bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccinia Virus Inhibits the Maturation of Human Dendritic Cells: A Novel Mechanism of Immune Evasion
Authors: Engelmayer Jose , Larsson Marie , Subklewe Marion , Chahroudi Ann , Cox William I. , Steinman Ralph M. , Bhardwaj Nina 
Published: December 2022

AbstractVaccinia virus employs multiple mechanisms to evade the immune system, yet is highly immunogenic. We studied the interaction between vaccinia and human dendritic cells (DCs), potent APCs. DCs develop from precursor cells in two stages: an immature stage in which Ag uptake and processing occur, and a mature stage in which there is up-regulation of costimulatory and HLA molecules and efficient T cell activation. Vaccinia virus undergoes an abortive replication in both stages of DCs and induces apoptotic cell death. Furthermore, maturation of immature DCs and consequently T cell activation are inhibited. Obstruction of DC maturation may constitute a novel mechanism by which vaccinia attempts to evade the immune response.
Utilization of Two Seven-Transmembrane, G Protein-Coupled Receptors, Formyl Peptide Receptor-Like 1 and Formyl Peptide Receptor, by the Synthetic Hexapeptide WKYMVm for Human Phagocyte Activation
Authors: Le Yingying , Gong Wanghua , Li Baoqun , Dunlop Nancy M. , Shen Weiping , Su Shao Bo , Ye Richard D. , Wang Ji Ming 
Published: December 2022

AbstractTrp-Lys-Tyr-Val-d-Met (WKYMVm) is a synthetic leukocyte-activating peptide postulated to use seven-transmembrane, G protein-coupled receptor(s). In the study to characterize the receptor(s) for WKYMVm, we found that this peptide induced marked chemotaxis and calcium flux in human phagocytes. The signaling induced by WKYMVm in phagocytes was attenuated by high concentrations of the bacterial chemotactic peptide fMLP, suggesting that WKYMVm might use receptor(s) for fMLP. This hypothesis was tested by using cells over expressing genes encoding two seven-transmembrane receptors, formyl peptide receptor (FPR) and formyl peptide receptor-like 1 (FPRL1), which are with high and low affinity for fMLP, respectively. Both FPR- and FPRL1-expressing cells mobilized calcium in response to picomolar concentrations of WKYMVm. While FPRL1-expressing cells migrated to picomolar concentrations of WKYMVm, nanomolar concentrations of the peptide were required to induce migration of FPR-expressing cells. In contrast, fMLP elicited both calcium flux and chemotaxis only in FPR-expressing cells with an efficacy comparable with WKYMVm. Thus, WKYMVm uses both FPR and FPRL1 to stimulate phagocytes with a markedly higher efficacy for FPRL1. Our study suggests that FPR and FPRL1 in phagocytes react to a broad spectrum of agonists and WKYMVm as a remarkably potent agonist provides a valuable tool for studying leukocyte signaling via these receptors.
Blockade of T Cell Costimulation by CTLA4-Ig Inhibits Lung Inflammation in Murine Hypersensitivity Pneumonitis
Authors: Israël-Assayag Evelyne , Fournier Marcien , Cormier Yvon 
Published: December 2022

AbstractHypersensitivity pneumonitis (HP) is characterized by an influx of activated T cells in the lungs. The CD28/B7 system provides costimulatory signals essential for complete T cell activation and differentiation. We have previously demonstrated that alveolar macrophages from patients with HP have an up-regulated expression of B7 molecules. In the present study, we investigated the effect of i.p. administration of CTLA4-Ig, a CD28/B7 antagonist, on the lung inflammation of mice inoculated with Saccharoplyspora rectivirgula (SR), a major causative agent of HP. Five groups of C57BL/6 mice were intranasally instilled with SR or saline for 3 consecutive days per wk during 3 wk. CTLA4-Ig was administered starting either after 1 wk of SR challenge or 6 h before the first antigenic exposure and continued during the whole period of sensitization. A control-IgG was given similarly during the 3 wk of SR exposure. The groups included: 1, saline; 2, SR; 3, SR + control-Ig; 4, SR + CTLA4-Ig for the last 2 wk; and 5, SR + CTLA4-Ig for 3 wk. CTLA4-Ig treatment markedly decreased lung inflammation as shown by significantly fewer inflammatory cells in the bronchoalveolar lavage and in lung tissue and reduced SR-specific serum and bronchoalveolar lavage Ig levels. Production of IL-4, IL-10, and IFN-γ by IL-2-stimulated pulmonary T cells was also decreased by CTLA4-Ig. Administration of CTLA4-Ig did not affect the SR-induced up-regulation of B7-2 expression. These results show that blockade of CD28/B7 interactions by CTLA4-Ig inhibits SR-induced lung inflammation and immune response to SR Ag in mice and may provide a novel approach in the treatment of HP.
Determination of the Contribution of Cysteinyl Leukotrienes and Leukotriene B4 in Acute Inflammatory Responses Using 5-Lipoxygenase- and Leukotriene A4 Hydrolase-Deficient Mice
Authors: Byrum Robert S. , Goulet Jennifer L. , Snouwaert John N. , Griffiths Richard J. , Koller Beverly H. 
Published: December 2022

AbstractArachidonic acid metabolism by 5-lipoxygenase leads to production of the potent inflammatory mediators, leukotriene (LT) B4 and the cysteinyl LT. Relative synthesis of these subclasses of LT, each with different proinflammatory properties, depends on the expression and subsequent activity of LTA4 hydrolase and LTC4 synthase, respectively. LTA4 hydrolase differs from other proteins required for LT synthesis because it is expressed ubiquitously. Also, in vitro studies indicate that it possesses an aminopeptidase activity. Introduction of cysteinyl LT and LTB4 into animals has shown LTB4 is a potent chemoattractant, while the cysteinyl LT alter vascular permeability and smooth muscle tone. It has been impossible to determine the relative contributions of these two classes of LT to inflammatory responses in vivo or to define possible synergy resulting from the synthesis of both classes of mediators. To address this question, we have generated LTA4 hydrolase-deficient mice. These mice develop normally and are healthy. Using these animals, we show that LTA4 hydrolase is required for the production of LTB4 in an in vivo inflammatory response. We show that LTB4 is responsible for the characteristic influx of neutrophils accompanying topical arachidonic acid and that it contributes to the vascular changes seen in this model. In contrast, LTB4 influences only the cellular component of zymosan A-induced peritonitis. Furthermore, LTA4 hydrolase-deficient mice are resistant to platelet-activating factor, identifying LTB4 as one mediator of the physiological changes seen in systemic shock. We do not identify an in vivo role for the aminopeptidase activity of LTA4 hydrolase.
Functional Analysis of Antigen-Specific T Lymphocytes by Serial Measurement of Gene Expression in Peripheral Blood Mononuclear Cells and Tumor Specimens
Authors: Kammula Udai S. , Lee Kang-Hun , Riker Adam I , Wang Ena , Ohnmacht Galen A. , Rosenberg Steven A. , Marincola Francesco M. 
Published: December 2022

AbstractThe cloning of cancer Ags recognized by T cells has provided potentially new tools to enhance immunity against metastatic cancer. The biological monitoring of effective immunization has, however, remained a dilemma. We describe here a sensitive molecular quantitation methodology that allows analysis of in vivo immune response to vaccination. Metastatic melanoma patients were immunized with a synthetically modified peptide epitope (209-2M) from the melanoma self-Ag gp100. Using serial gene expression analysis, we report functional evidence of vaccine-induced CTL reactivity in fresh cells obtained directly from the peripheral blood of postimmunized patients. Further, we demonstrate in vivo localization of vaccine-induced immune response within the tumor microenvironment. The results of these molecular assays provide direct evidence that peptide immunization in humans can result in tumor-specific CTL that localize to metastatic sites.
Activation of Eotaxin Gene Transcription by NF-κB and STAT6 in Human Airway Epithelial Cells
Authors: Matsukura Satoshi , Stellato Cristiana , Plitt James R. , Bickel Carol , Miura Katsushi , Georas Steve N. , Casolaro Vincenzo , Schleimer Robert P. 
Published: December 2022

AbstractThe C-C chemokine eotaxin is a potent chemoattractant for eosinophils and probably plays an important role in the pathogenesis of asthma, although the mechanisms of its regulation are not well known. Airway epithelial cells express eotaxin mRNA and protein after stimulation with a variety of cytokines. We focused on the molecular mechanisms of eotaxin gene regulation by TNF-α and IL-4 in the airway epithelial cell line, BEAS-2B. Cells were transfected with luciferase reporter plasmids, which contained up to 1363 bp of the eotaxin promoter. Eotaxin promoter activity was increased by TNF-α (2.5-fold) and IL-4 (1.5-fold), respectively. The combination of TNF-α and IL-4 produced 3.6-fold activation of the eotaxin promoter. The eotaxin promoter contains overlapping consensus binding sites for transcription factors, NF-κB and STAT6, which are known to mediate responses to TNF-α and IL-4, respectively. Electrophoretic mobility shift assays revealed NF-κB binding after TNF-α stimulation and STAT6 binding after IL-4 stimulation using a DNA probe derived from the eotaxin promoter. Mutant plasmids were generated to define the roles of these transcription factors in eotaxin promoter activity. TNF-α stimulation, but not IL-4 stimulation, was lost in plasmids mutated at the NF-κB binding site, whereas IL-4 stimulation, but not TNF-α stimulation, was lost in plasmids mutated at the STAT6 binding site. When both sites were mutated, all transcriptional activation was lost. These results imply that TNF-α and IL-4 stimulate expression of the eotaxin gene by activating NF-κB and STAT6.
Antibody Repertoires of Four- and Five-Feature Translocus Mice Carrying Human Immunoglobulin Heavy Chain and κ and λ Light Chain Yeast Artificial Chromosomes
Authors: Nicholson Ian C. , Zou Xiangang , Popov Andrei V. , Cook Graham P. , Corps Elaine M. , Humphries Sally , Ayling Christine , Goyenechea Beatriz , Xian Jian , Taussig Michael J. , Neuberger Michael S. , Brüggemann Marianne 
Published: December 2022

AbstractWe have produced mice that carry the human Ig heavy (IgH) and both κ and λ light chain transloci in a background in which the endogenous IgH and κ loci have been inactivated. The B lymphocyte population in these translocus mice is restored to about one-third of normal levels, with preferential (3:1) expression of human λ over human κ. Human IgM is found in the serum at levels between 50 and 400 μg/ml and is elevated following immunization. This primary human Ab repertoire is sufficient to yield diverse Ag-specific responses as judged by analysis of mAbs. The use of DH and J segments is similar to that seen in human B cells, with an analogous pattern of N nucleotide insertion. Maturation of the response is accompanied by somatic hypermutation, which is particularly effective in the light chain transloci. These mice therefore allow the production of Ag-specific repertoires of both IgM,κ and IgM,λ Abs and should prove useful for the production of human mAbs for clinical use.
Production of Soluble Granulocyte Colony-Stimulating Factor Receptors from Myelomonocytic Cells
Authors: Iwasaki Hiromi , Shimoda Kazuya , Okamura Seiichi , Otsuka Teruhisa , Nagafuji Koji , Harada Naoki , Ohno Yuju , Miyamoto Toshihiro , Akashi Koichi , Harada Mine , Niho Yoshiyuki 
Published: December 2022

AbstractIt has been speculated that a soluble form of G-CSFR might be physiologically present in humans, since G-CSFR mRNA that lacks a transmembrane domain has been identified from a human myelomonocytic cell line. Here, we demonstrate human soluble G-CSFR (sG-CSFR) of two different molecular sizes (80 and 85 kDa) on an immunoblot analysis using Abs generated against the amino-terminal, extracellular domain of the full-length G-CSFR. Both isoforms of sG-CSFR were able to bind recombinant human G-CSF (rhG-CSF). RT-PCR analysis with primers targeted outside of the transmenbrane region revealed that membrane-anchored G-CSFR is expressed at all maturation stages of purified myeloid cells, including CD34+CD13+ cells (blasts), CD11b−CD15+ cells (promyelocytes or myelocytes), CD11b+CD15+ cells (metamyelocytes and mature neutrophils), and CD14+ cells (monocytes). On the other hand, sG-CSFR mRNA was detectable in CD11b−CD15+, CD11b+CD15+, and CD14+ cells, but not in the CD34+CD13+ blast population. The serum concentration of both isoforms of sG-CSFR appeared to be correlated with the numbers of neutrophils/monocytes before and after rhG-CSF treatment in normal individuals. Thus, two isoforms of sG-CSFR are physiologically secreted from relatively mature myeloid cells and might play an important role in myelopoiesis through their binding to serum G-CSF.
Monomeric Complement-Activating IgG Paraproteins
Authors: Trendelenburg Marten , Hess Christoph , Kondo-Oestreicher Mitsuko , Tissot Jean D. , Späth Peter , Schifferli Jürg A. 
Published: December 2022

AbstractThree patients presented a unique syndrome of recurrent panniculitis with an IgGκ paraprotein and depletion of the early components of the classical pathway of complement. The IgGκ paraproteins were monomers with a normal structure, and with no evidence for aggregation, as assessed by electron microscopy and ultracentrifugation. Both heavy and light chains were of normal molecular size (SDS-PAGE), and the paraproteins were not heavily glycosylated. However, the paraproteins from all three patients had unusual features that included abnormal behavior on gel filtration chromatography and a heavy chain of high pI. When analyzed by fast protein liquid chromatography (Superdex 200), elution of the paraproteins was retarded, particularly when the ionic strength was increased. This retardation was partially reversed in 20% alcohol, and fully reversed in 6 M guanidine-HCl. Neither anti-C1 inhibitor nor anti-C1q autoantibodies were found in any of the patients’ sera. However, the paraproteins bound to the globular heads of C1q at normal ionic strength. They activated C4 in normal human serum, but not in C1q-deficient serum. Activation led to the formation of C1s-C1 inhibitor complexes. Taken together, the data suggest that the unusual paraproteins have the capacity to bind C1q, which then leads to activation of C1. The ability of these paraproteins to activate C1, in spite of their being soluble monomers, is likely to be related to their unique physicochemical features.
The Sensitiveness of Tuberculous Guinea Pigs One Month Old to the Toxicity of Tuberculin
Authors: Freund Jules 
Published: December 2022

Abstract
In a previous paper (1) it was demonstrated that young experimentally infected guinea pigs show slight if any reaction to the injection into the dermis of a watery extract of tubercle bacilli despite the presence of gross lesions of tuberculosis in the regional lymph nodes and in the spleen. The control adult guinea pigs infected under the same conditions reacted to the same extract with marked redness, edema and necrosis at the site of injection.
This observation was confirmed subsequently by Valtis (2), who employed old tuberculin instead of the watery extract used in our work.
The purpose of the experiments reported here is to establish whether young experimentally infected guinea pigs are sensitive to the toxic action of old tuberculin. By young guinea pigs is meant, in this paper, guinea pigs not more than one month old; by adults, those weighing from 400 to 500 grams.
Utilization of distinct antigen-presenting cells for induction of CD4+ T cell-dependent humoral immunity in response to an intact bacterium versus soluble conjugate vaccine (APP3P.105)
Authors: KAR SWAGATA , Snapper Clifford 
Published: December 2022

Abstract
We hypothesized that CD4+ T cell-dependent polysaccharide (PS)- and protein-specific IgG responses to intact bacteria versus soluble PS-protein conjugates involve utilization of distinct APC. Confocal microscopy demonstrated that intact Streptococcus pneumoniae (Pn) co-localized within splenic mouse monocytic CD11b+CD11c- cells following i.p. immunization, whereas a pneumococcal conjugate vaccine co-localized within splenic CD11c+ cells. To explore the functional implications of this dichotomy we used clodronate liposomes (CL), to selectively deplete phagocytic cells, including monocytic CD11b+ cells, marginal zone macrophages and marginal metallophilic macrophages but not CD11c+ cells. CL injection prior to i.p. immunization with OVA peptide-expressing Pn resulted in marked inhibition of OVA-specific CD4+ T cell proliferation, whereas it had no effect on OVA-specific CD4+ T cell proliferation in response to an OVA-polysaccharide conjugate or OVA protein alone. Of interest, CL markedly reduced primary and secondary protein-specific IgG responses to Pn, as well as conjugate vaccine or protein alone. CL only modestly reduced PS-specific IgG responses to intact Pn and conjugate vaccine. These data suggest that CL-sensitive cells critically mediate early CD4+ T cell proliferation in response to an intact bacterium, but that they are also required for downstream events in response to a soluble antigen.
Macrophages-releasing antigen-carrying exosomes enhance dendritic cells-mediated CD4+ T cell response (APP3P.107)
Authors: Xu Yingping , Liu Yi , Yang Chunqing , Zhu Guangming , Wang Meixiang , Hu Jingxia , Song Wengang , Tang Hua 
Published: December 2022

Abstract
The mutual interplay of immune cells plays a critical role in the optimal adaptive immune response. Macrophages (Mφs) and dendritic cells (DCs) are major professional antigen presenting cells (APCs) and are jointly involved in clearance of invading pathogens and maintenance of homeostasis. However, the underlying interaction mechanism remains poorly understood. In this study, we demonstrated that Mφs, DCs, and neutrophils were predominant phagocytes that uptook apoptotic cell-associated antigens (Ags) in the spleen. Moreover, by utilizing deletion approaches with clodronate liposome (CLL) to delete Mφ, we found that Mφs were required for fully initiating a CD4+ T response to apoptotic cell-associated Ags. Although Mφs themselves were inefficient to present Ags to CD4+ T cell, it was capable of transferring Ags to DCs to induce a perfect CD4+ T cell proliferation. We further discovered that the process of Ags transfer to activate CD4+ T cell was related to cell-migration and soluble factor released by Mφs. More importantly, an exosome secretion inhibitor GW4869 could inhibit CD4+ T cell proliferation to cell-associate Ags in vitro and in vivo, which suggesting exosomes released by Mφs acted as one of vectors to bridge DCs and Mφs. Thus, we illustrated a new crosstalk mechanism between Mφs and DCs, contributing to regulate the optimal adaptive immunity and maintain immune homeostasis.
Evidence of a functional CD1d lipid antigen presentation pathway in murine alveolar epithelial cells (APP3P.108)
Authors: Rizvi Zaigham , Puri Niti , Saxena Rajiv 
Published: December 2022

Abstract
Lipid antigen presentation by CD1 molecule is an evolutionary conserved pathway that elicits rapid yet efficient cytotoxic response against fast mutating pathogens. CD1d molecule, the only isoform of CD1 family in mouse, has been shown to recognise important component of the Mycobacterium tuberculosis (Mtb) cell wall like phosphatidylinositol mannosides. We have recently shown that alveolar epithelial cells (AECs) present Mycobacterium bovis - BCG (an avirulent model for Mtb infection) antigens to sensitized Th cells in vitro, however, it remains unexplored whether AECs can also participate in the presentation of lipid antigens through CD1d pathway; that is, so far, know to operate only in professional antigen presenting cells like dendritic cells (DCs) and B cells. We started by establishing the expression of CD1d on LA4 (mouse airway epithelial) cell line and murine AECs by flow cytometry and immuno-histochemistry. qPCR showed significant up-regulation of mRNA expression of some of the crucial molecules involved in CD1d pathway in AECs upon BCG infection. The protein CD1d expression was also found to be boosted upon BCG infection. Finally, a functional CD1d antigen presentation by AECs (in vitro) was shown by using α-GalactosylCeramide (α-GalCer) antigen as model. Our findings suggest that AECs are capable of lipid antigen presentation through the CD1d pathway and this ability of AECs may contribute to the immune defences against pathogens like Mtb.
Early overexpression of FAS in beta cells protects NOD mice from autoimmune diabetes (BA6P.119)
Authors: Mora-Giral Concepcion , Wong Florence , Panosa Anaïs , Green E , Flavell Richard 
Published: December 2022

Abstract
Fas receptor signaling is essential for the induction of pancreatic β cell death in autoimmune diabetes, upon being engaged by its ligand FasL (CD95L). We found that early overexpression of this proapoptotic receptor on pancreatic β cells delayed diabetes onset and reduced diabetes incidence in the NOD mice, and its late overexpression in β cells does not have any protective effect on the disease onset. We have further explored whether early Fas expression on β cells promotes the immunodeviation of the autorreactive CD4+T repertoire to the T regulatory phenotype, at the expense of the proinflammatory, diabetes-causing Th1-Th17 phenotypes. We did not find an increased frequency of CD4+Treg cells in the peripheral lymphoid organs or increased FoxP3 expression in islets from NOD mice overexpressing Fas early in life. Diabetes protection was improved by neutralizing the Th17 response in transgenic mice, which suggests that protection mediated by Fas overerexpression is not due to the abrogation of the Th17 response, at least not exclusively.
Bacterial amyloids promote type I interferon production and accelerate autoimmunity (BA6P.124)
Authors: Gallucci Stefania , Gallo Paul , Rapsinski Glenn , Oppong Gertrude , Sriram Uma , Wilson Ronald , Buttaro Bettina , Tukel Cagla 
Published: December 2022

Abstract
Infections can be pathogenic in systemic lupus erythematosus (SLE). Curli is a bacterial amyloid part of enteric bacterial biofilms, like those of E. coli and Salmonella. We have recently found that curli fibers form highly immunogenic composites with DNA within the biofilm. Here we studied the immune response to curli-DNA complexes in the context of murine SLE. For in vitro studies, we stimulated bone marrow-derived dendritic cells (cDCs) from WT and lupus-prone mice with curli amyloid from S. Typhimurium biofilms. A dose titration of curli amyloid induced robust proinflammatory cytokine and type I-IFN responsive gene expression in cDCs. Using synthetic curli peptide, we found that curli and nucleic acids synergize to activate cDCs. We injected in vivo pre-diseased lupus-prone NZB/W-F1 mice i.p. with curli-DNA complexes and found that they accelerate disease, inducing high titers of anti-dsDNA and anti-chromatin autoantibodies. Curli-DNA complexes induced autoantibodies also in non-autoimmune C57BL/6 mice. Finally, we infected NZB/W-F1 mice i.p. with curli-expressing or curli mutant E. coli or Salmonella. Curli-competent bacteria triggered far higher autoantibody titers than curli mutant strains. In conclusion, biofilm-derived curli-DNA complexes are potent activators of DCs and can rapidly break tolerance and accelerate autoimmunity in mice, suggesting that bacterial amyloids and biofilm-based bacterial infections are important environmental triggers in lupus.