bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nasopharyngeal-Associated Lymphoreticular Tissue (NALT) Immunity: Fimbriae-Specific Th1 and Th2 Cell-Regulated IgA Responses for the Inhibition of Bacterial Attachment to Epithelial Cells and Subsequent Inflammatory Cytokine Production
Authors: Yanagita Manabu , Hiroi Takachika , Kitagaki Noriko , Hamada Shigeyuki , Ito Hiro-o , Shimauchi Hidetoshi , Murakami Shinya , Okada Hiroshi , Kiyono Hiroshi 
Published: January 2023

Abstract
To investigate the antibacterial activity of mucosal Th1 and Th2 immune responses induced nasally and orally, mice were immunized with mucosal vaccine containing fimbrial protein of Porphyromonas gingivalis, a causative agent for a destructive chronic inflammation in the periodontium, and cholera toxin (CT) as mucosal adjuvant. Nasal vaccine containing low doses of fimbriae (10 μg) and CT (1 μg) induced Ag-specific Th1/Th2-type response in CD4+ T cells in mucosal effector tissues, including nasal passage and submandibular glands, which accounted for the generation of Ag-specific IgA-producing cells. In contrast, oral immunization required higher amounts of fimbriae and CT for the induction of Ag-specific IgA responses. Fimbriae-specific IgA mAbs generated from submandibular glands of nasally immunized mice inhibited P. gingivalis attachment to and reduced subsequent inflammatory cytokine production from epithelial cells. These findings suggest that nasal vaccination is an effective immunization regimen for the induction of Ag-specific Th1 and Th2 cell-driven IgA immune responses that possess the ability to inhibit bacterial attachment to epithelial cells and subsequent inflammatory cytokine production.
Amplification of the Antibody Response by C3b Complexed to Antigen Through an Ester Link
Authors: Villiers Marie-Bernadette , Villiers Christian L. , Laharie Anne-Marie , Marche Patrice N. 
Published: January 2023

AbstractComplement C3 has been described as playing an important role in the cell-mediated immune response. C3b has the capacity to covalently bind Ag and then to stimulate in vitro Ag presentation to T lymphocytes. To verify this observation in vivo, we prepared and purified covalent human C3b-Ag complexes using lysozyme (HEL) as Ag. The characterization of these HEL-C3b complexes indicates that they are representative of those susceptible to be generated in physiological conditions. Mice were immunized with 0.1 to 0.6 μg of either free HEL, HEL + C3b, HEL-C3b, or HEL + CFA. Response was assessed after two i.p. injections by quantification of specific Ab production. Immunization with either HEL-C3b complexes or HEL + CFA leads to anti-HEL IgG production whereas free HEL or HEL + C3b was ineffective. Either HEL-C3b or HEL + CFA immunizations led to a similar Ig subclasse patterns, including IgG1, IgG2a, IgA, and IgM.Our experiments provide the first evidence for modulation of specific Ab response by C3b when it is bound to Ag through a physiological-like link. Taken together with previous data concerning Ab response following recombinant HEL-C3d immunization, cellular events such as processing of C3b-Ag by APC and recognition by T lymphocytes, this present result underlines the importance of C3b and its fragments in stimulation of the immune system, through the multiplicity and complementarity of its interactions.
Colitis-Inducing Potency of CD4+ T Cells in Immunodeficient, Adoptive Hosts Depends on Their State of Activation, IL-12 Responsiveness, and CD45RB Surface Phenotype
Authors: Claesson Mogens H. , Bregenholt Søren , Bonhagen Kerstin , Thoma Stefan , Möller Peter , Grusby Michael J. , Leithäuser Frank , Nissen Mogens H. , Reimann Jörg 
Published: January 2023

AbstractWe studied the induction, severity, and rate of progression of inflammatory bowel disease (IBD) induced in SCID mice by the adoptive transfer of low numbers of the following purified BALB/c CD4+ T cell subsets: 1) unfractionated, peripheral, small (resting), or large (activated) CD4+ T cells; 2) fractionated, peripheral, small, or large, CD45RBhigh or CD45RBlow CD4+ T cells; and 3) peripheral IL-12-unresponsive CD4+ T cells from STAT-4-deficient mice. The adoptive transfer into SCID host of comparable numbers of CD4+ T cells was used to assess the colitis-inducing potency of these subsets. Small CD45RBhigh CD4+ T lymphocytes and activated CD4+ T blasts induced early (6–12 wk posttransfer) and severe disease, while small resting and unfractionated CD4+ T cells or CD45RBlow T lymphocytes induced a late-onset disease 12–16 wk posttransfer. SCID mice transplanted with STAT-4−/− CD4+ T cells showed a late-onset IBD manifest &gt;20 wk posttransfer. In SCID mice with IBD transplanted with IL-12-responsive CD4+ T cells, the colonic lamina propria CD4+ T cells showed a mucosa-seeking memory/effector CD45RBlow Th1 phenotype abundantly producing IFN-γ and TNF-α. In SCID mice transplanted with IL-12-unresponsive STAT-4−/− CD4+ T cells, the colonic lamina propria, mesenteric lymph node, and splenic CD4+ T cells produced very little IFN-γ but abundant levels of TNF-α. The histopathologic appearance of colitis in all transplanted SCID mice was similar. These data indicate that CD45RBhigh and CD45RBlow, IL-12-responsive and IL-12-unresponsive CD4+ T lymphocytes and lymphoblasts have IBD-inducing potential though of varying potency.
TCR Signaling Thresholds Regulating T Cell Development and Activation Are Dependent upon SHP-1
Authors: Johnson Kenneth G. , LeRoy Frances G. , Borysiewicz Leszek K. , Matthews R. James 
Published: January 2023

AbstractAn examination of thymocytes and peripheral T cells from SHP-1-deficient motheaten mice possessing a transgenic MHC class I-restricted TCR has implicated SHP-1 in regulating TCR signaling thresholds at three checkpoints in T cell development and activation. First, in the population of CD4−CD8− double negative thymocytes, SHP-1 appears capable of regulating signals from TCR complexes that control the maturation and proliferation of double negative thymocytes. Second, the loss of SHP-1 increased the number of CD4+CD8+ double positive thymocytes capable of maturing as TCRhigh single positive thymocytes. Third, the loss of SHP-1 altered the basal level of activation of naive lymph node T cells. Accordingly, SHP-1-deficient lymph node T cells bearing the transgenic TCR demonstrated a hyperresponsiveness to stimulation with cognate peptide. However, the loss of SHP-1 did not alter the cytolytic ability of mature effector cytotoxic T lymphocytes. Together these results suggest that SHP-1 contributes to establishing thresholds for TCR signaling in thymocytes and naive peripheral T cells.
Extracellular Signal-Regulated Kinase, Stress-Activated Protein Kinase/c-Jun N-Terminal Kinase, and p38mapkAre Involved in IL-10-Mediated Selective Repression of TNF-α-Induced Activation and Maturation of Human Peripheral Blood Monocyte-Derived Dendritic Cells
Authors: Sato Katsuaki , Nagayama Hitomi , Tadokoro Kenji , Juji Takeo , Takahashi Tsuneo A. 
Published: January 2023

AbstractTNF-α or IL-10 has been implicated to reversibly regulate physiological states of dendritic cells (DCs). However, little is known about dual stimulations of these cytokines on DC properties and the intracellular signaling events that are responsible for the regulation of these states. Here, we show that a family of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase 2 (ERK2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38mapk, are potentially involved in IL-10-mediated selective suppression of TNF-α-induced changes of the monocyte-derived DC properties. TNF-α induced the cluster formation of the cells and the enhancement of cell surface expression levels of CD83, CD86, and HLA-DR, and T cell stimulatory capacity, whereas the capacities for the endocytosis and the chemotactic migration were suppressed in these cells. Treatment of monocyte-derived DCs with IL-10 resulted in the reduction of the cell surface expression levels of CD86, HLA-DR, and T cell stimulatory capacity, whereas both endocytic and chemotactic migratory capacities were increased by IL-10. Dual stimulations of monocyte-derived DCs with TNF-α and IL-10 selectively antagonized their respective effects on these DC properties. TNF-α induced tyrosine phosphorylation and enzymatic activation of ERK2, SAPK/JNK, and p38mapk, whereas IL-10 did not induce these events. Dual stimulations of TNF-α plus IL-10 abolished TNF-α-induced changes of these MAPKs in DCs. These results suggest that the blockage in the MAPKs cascades contributes to IL-10-mediated repression of TNF-α-induced changes of DC properties.
Endotoxin-Mediated S-Nitrosylation of p50 Alters NF-κB-Dependent Gene Transcription in ANA-1 Murine Macrophages
Authors: delaTorre Andrew , Schroeder Rebecca A. , Punzalan Cecile , Kuo Paul C. 
Published: January 2023

Abstract
Nitric oxide (NO) regulates cellular function, in part, by S-nitrosylating active site thiol groups of proteins. Ex vivo S-nitrosylation of NF-κB p50 significantly decreases its capacity for DNA binding. To determine the cellular relevance of this observation, we utilized the ANA-l murine macrophage model of endotoxin (LPS)-mediated NO synthesis. In selected instances, the NO synthase inhibitor, l-arginine methyl ester (L-NAME; 100 μM), or the NO donor, S-nitroso-N-acetylcysteine (SNAC; 100 μM), was added. In contrast to that of LPS cells, nuclear extracts from LPS + L-NAME cells demonstrated increased NF-κB DNA binding on gel shift analysis. Addition of SNAC to LPS + L-NAME cells restored binding to a level equivalent to that of LPS cells. Spectrophotometric analysis of NF-κB p50 immunoprecipitates demonstrated S-NO bonds exclusively in LPS cells; these p50 protein isolates retained the same DNA binding characteristics as that of the nuclear extracts. Transfection assays utilizing NF-κB-dependent promoter-reporter constructs demonstrated increased activity in LPS + L-NAME cells compared with LPS cells; nuclear run-on assays confirmed increased transcription of the corresponding genes. These results suggest that LPS-mediated NO synthesis is associated with S-nitrosylation of NF-κB p50 and inhibition of NF-κB-dependent DNA binding, promoter activity, and gene transcription. We conclude that NO can regulate gene transcription by S-nitrosylation of NF-κB.
IL-16 as an Anti-Inflammatory Cytokine in Rheumatoid Synovitis
Authors: Klimiuk Piotr A. , Goronzy Jörg J. , Weyand Cornelia M. 
Published: January 2023

AbstractT lymphocytes are a major component of the inflammatory infiltrate in rheumatoid synovitis, but their exact role in the disease process is not understood. Functional activities of synovial T cells were examined by adoptive transfer experiments in human synovium-SCID mouse chimeras. Adoptive transfer of tissue-derived autologous CD8+ T cells induced a marked reduction in the activity of lesional T cells and macrophages. Injection of CD8+, but not CD4+, T cells decreased the production of tissue IFN-γ, IL-1β, and TNF-α by &gt;90%. The down-regulatory effect of adoptively transferred CD8+ T cells was not associated with depletion of synovial CD3+ T cells or synovial CD68+ macrophages, and it could be blocked by Abs against IL-16, a CD8+ T cell-derived cytokine. In the synovial tissue, CD8+ T cells were the major source of IL-16, a natural ligand of the CD4 molecule that can anergize CD4-expressing cells. The anti-inflammatory activity of IL-16 in rheumatoid synovitis was confirmed by treating synovium-SCID mouse chimeras with IL-16. Therapy for 14 days with recombinant human IL-16 significantly inhibited the production of IFN-γ, IL-1β, and TNF-α in the synovium. We propose that tissue-infiltrating CD8+ T cells in rheumatoid synovitis have anti-inflammatory activity that is at least partially mediated by the release of IL-16. Spontaneous production of IL-16 in synovial lesions impairs the functional activity of CD4+ T cells but is insufficient to completely abrogate their stimulation. Supplemental therapy with IL-16 may be a novel and effective treatment for rheumatoid arthritis.
Increased Peroxynitrite Activity in AIDS Dementia Complex: Implications for the Neuropathogenesis of HIV-1 Infection
Authors: Boven Leonie A. , Gomes Lucio , Hery Christiane , Gray Françoise , Verhoef Jan , Portegies Peter , Tardieu Marc , Nottet Hans S. L. M. 
Published: January 2023

AbstractOxidative stress is suggested to be involved in several neurodegenerative diseases. One mechanism of oxidative damage is mediated by peroxynitrite, a neurotoxic reaction product of superoxide anion and nitric oxide. Expression of two cytokines and two key enzymes that are indicative of the presence of reactive oxygen intermediates and peroxynitrite was investigated in brain tissue of AIDS patients with and without AIDS dementia complex and HIV-seronegative controls. RNA expression of IL-1β, IL-10, inducible nitric oxide synthase, and superoxide dismutase (SOD) was found to be significantly higher in demented compared with nondemented patients. Immunohistochemical analysis showed that SOD was expressed in CD68-positive microglial cells while inducible nitric oxide synthase was detected in glial fibrillary acidic protein (GFAP)-positive astrocytes and in equal amounts in microglial cells. Approximately 70% of the HIV p24-Ag-positive macrophages did express SOD, suggesting a direct HIV-induced intracellular event. HIV-1 infection of macrophages resulted in both increased superoxide anion production and elevated SOD mRNA levels, compared with uninfected macrophages. Finally, we show that nitrotyrosine, the footprint of peroxynitrite, was found more intense and frequent in brain sections of demented patients compared with nondemented patients. These results indicate that, as a result of simultaneous production of superoxide anion and nitric oxide, peroxynitrite may contribute to the neuropathogenesis of HIV-1 infection.
Autoantibodies to T Cell Costimulatory Molecules in Systemic Autoimmune Diseases
Authors: Matsui Toshihiro , Kurokawa Manae , Kobata Tetsuji , Oki Shinji , Azuma Miyuki , Tohma Shigeto , Inoue Tetsufumi , Yamamoto Kazuhiko , Nishioka Kusuki , Kato Tomohiro 
Published: January 2023

Abstract
To determine whether antilymphocyte Abs to T cell costimulatory molecules are generated in patients with autoimmune diseases and, if they exist, to clarify the mechanism of their production and pathological roles, we investigated the presence of autoantibodies to CTLA-4 (CD152), CD28, B7-1 (CD80), and B7-2 (CD86) in serum samples obtained from patients with various autoimmune diseases and from normal subjects using recombinant fusion proteins. In ELISAs, anti-CD28, anti-B7-1, and anti-B7-2 Abs were rarely seen, whereas anti-CTLA-4 Abs were detected in 8.2% of the patients with systemic lupus erythematosus, 18.8% of those with rheumatoid arthritis, 3.1% of those with systemic sclerosis, 31.8% of those with Behçet’s disease, 13.3% of those with Sjögren’s syndrome, and 0% of healthy donors. This reactivity was confirmed by immunoblotting. More importantly, the purified anti-CTLA-4 Abs reacted with CTLA-4 expressed on P815 cells by flow cytometry. In addition, we found at least three epitopes on the CTLA-4 molecule. Furthermore, among the patients with Behçet’s disease, uveitis was seen significantly less frequently in the anti-CTLA-4 Ab-positive patients. Taken collectively, these data indicate that anti-CTLA-4 autoantibodies are generated in systemic autoimmune diseases by an Ag-driven mechanism and may modulate the immune response in vivo by binding to CTLA-4 on T cells.
Accelerated Emigration of B Lymphocytes in the Xid Mouse
Authors: Cariappa Annaiah , Kim Tae Jin , Pillai Shiv 
Published: January 2023

AbstractThe B cell receptor is required for the emigration of newly generated B lymphocytes and for their maintenance in the periphery. A specific maintenance defect was noted in fraction I (IgDhighIgMlow) B cells in Xid mice (which harbor a mutation in Btk). Although Bcl-2 levels in fractions I and II (IgDhighIgMhigh) are equivalent in normal and Xid B cells, a novel peak of Bcl-2low fraction III (IgDlowIgMhigh) B cells was noted in the Xid mouse. Since this B cell population resembled bone marrow immature B cells, we examined the emigration of newly formed B cells in normal and Xid mice. These studies revealed the accelerated emigration of newly formed Xid B cells. We conclude that distinct Btk-independent and Btk-dependent signals mediate emigration and maintenance events during peripheral B cell maturation.
Negative Regulation of c-kit-Mediated Cell Proliferation by FcγRIIB
Authors: Malbec Odile , Fridman Wolf H. , Daëron Marc 
Published: January 2023

Abstract
FcγRIIB are single-chain low-affinity receptors for IgG that bear an immunoreceptor tyrosine-based inhibition motif in their intracytoplasmic domain and that negatively regulate immunoreceptor tyrosine-based activation motif-dependent cell activation. They are widely expressed by cells of hematopoietic origin. We investigated here whether FcγRIIB could also negatively regulate protein tyrosine kinase receptor (RTK)-dependent cell proliferation. As an experimental model, we used growth factor-dependent mast cells that constitutively express FcγRIIB and c-kit, an RTK prototype. We found that anti-c-kit Abs mimicked the effect of stem cell factor and induced thymidine incorporation in FcγRIIB−/−, but not in wild-type (wt) mast cells unless FcγRIIB were blocked or anti-c-kit F(ab′)2 were used. When coaggregated with c-kit by intact Abs in wt mast cells, FcγRIIB inhibited thymidine incorporation, as well as cell proliferation, and inhibition was correlated with an arrest of cells in G1 during the cell cycle. The coaggregation of c-kit with FcγRIIB did not affect ligand-induced c-kit phosphorylation and induced the tyrosyl-phosphorylation of FcγRIIB, which selectively recruited the Src homology 2 domain-bearing inositol 5-phosphatase SHIP. Our results indicate that IgG Abs to growth factors or growth factor receptors may control RTK-dependent proliferation of a variety of cells that express FcγRIIB.
Differential Cytokine and Chemokine Gene Expression by Human NK Cells Following Activation with IL-18 or IL-15 in Combination with IL-12: Implications for the Innate Immune Response
Authors: Fehniger Todd A. , Shah Manisha H. , Turner Matthew J. , VanDeusen Jeffrey B. , Whitman Susan P. , Cooper Megan A. , Suzuki Kazuhiro , Wechser Mark , Goodsaid Frederico , Caligiuri Michael A. 
Published: January 2023

AbstractNK cells constitutively express monocyte-derived cytokine (monokine) receptors and secrete cytokines and chemokines following monokine stimulation, and are therefore a critical component of the innate immune response to infection. Here we compared the effects of three monokines (IL-18, IL-15, and IL-12) on human NK cell cytokine and chemokine production. IL-18, IL-15, or IL-12 alone did not stimulate significant cytokine or chemokine production in resting NK cells. The combination of IL-18 and IL-12 induced extremely high amounts of IFN-γ protein (225 ± 52 ng/ml) and a 1393 ± 643-fold increase in IFN-γ gene expression over those in resting NK cells. IL-15 and IL-12 induced less IFN-γ protein (24 ± 10 ng/ml; p &lt; 0.007) and only a 45 ± 19-fold increase in IFN-γ gene expression over those in resting NK cells. The CD56bright NK cell subset produced significantly more IFN-γ following IL-18 and IL-12 compared with CD56dim NK cells (p &lt; 0.008). However, the combination of IL-15 and IL-12 was significantly more potent than that of IL-18 and IL-12 for NK cell production of IL-10, macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, and TNF-α at the protein and transcript levels. Granulocyte-macrophage CSF was optimally induced by IL-15 and IL-18. Resting CD56+ NK cells expressed IL-18R transcript that was up-regulated by IL-12 or IL-15. Our results show that distinct cytokine and chemokine patterns are induced in NK cells in response to different costimulatory signals from these three monokines. This suggests that NK cell cytokine production may be governed in part by the monokine milieu induced during the early proinflammatory response to infection and by the subset of NK cells present at the site of inflammation.
Differential Expression and Regulation of Cyclooxygenase Isozymes in Thymic Stromal Cells
Authors: Rocca Bianca , Spain Lisa M. , Ciabattoni Giovanni , Patrono Carlo , FitzGerald Garret A. 
Published: January 2023

Abstract
Prostaglandins (PGs) are lipid-derived mediators of rapid and localized cellular responses. Given the role of PG in supporting thymic T cell development, we investigated the expression of the PG synthases, also known as cyclooxygenases (COX)-1 and -2, in the biosynthesis of PGs in thymic stromal cell lines. The predominant isozyme expressed in cortical thymic epithelial cells was COX-1, while COX-2 predominated in the medulla. IFN-γ up-regulated expression and activity of COX-2 in medullary cells, in which COX-2 was expressed constitutively. In contrast, IFN-γ down-regulated COX-1 activity, but not expression, in cortical cells. Stromal cells support T cell development in the thymus, although the mediators of this effect are unknown. Selective inhibition of COX-2, but not COX-1, blocked the adhesion of CD4+CD8+ and CD4+CD8− thymocytes to medullary cell lines. No effect of the inhibitors was observed on the interactions of thymocytes with cortical epithelial lines. These data further support the differential regulation of COX-1 and COX-2 expression and function in thymic stromal cells. PGs produced by COX-2 in the medullary thymic stroma may regulate the development of thymocytes by modulating their interaction with stromal cells.
Two Mechanisms for the Non-MHC-Linked Resistance to Spontaneous Autoimmunity
Authors: Verdaguer2 Joan , Amrani2 Abdelaziz , Anderson Brad , Schmidt Dennis , Santamaria Pere 
Published: January 2023

AbstractGenetic susceptibility and resistance to most autoimmune disorders are associated with highly polymorphic genes of the MHC and with non-MHC-linked polygenic modifiers. It is known that non-MHC-linked polymorphisms can override or enhance the susceptibility to an autoimmune disease provided by pathogenic MHC genes, but the mechanisms remain elusive. In this study, we have followed the fate of two highly diabetogenic β cell-specific T cell receptors (Kd and I-Ag7 restricted, respectively) in NOR/Lt mice, which are resistant to autoimmune diabetes despite expressing two copies of the diabetogenic MHC haplotype H-2g7. We show that at least two mechanisms of non-MHC-linked control of pathogenic T cells operate in these mice. One segregates as a recessive trait and is associated with a reduction in the peripheral frequency of diabetogenic CD8+ (but not CD4+) T cells. The other segregates as a dominant trait and is mediated by IL-4- and TGF-β1-independent immune suppressive functions provided by lymphocytes that target diabetogenic CD4+ and CD8+ T cells, without causing their deletion, anergy, immune deviation, or ignorance. These results provide explanations as to how non-MHC-linked polymorphisms can override the susceptibility to an autoimmune disease provided by pathogenic MHC haplotypes, and demonstrate that protective non-MHC-linked genes may selectively target specific lymphoid cell types in cellularly complex autoimmune responses.