34 results match your criteria: "and National Jewish Medical and Research Center[Affiliation]"

Anergic B cells are autoreactive and are present in the periphery in an unresponsive state. Here we will discuss the difference in B cell receptor signaling between anergic B cells, chronically stimulated by autoantigen, and naïve B cell encountering antigen.

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Regulatory T cells (Tregs) can potentially be used as tools to suppress pathogenic T cells in autoimmune diseases such as type 1 diabetes. For use in therapy it is critically important to determine whether suppression by Tregs requires a population specific for the target of autoimmunity, such as pancreatic beta cells in type 1 diabetes. Current reports in the NOD mouse model of type 1 diabetes are in conflict as to whether suppression of disease by Tregs is Ag-dependent.

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Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death. MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response.

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Although IgM serves as a first barrier to Ag spreading, the cellular and molecular mechanisms following B lymphocyte activation that lead to IgM secretion are not fully understood. By virtue of their anatomical location, marginal zone (MZ) B cells rapidly generate Ag-specific IgM in response to blood-borne pathogens and play an important role in the protection against these potentially harmful Ags. In this study, we have explored the contribution of TLR agonists to MZ B cell activation and mobilization as well as their ability to promote primary IgM responses in a mouse model.

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To test whether highly crossreactive alphabeta T cell receptors (TCRs) produced during limited negative selection best illustrate evolutionarily conserved interactions between TCR and major histocompatibility complex (MHC) molecules, we solved the structures of three TCRs bound to the same MHC II peptide (IAb-3K). The TCRs had similar affinities for IAb-3K but varied from noncrossreactive to extremely crossreactive with other peptides and MHCs. Crossreactivity correlated with a shrinking, increasingly hydrophobic TCR-ligand interface, involving fewer TCR amino acids.

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Emerging evidence indicates that in addition to their well-characterized role in antigen presentation, MHC II molecules transmit signals that induce death of APCs. Appropriately timed APC death is important for prevention of autoimmunity. Though the exact mechanism of MHC II-mediated cell death signaling is unknown, the response appears independent of caspase activation and does not involve Fas-FasL interaction.

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Lsc is a hematopoietic-restricted protein that functions as an effector of G alpha(12/13)-associated G-protein coupled receptors that activates RhoA. In the absence of Lsc leukocytes exhibit impaired migration and B lymphocytes inefficiently resolve integrin-mediated adhesion. Here, we demonstrate that Lsc exists physiologically in primary B lymphocytes as a large molecular weight complex resembling a homo-tetramer.

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To reduce neural tube defects (NTDs), the U.S. Food and Drug Administration (FDA) mandated that by January 1998 all enriched grain products should contain 140 microg of folic acid (FA)/100 g of flour.

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Natural killer T cells expressing 'invariant' T cell receptor alpha-chains (TCRalpha chains) containing variable (V) and joining (J) region V(alpha)14-J(alpha)18 (V(alpha)14i) rearrangements recognize both endogenous and microbial glycolipids in the context of CD1d. How cells expressing an invariant TCRalpha chain and a restricted set of TCRbeta chains recognize structurally diverse antigens is not clear. Here we show that a V(alpha)14i TCR recognized many alpha-linked glycolipids by means of a 'hot-spot' of germline-encoded amino acids in complementarity-determining regions 3alpha, 1alpha and 2beta.

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Total IgE levels and peripheral eosinophilia: correlation with mucosal disease based on computed tomographic imaging of the paranasal sinus.

Arch Otolaryngol Head Neck Surg

July 2007

Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine, and National Jewish Medical and Research Center, 4200 E Ninth Ave, SOM Room 1812, B-205, Denver, CO 80262, USA.

Objective: To evaluate the relationship among peripheral eosinophilia, total IgE, and paranasal sinus mucosal disease based on computed tomography (CT) of the sinus.

Design: Retrospective review of a large medical information database from a tertiary referral medical center.

Setting: Tertiary referral medical center specializing in respiratory disorders.

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Study of Mg2+ homeostasis in continuously growing cells requires the capacity to measure total cellular Mg2+ and net Mg2+ fluxes per unit time. Our laboratory's protocols for measurement of total cellular Mg2+ by atomic absorption spectrophotometry and measurement of net Mg2+ fluxes using the stable Mg2+ isotope 26Mg are described below.

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Rationale: Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations.

Objectives: To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity.

Methods: Arhgef1-deficient (Arhgef1-/-) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine.

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An encounter of B cells with cognate self Ags in the periphery can lead to anergy, a condition characterized by altered anatomical localization, shortened life span, and refractility to Ag stimulation. We recently reported that an immature B cell encounter with cognate self-Ag in the bone marrow can also lead to anergy. In this study we show that anergic as well as acutely Ag-stimulated immature B cells are defective in stromal cell-derived factor-1 (SDF-1)-induced calcium mobilization and migration and do not localize to bone marrow following adoptive transfer.

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Respiratory distress syndrome (RDS) secondary to preterm birth and surfactant deficiency is characterized by severe hypoxemia, lung injury, and impaired production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Since hypoxia-inducible factors (HIFs) mediate the effects of both NO and VEGF in part through regulation by prolyl-hydroxylase-containing domains (PHDs) in the presence of oxygen, we hypothesized that HIF-1alpha and -2alpha in the lung are decreased following severe RDS in preterm neonatal lambs. To test this hypothesis, fetal lambs were delivered at preterm gestation (115-day gestation, term = 145 days; n = 4) and mechanically ventilated for 4 h.

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Immunological tolerance can be mediated by anergy, in which self-reactive B cells persist in the periphery yet remain unresponsive to immunogen. Whether anergy is induced after transient exposure to self antigen and is 'remembered' or requires continuous antigen receptor occupancy and transduction of signals remains unclear. We have explored this using an immunoglobulin-transgenic mouse in which B cells were hapten specific (arsonate) yet cross-reacted with a self antigen that induced anergy in vivo.

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Objective: Although studies have suggested that human cartilage (HC) gp-39 may be an antigen recognized by autoreactive CD4(+) T cells in rheumatoid arthritis, we previously failed to identify specific CD4(+) T cells in patients' synovial fluid or blood using a class II major histocompatibility complex-peptide tetramer composed of the immunodominant HC gp-39(263-275) epitope covalently linked to DR4. We undertook this study to better understand the parameters for specific binding of this tetramer.

Methods: DR4-transgenic mice were immunized with the HC gp-39 peptide, and a set of peptide-responsive hybridomas was derived.

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Article Synopsis
  • The study investigates the connection between autoantibodies produced in mice with lupus, specifically targeting chromatin components and the murine leukemia virus envelope gp70.
  • Researchers utilized monoclonal antibodies from NZB/NZW mice to determine how these autoantibodies react with various viral and chromatin antigens, finding distinct responses that still bind to viral particles.
  • Results indicate that retroviral particles might carry nuclear antigens, linking the autoimmune responses to both chromatin and gp70, suggesting a complex interaction in the development of glomerulonephritis in these mice.
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Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young animals. Here we review multiple studies that address the mechanisms that contribute to this decline.

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Recent studies demonstrate that MHC class II molecules can signal via associated Ig-alphabeta dimers, signal transducers previously thought to function only in B cell Ag receptor (BCR) signaling. Surprisingly, the biologic outputs of MHC class II and BCR ligation (by thymus-dependent Ags) differ, e.g.

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Oxidative stress in type 1 diabetes.

Ann N Y Acad Sci

November 2003

Department of Immunology, University of Colorado Health Sciences Center, and National Jewish Medical and Research Center, Denver, Colorado 80206, USA.

We have been investigating the effects of preventing oxidative stress on pathogenesis and complications of type 1 diabetes in the NOD mouse model. Our studies have shown that damage caused by oxidative stress is higher in islets and vascular tissue of NOD mice than in nonautoimmune controls or a diabetes-resistant NOD mouse. In addition, phagocytic function and cytokine production by macrophages are aberrant in the NOD.

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Most techniques that identify antigen-specific T cells are dependent on the response of these cells to the relevant antigen in culture. Soluble multimers of MHC molecules, when occupied with the same peptide, will bind selectively to T cells specific for that MHC/peptide complex. Techniques to produce fluorescent MHC class II/peptide multimers have recently been developed.

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A T-cell functional phenotype common among autoimmune-prone rodent strains.

Scand J Immunol

June 2002

Barbara Davis Center for Childhood Diabetes and the Integrated Department of Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado, USA.

The genetic basis and familial clustering of autoimmunity suggest that common phenotypic traits predispose individuals to disease. We found a hyporesponsive T-cell phenotype that was shared by all autoimmune-prone mouse and rat strains tested, including MRL, nonobese diabetic (NOD), NZB, NZW, NZB/W F1, SJL and SWR mice, as well as DA and BB rats, but was not evident in nonautoimmune-prone rodents. This T-cell intrinsic, age-independent hyporesponsiveness is measured as an increased activation threshold for upregulation of activation markers upon T-cell receptor (TCR) cross-linking both in vitro and in vivo.

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Aging is accompanied by greatly reduced B cell production in the bone marrow, yet peripheral B cell numbers do not decline. We hypothesize that this may reflect filling of the peripheral pool with B cells that are long-lived as a consequence of specificity for, and chronic stimulation by, environmental Ags. To begin to explore this possibility, we analyzed the effects of aging on B cell population dynamics in the anti-H2(k/b) 3-83 mu-delta Ig-transgenic mouse.

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B cell tolerance can be maintained by functional inactivation, or anergy, wherein B cell Ag receptors (BCR) remain capable of binding Ag, but are unable to transduce signals. Although the molecular mechanisms underlying this unresponsiveness are unknown, some models of B cell anergy are characterized by disruption of proximal BCR signaling events, and by destabilization of the BCR complex. Receptor destabilization is manifest by a reduced ability to coimmunoprecipitate membrane Ig with the Ig-alpha/Ig-beta signal-transducing complex.

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