoinformatics approaches
- COVID-19 Clinical Research Studies
- Myasthenia Gravis and Thymoma
- Glycosylation and Glycoproteins Research
- SARS-CoV-2 and COVID-19 Research
- Cancer-related gene regulation
- Immunotherapy and Immune Responses
- Influenza Virus Research Studies
- Genomics and Phylogenetic Studies
- CAR-T cell therapy research
- Single-cell and spatial transcriptomics
- Blood groups and transfusion
- Microbial infections and disease research
- Long-Term Effects of COVID-19
- Genetic diversity and population structure
- HIV Research and Treatment
- Antifungal resistance and susceptibility
- Virology and Viral Diseases
- Atherosclerosis and Cardiovascular Diseases
- Food Allergy and Anaphylaxis Research
- Cytomegalovirus and herpesvirus research
- Asthma and respiratory diseases
Yale University
2019-2024
Dartmouth College
2023-2024
Dartmouth Hospital
2023
University of Oxford
2014-2017
Centre for Human Genetics
2016-2017
Duke University
2011-2014
Abstract Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, signatures associated with immunopathology poorly understood. Here we use multi-omics single-cell analysis to probe dynamic hospitalized patients stable or progressive course of COVID-19, explore V(D)J repertoires, and assess cellular effects tocilizumab. Coordinated profiling gene expression cell lineage protein markers shows that S100A hi /HLA-DR lo classical monocytes...
B cells undergo rapid mutation and selection for antibody binding affinity when producing antibodies capable of neutralizing pathogens. This evolutionary process can be intermixed with migration between tissues, differentiation cellular subsets, switching functional isotypes. cell receptor (BCR) sequence data has the potential to elucidate important information about these processes. However, there is currently no robust, generalizable framework making such inferences from BCR data. To...
Age-associated B cells (ABCs) are formed under inflammatory conditions and considered a type of memory cell (MBC) expressing the transcription factor T-bet. In SLE, ABC frequency is correlated with disease, they thought to be source autoantibody-secreting cells. However, in conditions, whether autoreactive can become resting MBCs uncertain. Further, phenotypic identity ABCs their relationship other subsets, such as plasmablasts, unclear. Whether directly promote disease untested. Here we...
Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population CD23 + IgG1 cells arising type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing upon activation. The frequency correlated with circulating concentrations children allergy. A corresponding “type 2–marked” was identified single-cell...
Chromosomal inversions disrupt recombination in heterozygotes by both reducing crossing-over within inverted regions and increasing it elsewhere the genome. The reduction of facilitates maintenance hybridizing species, as outlined various models chromosomal speciation. We present a comprehensive comparison effects on rates nucleotide divergence. Within an inversion differentiating Drosophila pseudoobscura persimilis, we detected one double recombinant among 9,739 progeny from F1 hybrids...
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...
Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC peripheral blood HIV-infected individuals viremia. Despite their prevalence, it is unclear how these cells arise and whether they contribute to inefficiency antibody-mediated immunity infectious diseases. We addressed questions by characterizing T-bet-expressing lymph nodes (LN) identifying strong T-bet signature among HIV-specific poor...
T cell-B cell interaction is the key immune response to protect host from severe viral infection. However, how cells support B exert protective humoral immunity in humans not well understood. Here, we use COVID-19 as a model of acute infections and analyze CD4
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt critical gatekeeper mechanism strictly limits cell fitness during antibody affinity maturation. This converted into supercompetitors rapidly outstrip their normal...
Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma primarily generated. It is unclear how the maturation of within GC impacts breadth durability cell responses to influenza vaccination in humans. We used fine needle aspiration draining lymph nodes longitudinally track antigen-specific seasonal vaccination. Antigen-specific persisted for at least 13 wk after two out seven individuals. Monoclonal antibodies...
Abstract Phylogenetic methods have shown promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, mutational process that generates these lineages, somatic hypermutation, is biased by hotspot motifs which violates important assumptions most phylogenetic substitution models. Here, we develop a modified GY94-type model partially accounts for this context dependency while preserving independence sites during calculation. This shows substantially...
Rituximab, a B cell–depleting therapy, is indicated for treating growing number of autoantibody-mediated autoimmune disorders. However, relapses can occur after treatment, and autoantibody-producing cell subsets may be found during relapses. It not understood whether these emerge from the failed depletion preexisting cells or are generated de novo. To further define mechanisms that cause postrituximab relapse, we studied patients with muscle-specific kinase (MuSK) myasthenia gravis (MG) who...
Significance Myasthenia gravis is caused by autoantibodies, which target postsynaptic proteins, primarily the acetylcholine receptor, that inhibit neuromuscular signaling. The myasthenia thymus can serve as a reservoir of receptor-specific autoantibody-producing B cells. Thus, thymectomy provided treatment. However, many patients fail to improve; causes poor responses are not understood. This investigation demonstrated disease-associated cell clones mature in before emigrating circulation....
The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation vaccine-induced B cell responses. We previously showed that a subset lineages are recruited into germinal centers (GCs) following vaccination, suggesting affinity these against vaccine antigens can occur. However, it remains be determined whether vaccination stimulates additional evolution vaccine-specific lineages, previous work has found no...
Abstract Protective immunity against COVID-19 likely depends on the production of SARS-CoV-2–specific plasma cells and memory B postinfection or postvaccination. Previous work has found that germinal center reactions are disrupted in severe COVID-19. This may adversely affect long-term reinfection. Consistent with an extrafollicular cell response, patients have elevated frequencies clonally expanded, class-switched, unmutated plasmablasts. However, it is unclear whether populations...
Myasthenia gravis (MG) is an autoantibody-mediated autoimmune disorder of the neuromuscular junction. A small subset patients (<10%) with MG, have autoantibodies targeting muscle-specific tyrosine kinase (MuSK). MuSK MG respond well to CD20-mediated B cell depletion therapy (BCDT); most achieve complete stable remission. However, relapse often occurs. To further understand immunomechanisms underlying relapse, we studied autoantibody-producing cells over course BCDT. We developed a...
Protective immunity following vaccination is sustained by long-lived antibody-secreting cells and resting memory B (MBCs). Responses to two-dose SARS-CoV-2 mRNA-1273 are evaluated longitudinally multimodal single-cell analysis in three infection-naïve individuals. Integrated surface protein, transcriptomics, cell receptor (BCR) repertoire of sorted plasmablasts spike
Abstract A dysregulated immune response against the SARS-CoV-2 virus plays a critical role in severe COVID-19. However, molecular and cellular mechanisms by which causes lethal immunopathology are poorly understood. Here, we utilize multiomics single-cell analysis to probe dynamic responses patients with stable or progressive manifestations of COVID-19, assess effects tocilizumab, an anti-IL-6 receptor monoclonal antibody. Coordinated profiling gene expression cell lineage protein markers...
Abstract Food allergy is caused by allergen-specific IgE antibodies but little known about the B cell memory of persistent responses. Here we describe in human pediatric peanut CD23 + IgG1 cells arising type 2 responses that contain specific clones and generate on activation. These ‘type2-marked’ differentially express IL-4/IL-13 regulated genes FCER2 / CD23, IL4R , germline IGHE carry highly mutated receptors (BCRs). Further, high affinity for main allergen Ara h mapped to population...
Advances in immunoglobulin (Ig) sequencing technology are leading to new perspectives on immune system dynamics. Much research this nascent field has focused resolving responses viral infection. However, the dynamics of B-cell diversity early HIV infection, and response anti-retroviral therapy, still poorly understood. Here, we investigate these through bulk Ig samples collected over 2 years from a group eight HIV-1 infected patients, five whom received therapy during first half study...