A5000854416- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Immunotherapy and Immune Responses
- Peroxisome Proliferator-Activated Receptors
- Virus-based gene therapy research
- Immunodeficiency and Autoimmune Disorders
- Innovative Teaching Methods
- Immune Response and Inflammation
- Glycosylation and Glycoproteins Research
- CAR-T cell therapy research
- Eicosanoids and Hypertension Pharmacology
- SARS-CoV-2 detection and testing
- Immune cells in cancer
- Viral Infections and Outbreaks Research
- Educational Strategies and Epistemologies
- COVID-19 epidemiological studies
- NF-κB Signaling Pathways
- Cell Adhesion Molecules Research
- Animal Genetics and Reproduction
- Diverse Educational Innovations Studies
- Higher Education Practises and Engagement
- Education and Critical Thinking Development
National Jewish Health
2010-2023
University of Colorado Denver
2011-2023
University of Colorado Anschutz Medical Campus
2003-2021
University of Colorado Health
2000-2007
Office of Basic Energy Sciences
1999
University of Konstanz
1997
The newly emerging variants of SARS-CoV-2 from South Africa (B.1.351/501Y.V2) and Brazil (P.1/501Y.V3) have led to a higher infection rate reinfection COVID-19 patients. We found that the mutations K417N, E484K, N501Y within receptor-binding domains (RBDs) virus could confer ~2-fold binding affinity human receptor, angiotensin converting enzyme 2 (ACE2), compared wildtype RBD. mutated version RBD also completely abolishes bamlanivimab, therapeutic antibody, in vitro. Detailed analysis shows...
Systemic lupus erythematosus (SLE) is characterized by high-avidity IgG antinuclear antibodies (ANAs) that are almost certainly products of T cell–dependent immune responses. Whether critical amino acids in the third complementarity-determining region (CDR3) ANA originate from V(D)J recombination or somatic hypermutation (SHM) not known. We studied a mouse model SLE which all mutations within V regions, including those CDR3, could be unequivocally identified. Mutation reversion analyses...
The newly emerging variants of SARS-CoV-2 from India (Delta variant) and South America (Lambda have led to a higher infection rate either vaccinated or unvaccinated people. We found that sera Pfizer-BioNTech vaccine remain high reactivity toward the receptor binding domain (RBD) Delta variant while it drops dramatically Lambda variant. Interestingly, overall titer antibodies individuals 3-fold after 6 months, which could be one major reasons for breakthrough infections, emphasizing...
Abstract Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing a world-wide pandemic. A variant of SARS-COV-2 (20I/501Y.V1) recently discovered in the United Kingdom has single mutation from N501 to Y501 within receptor binding domain (Y501-RBD), Spike protein virus. This much more contagious than original version (N501-RBD). We found that this mutated RBD binds human Angiotensin Converting Enzyme (ACE2) ~10 times tightly native Modeling analysis showed N501Y would...
Abstract We generated several versions of the receptor binding domain (RBD) Spike protein with mutations existing within newly emerging variants from South Africa and Brazil. found that mutant RBD K417N, E484K, N501Y exchanges has higher affinity to human compared wildtype RBD. This mutated version also completely abolishes a therapeutic antibody, Bamlanivimab, in vitro .
Somatic mutations are not distributed randomly throughout Ab V region genes. A sequence-specific target bias is revealed by a defined hierarchy of mutability among di- and trinucleotide sequences located within Ig intronic DNA. Here we report that the preference pattern shared mouse JH Jkappa clusters human VH genes, suggesting common mutation mechanism exists for all genes both species. Using preferences, performed comprehensive analysis murine germline to predict regional mutabilities....
Abstract We previously reported that selective ablation of certain γδ T cell subsets, rather than removal all cells, strongly affects serum Ab levels in nonimmunized mice. This type manipulation also changed including residual revealing some interdependence populations. For example, mice lacking Vγ4+ and Vγ6+ cells (B6.TCR-Vγ4−/−/6−/−), we observed expanded Vγ1+ which composition activation produced more IL-4 upon stimulation vitro, increased production by αβ as well spontaneous germinal...
Abstract Ig variable (V) region genes are subjected to a somatic hypermutation process as B lymphocytes participate in immune reactions protein Ags. Although little is known regarding the mechanism of mutagenesis, consistent hierarchy trinucleotide target preferences evident. Analysis regional distributions predicted and we now empirically confirm surprising finding that framework 2 κ V highly mutable despite its importance structural integrity function Ab molecule. Interestingly, much this...
Rationale: A subpopulation of B cells (age-associated [ABCs]) is increased in mice and humans with infections or autoimmune diseases. Because depletion these might be valuable patients certain lung diseases, the goal was to find out if ABC-like were at elevated levels such patients.Objectives: To measure cell percentages granulomatous diseases.Methods: Peripheral blood BAL from sarcoidosis, beryllium sensitivity, hypersensitivity pneumonitis healthy subjects analyzed for percentage that...
Resolution of inflammation is an active process that tightly regulated to achieve repair and tissue homeostasis. In the absence resolution, persistent underlies pathogenesis chronic lung disease such as obstructive pulmonary (COPD) with recurrent exacerbations. Over course inflammation, macrophage programming transitions from pro-inflammatory pro-resolving, which in part by nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ). Our previous work demonstrated association...
Somatic gene rearrangement generates a diverse repertoire of B cells, many which have receptors possessing range affinities for self-Ag. Newly generated cells express high and relatively uniform amounts surface IgM (sIgM), while follicular (FO) sIgM at widely varying levels. It is plausible, therefore, that downmodulation serves as mechanism to maintain weakly self-reactive in responsive state by decreasing their avidity We tested this hypothesis performing comparative functional tests with...
Antibody diversity creates an immunoregulatory challenge for T cells that must cooperate with B cells, yet discriminate between self and nonself. To examine the consequences of cell reactions to receptor (BCR), we generated a transgenic (Tg) line mice expressing (TCR) specific κ variable region peptide in monoclonal antibody (mAb) 36-71. The epitope was originally by pair somatic mutations arose naturally during immune response. By crossing this TCR Tg mouse chain mAb 36-71, found κ-specific...
Linked recognition of Ag by B and T lymphocytes is ensured in part a state tolerance acquired CD4 cells to germline-encoded sequences within the cell receptor (BCR). We sought determine how such attained when peptide from BCR variable (V) region expressed small numbers as it physiological state. Mixed bone marrow (BM) chimeras were generated using donor BM mice with that transgene (Tg)-encoded κ L chain TCR Tg which (CA30) specific for Vκ encoded κTg. In where few express κTg, many CA30...
A paradox in monoclonal antibody (mAb) therapy is that despite the well-documented tolerogenic properties of deaggregated IgG, most therapeutic IgG mAb induce anti-mAb responses. To analyze CD4 T cell reactions against various physical states, we developed an adoptive transfer model using CD4+ cells specific for a Vκ region-derived peptide hapten-specific 36–71. We found heat-aggregated or immune complexes (IC) 36–71 elicited anti-idiotypic (anti-Id) antibodies, while form was tolerogenic....
The SARS-CoV-2 Delta and Lambda variants had been named of concern (VOC) interest (VOI), respectively, by the World Health Organization (WHO). Both have two mutations in spike receptor binding domain (RBD) region, with L452R T478K variant, L452Q F490S variant. We used surface plasmon resonance (SPR)-based technology to evaluate effect these on human angiotensin-converting enzyme 2 (ACE2) Bamlanivimab binding. affinity for RBD ligand, ACE2, is approximately twice as strong that wild type RBD,...
While vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides significant protection from disease 2019, the afforded to individuals with chronic lung is less well established. This study seeks understand how impacts SARS-CoV-2 vaccine-elicited immunity.
Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist days constitute ∼5% the cell pool. We assessed functional in Ars/A1 transgene model, where cells express a dual-reactive Ag receptor that binds, addition self-Ag, hapten p-azophenylarsonate (Ars). When were transferred adoptive recipients immunized with foreign proteins covalently conjugated Ars, endogenous IgG immune...
Abstract The BCR V region has been implicated as a potential avenue of T cell help for autoreactive B cells in systemic lupus erythematosus. In principle, either germline-encoded or somatically generated sequences could function targets such help. Preceding studies have indicated that class II MHC-restricted normal mice attain state tolerance to Ab diversity. this study, we tested whether is intact erythematosus-prone (New Zealand Black × SWR)F1 (SNF1). Using hybridoma sampling approach,...
T cell-dependent immune responses generate long-lived plasma cells and memory B cells, both of which express hypermutated Ab genes. The relationship between these cell types is not entirely understood. Both appear to emanate from the germinal center reaction, but it unclear whether evolve while obligatorily generating by siblings under all circumstances. In experiments we report, development was functionally segregated a series closely spaced injections Ag delivered during period...