A5029110136- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunodeficiency and Autoimmune Disorders
- Inhalation and Respiratory Drug Delivery
- Cystic Fibrosis Research Advances
- Bacterial biofilms and quorum sensing
- SARS-CoV-2 and COVID-19 Research
- Immunotherapy and Immune Responses
- Biosensors and Analytical Detection
- COVID-19 Clinical Research Studies
- Chronic Lymphocytic Leukemia Research
- Long-Term Effects of COVID-19
- Systemic Lupus Erythematosus Research
- Lymphoma Diagnosis and Treatment
- Complement system in diseases
- Cytomegalovirus and herpesvirus research
- Malaria Research and Control
- Calcium signaling and nucleotide metabolism
- Diabetes and associated disorders
- Monoclonal and Polyclonal Antibodies Research
- Tuberculosis Research and Epidemiology
- Phagocytosis and Immune Regulation
- Viral-associated cancers and disorders
- Cell Adhesion Molecules Research
- Polyomavirus and related diseases
Seattle Children's Hospital
2025
University of Washington
2008-2021
Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B (MBC). Recent studies MBC development function after protein immunization have uncovered significant heterogeneity. To clarify functional roles for distinct subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans mice. Long-lived murine consisted three populations: somatically hypermutated immunoglobulin M+ (IgM+) IgG+...
Humoral immunity to SARS-CoV-2 can be supplemented with polyclonal sera from convalescent donors or an engineered monoclonal antibody (mAb) product. While pentameric IgM antibodies are responsible for much of sera’s neutralizing capacity, all available mAbs based on the monomeric IgG subtype. We now show that derived immune memory B cell receptors potent neutralizers SARS-CoV-2. outperformed clonally identical across a range affinities and receptor-binding domain epitopes. Strikingly,...
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)-deficient B cells have increased cell receptor (BCR) and Toll-like (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated specificity composition in WASp-deficient mice subjects (n = 12)....
Multimeric immunoglobulin-like molecules arose early in vertebrate evolution, yet the unique contributions of multimeric IgM antibodies to infection control are not well understood. This is partially due difficulty distinguishing low-affinity IgM, secreted rapidly by plasmablasts, from high-affinity derived later-arising memory cells. We developed a pipeline express B cell receptors (BCRs) Plasmodium falciparum–specific IgM+ and IgG+ human cells (MBCs) as both IgG molecules. BCRs subsets...
Abstract Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear Abs. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but developmental subsets undergoing TACI-dependent activation in settings excess BAFF remain unclear. We report that, although surface TACI expression is usually limited to mature cells, promotes expansion TACI-expressing...
Abstract Age-associated B cells (ABCs) are a unique subset of defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human animal studies the setting advanced age, during humoral autoimmunity following viral infection, functional properties this cellular remain incompletely defined. In current study, we demonstrate that ABCs fulfill criteria for memory (MBCs), based on evidence Ag-dependent persistence state poised rapid differentiation into...
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease a variety of animal models. However, clinical trials PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations antibodies identified using protein-immunized systems required extensive engineering optimize...
Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is causing a global pandemic, and cases continue to rise. Most infected individuals experience mildly symptomatic disease 2019 (COVID-19), but it unknown whether this can induce persistent immune memory that could contribute immunity. We performed longitudinal assessment of recovered from mild COVID-19 determine they develop sustain multifaceted SARS-CoV-2-specific immunological memory. Recovered developed...
A novel FAD-dependent thymidylate synthase, ThyX, is present in a variety of eubacteria and archaea, including the mycobacteria. short motif found all thyX genes, RHRX(7-8)S, has been identified. The three-dimensional structure Mycobacterium tuberculosis ThyX enzyme solved. Building upon this information, we used directed mutagenesis to produce 67 mutants M. gene. Each was assayed determine its ability complement defect thymidine biosynthesis delta thyA strain Escherichia coli. Enzymes from...
Abstract A common genetic variant in the gene encoding protein tyrosine phosphatase nonreceptor type 22 (PTPN22 C1858T) has been linked to a wide range of autoimmune disorders. Although B cell–intrinsic role promoting disease reported, mechanism(s) through which this functions alter preimmune cell repertoire remains unknown. Using series polyclonal and transgenic self-reactive models harboring analogous mutation murine Ptpn22, we show evidence for enhanced BCR, cell–activating factor...
While phosphatidylinositide 3-kinase delta (PI3Kδ) plays a critical role in humoral immunity, the requirement for PI3Kδ signaling plasma cells remains poorly understood. Here, we used conditional mouse model of activated syndrome (APDS), to interrogate function cell biology. Mice expressing PIK3CD gain-of-function mutation (aPIK3CD) B generated increased numbers memory and mounted an enhanced secondary response but exhibited rapid decay antibody levels over time. Consistent with these...
Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of lack suitable models for mechanistic characterization. Here, we show ex vivo-differentiated B isolated from subset healthy donors can elicit pathologies similar PTLD when transferred into immunodeficient mice. The primary driver PTLD-like were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes expressed genes commonly associated EBV...
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease a variety of animal models. However, clinical trials PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations antibodies identified using protein-immunized systems required extensive engineering optimize...
Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid cell APCs express B7 ligands (CD80 CD86), the prevailing model holds that dendritic costimulation is sufficient for CD28-dependent activation. In this study, we report cell-intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent differentially impacted serum...
Summary Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting during re-infection. GC formation and cellular interactions within the have been studied in detail, yet exact signals that allow selection exit of MBCs not understood. Here, we show IL-4 signaling directly downregulates BCL6 via negative autoregulation to release from program promote MBC formation. This event requires additional survival cues...
(PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease a variety of animal models. However, clinical trials PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations antibodies identified using protein-immunized systems required extensive engineering optimize binding and/or reduce...
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease a variety of animal models. However, clinical trials PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations antibodies identified using protein-immunized systems required extensive engineering optimize...
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease a variety of animal models. However, clinical trials PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations antibodies identified using protein-immunized systems required extensive engineering optimize...
<h3>Background</h3> Although excess levels of B cell activating factor the TNF family (BAFF, also known as BLyS) have been implicated in pathogenesis SLE, how BAFF promotes breaks tolerance is not completely understood. Transgenic mice (Tg) overexpressing develop an autoimmune disease resembling human SLE. binds to distinct receptors expressed on cells, receptor (BAFF-R) and transmembrane activator CAML interactor (TACI). Since BAFF-R deletion results loss mature BAFF-R-dependent signals are...