bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Autoimmunity in a Transgenic Model of B Cell Receptor Peripheral Tolerance: Changes in Coreceptors and B Cell Receptor-Induced Tyrosine-Phosphoproteins
Authors: Feuerstein Nili , Chen Fangqi , Madaio Michael , Maldonado Michael , Eisenberg Robert A. 
Published: December 2022

AbstractAbrogation of peripheral tolerance in transgenic mice that express a uniform B-cell receptor may create a powerful tool to examine the molecular mechanisms that underlie the autoimmune response in B cells. Here we report that processes that induce a systemic lupus erythematosus-like syndrome in normal mice, namely chronic graft vs host reaction, trigger systemic autoimmunity in a well-established transgenic mice model of B cell receptor peripheral tolerance. The induction of graft vs host reaction in mice that carry both a rearranged B cell Ag receptors specific for hen egg lysozyme and expressing chronically circulating hen egg lysozyme Ag resulted in induction of high and sustained levels of circulating anti-hen egg lysoyme autoantibodies and glomerulonephritis with proteinuria. This was associated with marked changes in expression of cell-surface proteins, such as CD23 and complement receptor 2. B cells from the graft vs host-induced mice could proliferate in vitro in response to self-Ag, and upon stimulation with anti-IgD demonstrated rapid phosphotyrosine phosphorylation of specific proteins, which could not be induced in the anergic double transgenic B cells. Conversely, loss of tolerance was not associated with a higher induction in the level of Syk kinase phosphorylation following stimulation with anti-IgD. Taken collectively, these data establish that 1) processes that induce a systemic lupus erythematosus-like syndrome in normal mice can abrogate peripheral tolerance in transgenic mice expressing self-tolerized B cells, and that 2) loss of tolerance in this model is associated with marked changes in surface expression of B cell coreceptors as well as with selective changes in IgD-induced signaling by discrete tyrosine-phosphoproteins, but not Syk kinase.
NK Cell-Deficient Mice Develop a Th1-Like Response but Fail to Mount an Efficient Antigen-Specific IgG2a Antibody Response
Authors: Satoskar Abhay R. , Stamm Luisa M. , Zhang Ximing , Okano Mitsuhiro , David John R. , Terhorst Cox , Wang Baoping 
Published: December 2022

AbstractNK cells have been shown to play a role in the modulation of B cell differentiation and Ab production. Using a novel murine model of NK cell deficiency, we analyzed the in vivo role of NK cells in the regulation of Ag-specific Ab production. After immunization with OVA or keyhole limpet hemocyanin in CFA, NK cell-deficient (NK−T+) mice developed an efficient Th1 response and produced significant levels of IFN-γ but displayed markedly reduced or absent Ag-specific IgG2a production. There were no differences in the levels of Ag-specific IgG, IgG1, and IgG2b between NK−T+ and NK+T+ mice. Furthermore, NK cell-reconstituted, NK+T+ (tgε26Y) mice produced significant amounts of Ag-specific IgG2a after immunization with OVA. These results indicate that NK cells are involved in the induction of Ag-specific IgG2a production in vivo. Moreover, they also demonstrate that the lack of Ag-specific IgG2a Ab production in NK−T+ mice is not associated with the impaired Th1 response and IFN-γ production.
The Role of CD8α′ in the CD4 Versus CD8 Lineage Choice
Authors: Salmon Patrick , Mong Mimi , Kang Xiao-Jun , Cado Dragana , Robey Ellen 
Published: December 2022

AbstractDuring thymic development the recognition of MHC proteins by developing thymocytes influences their lineage commitment, such that recognition of class I MHC leads to CD8 T cell development, whereas recognition of class II MHC leads to CD4 T cell development. The coreceptors CD8 and CD4 may contribute to these different outcomes through interactions with class I and class II MHC, respectively, and through interactions with the tyrosine kinase p56lck (Lck) via their cytoplasmic domains. In this paper we provide evidence that an alternatively spliced form of CD8 that cannot interact with Lck (CD8α′) can influence the CD4 vs CD8 lineage decision. Constitutive expression of a CD8 minigene transgene that encodes both CD8α and CD8α′ restores CD8 T cell development in CD8α mutant mice, but fails to permit the development of mismatched CD4 T cells bearing class I-specific TCRs. These results indicate that CD8α′ favors the development of CD8-lineage T cells, perhaps by reducing Lck activity upon class I MHC recognition in the thymus.
Heterogeneity of NK1.1+ T Cells in the Bone Marrow: Divergence from the Thymus
Authors: Zeng Defu , Gazit Gadi , Dejbakhsh-Jones Sussan , Balk Steven P. , Snapper Scott , Taniguchi Masaru , Strober Samuel 
Published: December 2022

AbstractNK1.1+ T cells in the mouse thymus and bone marrow were compared because some marrow NK1.1+ T cells have been reported to be extrathymically derived. Almost all NK1.1+ T cells in the thymus were depleted in the CD1−/−, β2m−/−, and Jα281−/− mice as compared with wild-type mice. CD8+NK1.1+ T cells were not clearly detected, even in the wild-type mice. In bone marrow from the wild-type mice, CD8+NK1.1+ T cells were easily detected, about twice as numerous as CD4+NK1.1+ T cells, and were similar in number to CD4−CD8−NK1.1+ T cells. All three marrow NK1.1+ T cell subsets were reduced about 4-fold in CD1−/− mice. No reduction was observed in CD8+NK1.1+ T cells in the bone marrow of Jα281−/− mice, but marrow CD8+NK1.1+ T cells were markedly depleted in β2m−/− mice. All NK1.1+ T cell subsets in the marrow of wild-type mice produced high levels of IFN-γ, IL-4, and IL-10. Although the numbers of marrow CD4−CD8−NK1.1+ T cells in β2m−/− and Jα281−/− mice were similar to those in wild-type mice, these cells had a Th1-like pattern (high IFN-γ, and low IL-4 and IL-10). In conclusion, the large majority of NK1.1+ T cells in the bone marrow are CD1 dependent. Marrow NK1.1+ T cells include CD8+, Vα14-Jα281−, and β2m-independent subsets that are not clearly detected in the thymus.
Generation of Polymeric Immunoglobulin Receptor-Deficient Mouse with Marked Reduction of Secretory IgA
Authors: Shimada Shin-ichiro , Kawaguchi-Miyashita Mariko , Kushiro Akira , Sato Takashi , Nanno Masanobu , Sako Tomoyuki , Matsuoka Yoshiaki , Sudo Katsuko , Tagawa Yoh-ichi , Iwakura Yoichiro , Ohwaki Makoto 
Published: December 2022

AbstractWe generated mouse lacking exon 2 of polymeric Ig receptor (pIgR) gene by a gene-targeting strategy (pIgR-deficient mouse; pIgR−/− mouse) to define the physiological role of pIgR in the transcytosis of Igs. pIgR−/− mice were born at the expected ratio from a cross between pIgR+/− mice, indicating that disruption of the pIgR gene in mice is not lethal. pIgR and secretory component proteins were not detected in pIgR−/− mice by Western blot analysis. Moreover, immunohistochemical analysis showed that pIgR protein is not expressed in jejunal and colonic epithelial cells of pIgR−/− mice, whereas IgA+ cells are present in the intestinal mucosa of pIgR−/− mice as well as wild-type littermates. Disruption of the pIgR gene caused a remarkable increase in serum IgA concentration and a slight increment of serum IgG and IgE levels, leaving serum IgM level unaltered. In contrast, IgA was much reduced but not negligible in the bile, feces, and intestinal contents of pIgR−/− mice. Additionally, IgA with a molecular mass of 280 kDa preferentially accumulated in the serum of pIgR−/− mice, suggesting that transepithelial transport of dIgA is severely blocked in pIgR−/− mice. These results demonstrate that dIgA is mainly transported by pIgR on the epithelial cells of intestine and hepatocytes, but a small quantity of IgA may be secreted via other pathways.
γ-Chain Dependent Recruitment of Tyrosine Kinases to Membrane Rafts by the Human IgA Receptor FcαR
Authors: Lang Mark L. , Shen Li , Wade William F. 
Published: December 2022

AbstractWe show that the human IgA receptor, FcαR, redistributes to plasma membrane rafts after cross-linking and that tyrosine kinases are relocated to these sites following FcαR capping. We demonstrate by confocal microscopy that FcαR caps in membrane rafts by a γ-chain-independent mechanism but that γ-chain expression is necessary for Lyn redistribution. Immunoblotting of rafts isolated by sucrose density gradient centrifugation demonstrated recruitment of γ-chain and phosphorylated tyrosine kinases Lyn and Bruton’s tyrosine kinase to membrane rafts after FcαR cross-linking. Time-dependent differences in Lyn phosphorylation and Bruton’s tyrosine kinase distribution were observed between cells expressing FcαR plus γ-chain and cells expressing FcαR only. This study defines early FcαR-triggered membrane dynamics that take place before FcαR internalization.
Reactive Oxygen Intermediates During Programmed Cell Death Induced in the Thymus of the Ts(1716)65Dn Mouse, a Murine Model for Human Down’s Syndrome
Authors: Paz-Miguel Jesús E. , Flores Reyes , Sánchez-Velasco Pablo , Ocejo-Vinyals Gonzalo , Escribano de Diego Juan , López de Rego Jacobo , Leyva-Cobián Francisco 
Published: December 2022

AbstractDown’s syndrome (DS) is one of the most frequent genetic disorders in humans. It has been suggested that overexpression of copper-zinc superoxide dismutase (SOD-1) in DS may be involved in some of the abnormalities observed, mainly neurodegenerative and immunopathological processes. One of the consequences is early thymic involution. Recently, Ts(1716)65Dn mice (Ts65Dn mice), made segmentally trisomic for a chromosome 16 segment, fulfill the criteria for a DS model. To study the possible role of SOD-1 overexpression in thymocyte biology, we analyzed the role of reactive oxygen intermediates during in vivo and in vitro programmed cell death (PCD) induced in the thymus of Ts65Dn mice. Our main findings can be summarized as follows. Ts65Dn thymuses exhibit greater PCD activity than controls, as ascertained by a combination of morphological, histochemical, and ultrastructural procedures. Ts65Dn thymocytes were highly susceptible to PCD induced by both LPS (in vivo) and dexamethasone, a synthetic glucocorticoid agonist (both in vivo and in vitro). Thymus abnormalities were probably caused by SOD-1 hyperexpression in Ts65Dn cells, in that reactive oxygen intermediate generation (specifically H2O2 production) is enhanced in thymocytes and clearly correlates with apoptosis. Similarly, oxidative injury correlated with the formation of lipid peroxidation by-products and antioxidants which partly inhibit PCD in thymocytes.
Differential Activation of Mitogen-Activated Protein Kinases in AGS Gastric Epithelial Cells bycag+ andcag− Helicobacter pylori
Authors: Keates Sarah , Keates Andrew C. , Warny Michel , Peek Richard M. , Murray Paul G. , Kelly Ciarán P. 
Published: December 2022

AbstractThe aim of this study was to determine whether Helicobacter pylori activates mitogen-activated protein (MAP) kinases in gastric epithelial cells. Infection of AGS cells with an H. pylori cag+ strain rapidly (5 min) induced a dose-dependent activation of extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) MAP kinases, as determined by Western blot analysis and in vitro kinase assay. Compared with cag+ strains, cag− clinical isolates were less potent in inducing MAP kinase, particularly JNK and p38, activation. Isogenic inactivation of the picB region of the cag pathogenicity island resulted in a similar loss of JNK and p38 MAP kinase activation. The specific MAP kinase inhibitors, PD98059 (25 μM; MAP kinase kinase (MEK-1) inhibitor) and SB203580 (10 μM; p38 inhibitor), reduced H. pylori-induced IL-8 production in AGS cells by 78 and 82%, respectively (p &lt; 0.01 for each). Both inhibitors together completely blocked IL-8 production (p &lt; 0.001). However, the MAP kinase inhibitors did not prevent H. pylori-induced IκBα degradation or NF-κB activation. Thus, H. pylori rapidly activates ERK, p38, and JNK MAP kinases in gastric epithelial cells; cag+ isolates are more potent than cag− strains in inducing MAP kinase phosphorylation and gene products of the cag pathogenicity island are required for maximal MAP kinase activation. p38 and MEK-1 activity are required for H. pylori-induced IL-8 production, but do not appear to be essential for H. pylori-induced NF-κB activation. Since MAP kinases regulate cell proliferation, differentiation, programmed death, stress, and inflammatory responses, activation of gastric epithelial cell MAP kinases by H. pylori cag+ strains may be instrumental in inducing gastroduodenal inflammation, ulceration, and neoplasia.
Modulation of Chemokine Expression During Ischemia/Reperfusion in Transgenic Mice Overproducing Human Glutathione Peroxidases
Authors: Ishibashi Nobuya , Weisbrot-Lefkowitz Miriam , Reuhl Kenneth , Inouye Masayori , Mirochnitchenko Oleg 
Published: December 2022

AbstractRenal ischemia/reperfusion (I/R) injury is a major cause of kidney damage. There is accumulating evidence that inflammatory reactions are involved in the pathogenesis of this process. Our studies demonstrate that transgenic mice overexpressing human extracellular and intracellular glutathione peroxidases (GP) are protected against kidney I/R injury. Importantly, significant reduction in neutrophil migration was observed in GP mice compared with nontransgenic mice. Analysis of signaling molecules mediating neutrophil activation and recruitment indicates reduction in the level of KC and macrophage inflammatory protein-2 chemokine expression in transgenic animals. The molecular mechanism mediating this effect appears to involve repression of NF-κB activation at the level of IκBα and IκBβ degradation. In the case of IκBα, no apparent phosphorylation was detected. These results suggest that IκBα proteolysis is triggered during the renal I/R pro-oxidant state by a still unknown mechanism, which might be different from other stimuli. A central role of NF-κB in CXC chemokine activation was demonstrated in cell culture anoxia/ATP repletion experiments as a model of I/R. The data presented indicate the important role of GP-sensitive signal transduction pathways in the development of inflammatory response and tissue injury during I/R.
Isolation of Self Antigen-Reactive Cells from Inflamed Islets of Nonobese Diabetic Mice Using CD4high Expression as a Marker
Authors: Lejon C. Kristina , Fathman Garrison 
Published: December 2022

AbstractThe low precursor frequency of Ag-reactive CD4+ T cells has been a barrier to the study of CD4+ T cell responses to conventional Ags as well as CD4+ T cell responses to autoantigens recognized during the course of an autoimmune disease. We have recently reported that all “conventional Ag” reactive CD4+ T cells are contained within the subpopulation expressing high levels of the CD4 molecule, termed CD4high. We have identified a CD4high population in the islets of Langerhans of prediabetic nonobese diabetic (NOD) mice that is extremely potent in transferring disease. As few as 500 CD4high islet-infiltrating CD4+ T cells transferred insulin-dependent diabetes mellitus to CD8 reconstituted NOD-SCID mice within 30 days of transfer. In contrast, CD4high T cells isolated from either NOD spleen or salivary glands did not transfer insulin-dependent diabetes mellitus into similar CD8-reconstituted NOD-SCID recipients. These data indicate that the precursor frequency of NOD islet-reactive, pathogenic CD4+ T cells is much higher in the prediabetic NOD pancreas than in these other organs. The islet-infiltrating CD4high T cells displayed selected memory markers, by cell surface analysis, and displayed a Th 1 phenotype by RNase protection assay, but had a marked decrease in IL-4 mRNA determined by quantitative real time PCR when compared with the less pathogenic CD4normal islet-infiltrating T cells. Use of the CD4high marker to select Ag activated T cells represents a tool to isolate and study pathogenic CD4+ T cells from autoimmune lesions in which the Ag has not been previously defined.
Transfer of the Enhancing Effect of Respiratory Syncytial Virus Infection on Subsequent Allergic Airway Sensitization by T Lymphocytes
Authors: Schwarze Jürgen , Makela Mika , Cieslewicz Grzegorz , Dakhama Azzeddine , Lahn Michael , Ikemura Toshihide , Joetham Anthony , Gelfand Erwin W. 
Published: December 2022

AbstractIn mice, respiratory syncytial virus (RSV) infection enhances allergic airway sensitization, resulting in lung eosinophilia and in airway hyperresponsiveness (AHR). The mechanisms by which RSV contributes to development of asthma and its effects on allergic airway sensitization in mice are not known. We tested whether these consequences of RSV infection can be adoptively transferred by T cells and whether depletion of T cell subsets prevents the effects of RSV infection on subsequent airway sensitization. Mononuclear cells, T lymphocytes, or CD4 or CD8 T cells from peribronchial lymph nodes (PBLN) of RSV-infected mice were transferred into naive BALB/c mice which were then exposed to OVA via the airways. Additionally, RSV-infected mice were depleted of CD4 or CD8 T cells following acute RSV infection but prior to airway sensitization. Following sensitization, airway responsiveness to inhaled methacholine, numbers of lung eosinophils, and levels of IFN-γ, IL-4, and IL-5 in PBLN cell cultures were monitored. Transfer of T cells from RSV-infected mice resulted in increased eosinophil influx into the lungs, increased IL-5 production, and development of AHR following airway sensitization to allergen. Transfer of CD8 but not CD4 T cells from the PBLN of RSV-infected mice also resulted in AHR following 10 days of OVA exposure. Further, depletion of CD8 T cells prevented these consequences of RSV infection while CD4 T cell depletion reduced them. We conclude that T cells, in particular CD8 T cells, are critical in mediating RSV-induced development of lung eosinophilia and AHR following allergic airway sensitization.
Antigen-Driven Expansion and Contraction of CD8+-Activated T Cells in Primary EBV Infection
Authors: Hoshino Yo , Morishima Tsuneo , Kimura Hiroshi , Nishikawa Kazuo , Tsurumi Tatsuya , Kuzushima Kiyotaka 
Published: December 2022

AbstractThe origin of the increased numbers of CD8+ atypical lymphocytes, expressing activated markers such as HLA-DR or CD45RO, in the peripheral blood of patients with infectious mononucleosis (IM) has been debated. Using a recently developed assay to detect intracellular accumulation of IFN-γ in EBV-reactive T cells by FACS, we have demonstrated that 34–54% of HLA-DR+/CD8+ and 34–60% of CD45RO+/CD8+ T cells in the PBMCs of febrile patients suffering from IM are EBV-specific. The EBV-specific CD8+ T cell counts in the PBMCs of four febrile patients suffering from IM ranged between 2260 and 8200/μl, decreasing to 5.1% and 7.9% of the counts in the first samples over 10 days in two donors. The decline of CD8+ T cell subpopulations, namely HLA-DR+, CD45RO+, and EBV-specific T cells, was in parallel with the drop in the EBV genome load. These data indicate that the Ag-driven expansion of CD8+ T cells and subsequent contraction with the Ag decline in vivo in humans is effective for clearing virus-infected cells with minimal disturbance of the homeostasis of the immune system.
Identification of New HER2/neu-Derived Peptide Epitopes That Can Elicit Specific CTL Against Autologous and Allogeneic Carcinomas and Melanomas
Authors: Rongcun Yang , Salazar-Onfray Flavio , Charo Jehad , Malmberg Karl-Johan , Evrin Kristina , Maes Hubert , Kono Koji , Hising Christina , Petersson Max , Larsson Olle , Lan Li , Appella Ettore , Sette Alessandro , Celis3 Esteban , Kiessling Rolf 
Published: December 2022

AbstractTwenty-two new HLA-A2.1-binding peptides derived from the protooncogene HER2/neu were identified and analyzed for their capacity to elicit peptide and tumor-specific CTL responses. We used peptide-pulsed autologous DC from the ascites of patients with ovarian carcinomas to induce CTL. Of the 22 tested new HER2/neu-derived epitopes that could bind HLA-A2 with high (IC50 &lt; 50 nM) or intermediate (50 nM &lt; IC50 &lt; 500 nM) affinity, we report the recognition by CTL of at least four novel epitopes, including HER2(9435), HER2(9665), HER2(9689), and HER2(10952), and confirm that of the known HER2 (9369) epitope. These epitopes were able to elicit CTL that specifically killed peptide-sensitized target cells and, most importantly, a HER2/neu-transfected cell line and the autologous tumor cells. We also confirm that HER2/neu is overexpressed in several melanoma lines, and as a new finding, report that some of these lines are sensitive to CTL induced by the HER2 (9369), HER2(9435), and HER2(9689) epitopes. Finally, CTL clones specific for HER2 (9369), HER2(9435), and HER2(9689) epitopes were isolated from tumor-specific CTL lines, further demonstrating the immunodominance of these epitopes. These findings broaden the potential application of HER2/neu-based immunotherapy.
Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 Are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively
Authors: Hashimoto Wataru , Osaki Tadashi , Okamura Haruki , Robbins Paul D. , Kurimoto Masashi , Nagata Shigekazu , Lotze Michael T. , Tahara Hideaki 
Published: December 2022

AbstractSystemic administration of rIL-18 protein to mice significantly suppresses the growth of murine tumor cell lines. The antitumor effect of IL-18 appears to be primarily mediated by asialo GM1+ cells. Since IL-18 enhances Fas ligand (FasL) expression on NK cell lines, the IL-18 antitumor effects could be mediated by FasL-induced cross-linking of Fas and subsequent tumor apoptosis. To address this question, rIL-18 or rIL-12 was administered to animals bearing the CL8-1 melanoma inoculated intradermally into wild type (wt), lymphoproliferation gene (lpr) (Fas deficient), or generalized lymphoproliferative disease gene (gld) (FasL deficient) mice. Although rIL-12 treatment retained significant antitumor effects in gld and lpr mice, those of rIL-18 administration were completely abrogated in gld but not lpr or wt mice. In vitro cytotoxicity was significantly enhanced against NK-sensitive YAC-1 cells and CL8-1 cells by rIL-18 administration to wt mice, but not to gld mice. Furthermore, rIL-18 administration augmented the cytotoxicity of liver lymphocytes harvested from perforin-deficient mice, whereas rIL-12 administration did not. Consistent with the role of this pathway, rIL-18 administration also up-regulates the expression of FasL mRNA in splenocytes. Lysis of CL8-1 cells induced by anti-Fas agonistic Ab was enhanced about 1.4-fold by IFN-γ, a cytokine that is induced by IL-18 in vitro and in vivo. We conclude that the antitumor effect of IL-18 is exerted predominantly through a Fas-dependent pathway. The perforin pathway, however, appears to be the predominant cytolytic pathway mediating IL-12 antitumor effects.