bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rhinovirus Regulation of IL-1 Receptor Antagonist In Vivo and In Vitro: A Potential Mechanism of Symptom Resolution
Authors: Yoon Ho Joo , Zhu Zhou , Gwaltney Jack M. , Elias Jack A. 
Published: December 2022

AbstractRhinovirus (RV) upper respiratory tract infections are prototypic transient inflammatory responses. To address the mechanism of disease resolution in these infections, we determined if RV stimulated the production of the IL-1 receptor antagonist (IL-1ra) in vivo and in vitro. In contrast to IL-1α and IL-1β, immunoreactive IL-1ra was readily detected in the nasal washings of normal human volunteers. Symptomatic RV infection caused a small increase in IL-1α, a modest increase in IL-1β, and an impressive increase in IL-1ra. Maximal induction of IL-1α and IL-1β was transiently noted 48 h after RV infection. In contrast, maximal induction of IL-1ra was prolonged appearing 48–72 h after RV infection. These time points corresponded to the periods of peak symptomatology and the onset of symptom resolution, respectively. Western analysis of nasal washings demonstrated that RV stimulated the accumulation of intracellular IL-1ra type I in all and secreted IL-1ra in a subset of volunteers. Unstimulated normal respiratory epithelial cells contained intracellular IL-1ra type I mRNA and protein. RV infection increased the intracellular levels and extracellular transport of this IL-1ra moiety without causing significant changes in the levels of IL-1ra mRNA. IL-1ra may play an important role in the resolution of RV respiratory infections. RV stimulates epithelial cell IL-1ra elaboration, at least in part, via a novel translational and/or posttranslational mechanism.
Effect of an Orally Active Th1/Th2 Balance Modulator, M50367, on IgE Production, Eosinophilia, and Airway Hyperresponsiveness in Mice
Authors: Kato Yutaka , Manabe Tadashi , Tanaka Yukiko , Mochizuki Hidenori 
Published: December 2022

AbstractWe have found a novel anti-allergic agent, M50367, which suppresses IgE biosynthesis and eosinophil accumulation in vivo. In this study, we evaluated the ability of M50367 to modulate Th1/Th2 balance in Th2-background BALB/c mice and to inhibit airway hyperresponsiveness in a murine model of atopic asthma. Oral M50367 at 3–30 mg/kg/day exhibited 51 to 73% reduction of IL-4/IL-5 production and 2- to 5-fold augmentation of IFN-γ production by Ag-stimulated cultured splenocytes of the mice sensitized with DNP-Ascaris. These alterations in Th1/Th2 cytokine production were accompanied by 55–85% suppression of plasma IgE level. Oral M50367 at a dose of 10 mg/kg/day significantly inhibited Ig-independent peritoneal eosinophilia by 54%, which was induced by repeated i.p. injections of Ascaris suum extract. To develop airway hyperresponsiveness caused by allergic airway inflammation, BALB/c mice were sensitized with i.p. OVA injections, followed three times by OVA inhalation. Oral M50367 significantly inhibited the increase in airway reactivity to acetylcholine, together with the elevation of plasma IgE level and pulmonary eosinophilia, which were observed in vehicle-treated mice 1 day after the last inhalation. Moreover, M50367 treatment reduced IL-4 and IL-5 production and tended to enhance IFN-γ production, not only by cultured splenocytes, but also in bronchoalveolar lavage fluid. These results suggest that M50367 has a modulating ability of Th1/Th2 balance to down-regulate Th2 response in the circulating system as well as at the sites of inflammation, and may be beneficial for the treatment of allergic disorders such as atopic asthma.
IL-13 and IFN-γ Secretion by Activated T Cells in HIV-1 Infection Associated with Viral Suppression and a Lack of Disease Progression
Authors: Bailer Robert T. , Holloway Alvy , Sun Junwei , Margolick Joseph B. , Martin Melissa , Kostman Jay , Montaner Luis J. 
Published: December 2022

AbstractThe immunopathology of HIV-1 infection includes immune defects in T cell cytokine secretion, resulting in decreased Ag-specific responses. In this report, IL-13 and IFN-γ were analyzed in progressive HIV-1 disease. Both cytokines exert positive effects on Ag presentation and inhibit HIV-1 infection of macrophages. Anti-CD3/anti-CD28-activated PBMC from HIV-1-infected individuals (n = 74) compared with uninfected subjects (n = 30) secreted significantly less IL-13 (median, 0.64 ng/ml vs 2.07 ng/ml; p &lt; 0.001) and IFN-γ (median, 40.96 ng/ml vs 129.5 ng/ml; p &lt; 0.005). Decreased IL-13 and IFN-γ secretion in HIV infection was present in sorted CD4+ and CD8+ T cell subsets, and additional analysis determined concurrent deficiency at the protein and transcriptional level. Longitudinal analysis showed that cytokine secretion levels correlated positively with CD4 count and negatively with plasma HIV-1 viral load. Patients changing to suppressive antiretroviral therapy during the study showed increases in IL-13 and IFN-γ secretion. Overall, results show a decline in IL-13 and IFN-γ secretion in progressive HIV-1 infection and suggest a role for both cytokines as part of T cell adaptive responses associated with a lack of disease progression.
Complement Receptor 1 (CD35) on Human Reticulocytes: Normal Expression in Systemic Lupus Erythematosus and HIV-Infected Patients
Authors: Lach-Trifilieff Estelle , Marfurt Jutta , Schwarz Sybille , Sadallah Salima , Schifferli Jürg A. 
Published: December 2022

AbstractThe low levels of complement receptor 1 (CR1) on erythrocytes in autoimmune diseases and AIDS may be due to accelerated loss in the circulation, or to a diminished expression of CR1 on the red cell lineage. Therefore, we analyzed the expression of CR1 on reticulocytes (R) vs erythrocytes (E). Healthy subjects had a significant higher CR1 number per cell on R (919 ± 99 CR1/cell) than on E (279 ± 30 CR1/cell, n = 23), which corresponded to a 3.5- ± 1.3-fold loss of CR1. This intravascular loss was confirmed by FACS analysis, which showed that all R expressed CR1, whereas a large fraction of E was negative. The systemic lupus erythematosus (SLE), HIV-infected, and cold hemolytic Ab disease (CHAD) patients had a CR1 number on R identical to the healthy subjects, contrasting with a lower CR1 on their E. The data indicated a significantly higher loss of CR1 in the three diseases, i.e., 7.0- ± 3.8-, 6.1- ± 2.9-, and 9.6- ± 5.6-fold, respectively. The intravascular loss was best exemplified in a patient with factor I deficiency whose CR1 dropped from 520 CR1/R to 28 CR1/E, i.e., 18.6-fold loss. In one SLE patient and in the factor I-deficient patient, the FACS data were consistent with a loss of CR1 already on some R. In conclusion, CR1 is lost progressively from normal E during in vivo aging so that old E are almost devoid of CR1. The low CR1 of RBC in autoimmune diseases and HIV-infection is due to a loss occurring in the circulation by an active process that remains to be defined.
C1.7 Antigen Expression on CD8+ T Cells Is Activation Dependent: Increased Proportion of C1.7+CD8+ T Cells in HIV-1-Infected Patients with Progressing Disease
Authors: Peritt David , Sesok-Pizzini Deborah A. , Schretzenmair Richard , Macgregor Rob R. , Valiante Nicholas M. , Tu Xin , Trinchieri Giorgio , Kamoun Malek 
Published: December 2022

AbstractThe C1.7 Ag is a surface marker previously shown to be expressed on all NK cells and on a subset of CD8+ T cells. We report in this study that C1.7 Ag expression on peripheral blood-derived CD8+ T cells overlaps with activation markers S6F1high and CD29high and is reciprocally expressed with CD62L. C1.7 Ag expression can be induced in vitro on CD8+ T cells by anti-CD3 cross-linking, suggesting that C1.7 Ag is activation dependent. In contrast to NK cells, C1.7 Ag does not signal on CD8+ T cells, nor does it induce redirected lysis upon ligation. The proportion of C1.7 Ag+CD8+ T cells is increased in HIV-infected patients compared with healthy donors. In 69 HIV-infected patients, we observed a significant inverse correlation between the percentage of C1.7 Ag-expressing CD8+ T cells and the absolute CD4+ T cell count. Two-year clinical follow-up of patients with initial CD4+ T cell count of &gt;400 cells/mm3 and a normal proportion of C1.7 Ag+CD8+ T cells revealed that these patients were clinically stable with minimal HIV-associated symptoms. In contrast, 10 of 12 patients with CD4+ T cell counts of &gt;400 cells/mm3 and an elevated proportion of C1.7 Ag+CD8+ T cells were symptomatic. ANOVA analysis of patients indicates that C1.7 Ag is a better predictor of disease progression than CD4 count. Overall, our findings indicate that C1.7 Ag is the first described marker for activated/memory CD8+ T cells and a useful parameter for evaluating the level of CD8+ T cell activation in vivo.
Cutting Edge: Absence of Expression of RAG1 in Peritoneal B-1 Cells Detected by Knocking into RAG1 Locus with Green Fluorescent Protein Gene
Authors: Kuwata Naomi , Igarashi Hideya , Ohmura Takafumi , Aizawa Shinichi , Sakaguchi Nobuo 
Published: December 2022

Abstract
It has been proposed that Ig gene rearrangement in the peritoneal cavity (Pc) B-1 cells might be involved in autoantibody generation. To study possible secondary B cell maturation, we prepared mice carrying a target integration of gfp gene into a rag1 locus (rag1/gfp mice). The GFP+ cells express rag1 mRNA and are undergoing Ig gene rearrangement. RAG1 expression was studied in Pc B-1 cells to detect cells during the stage of Ig gene rearrangement. In contrast to previous reports, Pc B-1 cells did not show RAG1 expression in adolescent or elderly mice. RAG1 expression was not induced in Pc B-1 cells in vivo after stimulation by oral or i.p. administration of LPS. Our results suggest that RAG1 expression in Pc B-1 cells is inhibited for a long period under normal condition and that this suppression is an essential state which maintains allelic exclusion of Ig genes.
Immunogenicity. I. Use of Peptide Libraries to Identify Epitopes That Activate Clonotypic CD4+ T Cells and Induce T Cell Responses to Native Peptide Ligands
Authors: Wilson Darcy B. , Pinilla Clemencia , Wilson Dianne H. , Schroder Kim , Boggiano César , Judkowski Valeria , Kaye Jonathan , Hemmer Bernhard , Martin Roland , Houghten Richard A. 
Published: December 2022

AbstractRecent studies have demonstrated the utility of synthetic combinatorial libraries for the rapid identification of peptide ligands that stimulate clonotypic populations of T cells. Here we screen a decapeptide combinatorial library arranged in a positional scanning format with two different clonotypic populations of CD4+ T cells to identify peptide epitopes that stimulate proliferative responses by these T cells in vitro. An extensive collection of mimic peptide sequences was synthesized and used to explore the fine specificity of TCR/peptide/MHC interactions. We also demonstrate that many of these deduced ligands are not only effective immunogens in vivo, but are capable of inducing T cell responses to the original native ligands used to generate the clones. These results have significant implications for considerations of T cell specificity and the design of peptide vaccines for infectious disease and cancer using clinically relevant T cell clones of unknown specificity.
Negative Regulation of CD4 Lineage Development and Responses by CD5
Authors: Peña-Rossi Claudia , Zuckerman Linda A. , Strong Julie , Kwan Joanne , Ferris William , Chan Susan , Tarakhovsky Alexander , Beyers Albert D. , Killeen Nigel 
Published: December 2022

AbstractCD5 deficiency results in a hyper-responsive phenotype to Ag receptor stimulation. Here we show that the development and responses of CD4 lineage T cells are regulated by the function of CD5. Thymocytes expressing the I-Ad-restricted DO11.10 TCR undergo abnormal selection without CD5. In H-2d mice, the absence of CD5 causes deletion of double-positive thymocytes, but allows for efficient selection of cells expressing high levels of the DO11.10 clonotype. By contrast, there is enhanced negative selection against the DO11.10 clonotype in the presence of I-Ab. T cell hybridomas and DO11.10 T cells are more responsive to TCR stimulation in the absence of CD5. Such hypersensitivity can be eliminated by expression of wild-type CD5, but not by a form of CD5 that lacks the cytoplasmic tail. Finally, CD5 deficiency partially suppresses the block of CD4 lineage development in CD4-deficient mice. Taken together, the data support a general role for CD5 as a negative regulator of Ag receptor signaling in the development and immune responses of CD4 lineage T cells.
Stat6-Dependent and -Independent Pathways for IL-4 Production
Authors: Kaplan Mark H. , Wurster Andrea L. , Smiley Stephen T. , Grusby3 Michael J. 
Published: December 2022

AbstractStat6 has been shown to have a crucial role in the IL-4-dependent differentiation of Th2 cells. In this report, we explore whether in vitro Th2 differentiation driven by altered costimulatory signals or Ag dose is Stat6 dependent. We find that blocking B7-1 signaling in vitro promotes the differentiation of IL-4-secreting Th2 cells in wild-type but not Stat6-deficient T cell cultures. Additionally, stimulation with peptide Ag doses that normally result in the production of Th2 cells in vitro fails to do so in cultures of Stat6-deficient cells. We also demonstrate that Stat6 is required for the in vitro differentiation of CD8+ T cells into IL-4-secreting cytotoxic T cell type 2 cells. However, IL-4 expression is not absolutely dependent on Stat6. We demonstrate that populations of T cells that do not require IL-4 for their development, such as NK T cells, are still competent to secrete IL-4 in the absence of Stat6. These results demonstrate that Stat6 is required for the differentiation program leading to the generation of Th2 and cytotoxic T cell type 2 cells but not for IL-4 expression in cells that do not undergo differentiation in response to IL-4.
Distinct Subcellular Localization and Substrate Specificity of Extracellular Signal-Regulated Kinase in B Cells upon Stimulation with IgM and CD40
Authors: Shirakata Yumiko , Ishii Kumiko , Yagita Hideo , Okumura Ko , Taniguchi Masaru , Takemori Toshitada 
Published: December 2022

AbstractWe and others previously observed that IgM and CD40 stimulation in murine B cells resulted in activation of extracellular signal-regulated kinase (ERK), a subfamily of mitogen-activated protein kinase. The present study demonstrated that ERK was rapidly phosphorylated and translocated to the nucleus in murine B cells upon stimulation with CD40, whereas it was preferentially localized within the cytosol after stimulation with IgM, suggesting that signaling through CD40 and IgM differentially regulates ERK subcellular localization. Costimulation with CD40 and IgM (CD40/IgM) resulted in subcellular localization of ERK within the cytosol, supporting the notion that stimulation with IgM delivers the signal responsible for inhibition of ERK nuclear transport. Consistent with these observations, IgM and CD40/IgM stimulation resulted in activation of ribosomal S6 kinase, which is a cytoplasmic substrate for ERK, whereas CD40 stimulation had little effect on its activity. Disruption of the microtubule by colchicine in WEHI231 cells resulted in reduction of ERK activity in IgM signaling, but not in CD40 signaling, compatible with the notion that the microtubule network may hold cytoplasmic ERK activity mediated by IgM stimulation. These results support the notion that ERK could mediate different effector functions in B cells upon stimulation with IgM and CD40.
Ligation of Microglial CD40 Results in p44/42 Mitogen-Activated Protein Kinase-Dependent TNF-α Production That Is Opposed by TGF-β1 and IL-10
Authors: Tan Jun , Town Terrence , Saxe Michael , Paris Daniel , Wu Yajuan , Mullan Michael 
Published: December 2022

AbstractRecently, it has been demonstrated that the CD40 receptor is constitutively expressed on cultured microglia at low levels. Ligation of CD40 by CD40 ligand on these cells results in microglial activation, as measured by TNF-α production and neuronal injury. However, the intracellular events mediating this effect have yet to be investigated. We report that ligation of microglial CD40 triggers activation of p44/42 mitogen-activated protein kinase (MAPK). This effect is evident 30 min posttreatment, and progressively declines thereafter (from 30 to 240 min). Phosphorylated p38 MAPK is not observed in response to ligation of microglial CD40 across the time course examined. Inhibition of the upstream activator of p44/42 MAPK, mitogen-activated protein/extracellular signal-related kinase kinase 1/2, with PD98059, decreases phosphorylation of p44/42 MAPK and significantly reduces TNF-α release following ligation of microglial CD40. Furthermore, cotreatment of microglial cells with CD40 ligand and TGF-β1 or IL-10, or both, inhibits CD40-mediated activation of p44/42 MAPK and production of TNF-α in a statistically interactive manner. Taken together, these data show that ligation of microglial CD40 triggers TNF-α release through the p44/42 MAPK pathway, an effect that can be opposed by TGF-β1 and IL-10.
T Cell Activation Up-Regulates the Expression of the Focal Adhesion Kinase Pyk2: Opposing Roles for the Activation of Protein Kinase C and the Increase in Intracellular Ca2+
Authors: Tsuchida Masahiro , Manthei Eric R. , Alam Tausif , Knechtle Stuart J. , Hamawy Majed M. 
Published: December 2022

AbstractT cell activation initiates signals that control gene expression of molecules important for T cell function. The focal adhesion kinase Pyk2 has been implicated in T cell signaling. To further analyze the involvement of Pyk2 in T cell processes, we examined the effect of T cell stimulation on the expression of Pyk2. We found that TCR ligation or PMA increased Pyk2 expression in Jurkat T cells and in normal T cells. In contrast, TCR ligation and PMA failed to induce any detectable increase in the expression of the other member of the focal adhesion kinase family, Fak, in Jurkat T cells and induced only a weak increase in Fak expression in normal T cells. The serine/threonine kinases, protein kinase C and mitogen-activated protein/extracellular signal-related kinase kinase (MEK), regulated Pyk2 expression, as inhibitors of these kinases blocked stimulus-induced Pyk2 expression. Cyclosporin A, FK506, and KN-62 did not block Pyk2 expression; thus, calcineurin and Ca2+/calmodulin-activated kinases are not critical for augmenting Pyk2 expression. TCR ligation increased Pyk2 mRNA, and the transcriptional inhibitor actinomycin D blocked Pyk2 expression. Strikingly, Ca2+ ionophores, at concentrations that in combination with other stimuli induced IL-2 expression, blocked TCR- and PMA-induced up-regulation of Pyk2 expression. Thus, the increase in Ca2+ has opposing effects on IL-2 and Pyk2 expression. Cyclosporin A and FK506, but not KN-62, blocked Ca2+ ionophore-mediated inhibition of Pyk2 expression, implicating calcineurin in down-regulating Pyk2 expression. These results show that TCR-triggered intracellular signals increase Pyk2 expression and shed light on the molecular mechanisms that regulate Pyk2 expression in T cells.
Microphthalmic Mice Display a B Cell Deficiency Similar to that Seen for Mast and NK Cells
Authors: Roundy Kirstin , Kollhoff Angela , Eichwald E. J. , Weis Janis J. , Weis John H. 
Published: December 2022

AbstractThe microphthalmic mouse (mi) possesses a 3-bp deletion of the Mi gene that alters the DNA binding site of the transcription factor gene product. This animal has diminished numbers of NK and mast cells (MC) and is osteopetrotic due to a lack of the normal complement of functional osteoclasts. The reduction of MC has been proposed to be due to the lack of adequate c-Kit expression that is required for MC differentiation. However, data from other labs has questioned this interpretation. In this report, we present data suggesting bone marrow-derived deficiencies of the mi mouse are not due to a lack of c-Kit expression and function, but instead due to an inhospitable environment within the bone marrow itself. Specifically, we have found that such animals also lack virtually all B cell precursors within the marrow and rely upon other lymphatic sites, such as the spleen, for B cell development and maturation. Although the animal has depressed numbers of NK cells, B cells, and MC, it still possesses a normal thymus and peripheral T cells. Therefore, the block in cellular differentiation must be within the marrow environment, which is essential for maturing B cells, NK cells, and MC but not T cells.
Expression and Regulation of the Human β-Defensins hBD-1 and hBD-2 in Intestinal Epithelium
Authors: O’Neil Deborah A. , Porter Edith Martin , Elewaut Dirk , Anderson G. Mark , Eckmann Lars , Ganz Tomas , Kagnoff Martin F. 
Published: December 2022

AbstractThe intestinal epithelium forms a physical barrier to limit access of enteric microbes to the host and contributes to innate host defense by producing effector molecules against luminal microbes. To further define the role of the intestinal epithelium in antimicrobial host defense, we analyzed the expression, regulation, and production of two antimicrobial peptides, human defensins hBD-1 and hBD-2, by human intestinal epithelial cells in vitro and in vivo. The human colon epithelial cell lines HT-29 and Caco-2 constitutively express hBD-1 mRNA and protein but not hBD-2. However, hBD-2 expression is rapidly induced by IL-1α stimulation or infection of those cells with enteroinvasive bacteria. Moreover, hBD-2 functions as a NF-κB target gene in the intestinal epithelium as blocking NF-κB activation inhibits the up-regulated expression of hBD-2 in response to IL-1α stimulation or bacterial infection. Caco-2 cells produce two hBD-1 isoforms and a hBD-2 peptide larger in size than previously described hBD-2 isoforms. Paralleling the in vitro findings, human fetal intestinal xenografts constitutively express hBD-1, but not hBD-2, and hBD-2 expression, but not hBD-1, is up-regulated in xenografts infected intraluminally with Salmonella. hBD-1 is expressed by the epithelium of normal human colon and small intestine, with a similar pattern of expression in inflamed colon. In contrast, there is little hBD-2 expression by the epithelium of normal colon, but abundant hBD-2 expression by the epithelium of inflamed colon. hBD-1 and hBD-2 may be integral components of epithelial innate immunity in the intestine, with each occupying a distinct functional niche in intestinal mucosal defense.
Reduced Ultraviolet-Induced Carcinogenesis in Mice with a Functional Disruption in B7-Mediated Costimulation
Authors: Beissert Stefan , Bluestone Jeffrey A. , Mindt Iris , Voskort Maik , Metze Dieter , Mehling Annette , Luger Thomas A. , Schwarz Thomas , Grabbe Stephan 
Published: December 2022

AbstractImmunosuppression by UV light contributes significantly to the induction of skin cancer by suppressing the cell-mediated immune responses which control the development of carcinogenesis. The B7/CD28-CTLA-4 signaling pathway provides costimulatory signals essential for Ag-specific T cell activation. To investigate the role of this pathway in photocarcinogenesis, we utilized transgenic (Tg) mice which constitutively express CTLA-4Ig, a high-affinity CD28/CTLA-4 antagonist that binds to both B7-1 and B7-2. The transgene is driven by a skin-specific promoter yielding high levels of CTLA-4Ig in the skin and serum. Chronic UV exposure of CTLA-4Ig Tg mice resulted in significantly reduced numbers of skin tumors, when compared to control mice. In addition, Tg mice were resistant to UV-induced suppression of delayed-type hypersensitivity responses to alloantigens. Most importantly, upon stimulation with mitogens and alloantigens, T cells isolated from CTLA-4Ig Tg mice produced significantly less IL-4 but more IFN-γ compared to control T cells, suggesting an impaired Th2 response and a relative increase of Th1-type immunity. Together, these data show that overall B7 engagement directs immune responses toward the Th2 pathway. Moreover, they point out the crucial role of Th1 immune reactions in the protection against photocarcinogenesis.