bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mobilization of granules and secretory vesicles during in vivo exudation of human neutrophils.
Authors: Sengeløv H , Follin P , Kjeldsen L , Lollike K , Dahlgren C , Borregaard N 
Published: December 2022

Abstract
The extent of mobilization of four different intracellular compartments was measured during in vivo exudation of neutrophils into skin chambers and compared with resting neutrophils obtained from blood. Exudation of neutrophils induced increased surface expression of alkaline phosphatase, complement receptor 1, and Mac-1, and a complete loss of L-selectin. The increase in the content of surface molecules in the plasma membrane is in accordance with complete mobilization of secretory vesicles. Granule matrix proteins were secreted into the chamber fluid by the exudated neutrophils and the exocytosed proteins were recovered in the skin chamber fluid. Release of gelatinase from gelatinase granules was 38.1%, lactoferrin release from specific granules was 21.9%, and myeloperoxidase release from azurophil granules was 7.0%, clearly illustrating a hierarchy in mobilization among granules. When exudate neutrophils were stimulated with FMLP, additional mobilization of granules was observed and the rank order regarding release was preserved. This is the first report to evaluate the mobilization of secretory vesicles during in vivo exudation of human neutrophils. It is shown that secretory vesicles are regulated exocytotic vesicles that are fully mobilized during in vivo exudation. Once exocytosed, secretory vesicles are not re-formed within a period of 6 h.
Human IL-17: a novel cytokine derived from T cells.
Authors: Yao Z , Painter S L , Fanslow W C , Ulrich D , Macduff B M , Spriggs M K , Armitage R J 
Published: December 2022

Abstract
A cDNA encoding human IL-17 (hIL-17) was cloned from a CD4+ T cell library. The predicted 155-amino acids sequence contains an N-terminal signal peptide and exhibits 72% amino acid identity with HVS13, an open reading frame from a T-lymphotropic Herpesvirus saimiri, and 63% with murine CTLA8. High levels of hIL-17 were induced from primary peripheral blood CD4+ T cells upon stimulation. When expressed in CV1/EBNA cells, recombinant hIL-17 was secreted in both glycosylated and nonglycosylated forms. A hIL-17.Fc fusion protein and supernatants from cells transfected with hIL-17 induced IL-6 and IL-8 production and enhanced the surface expression of the intracellular adhesion molecule-1 (ICAM-1) in human fibroblasts.
Natural killer cell ontogeny in the athymic rat. Relationship between functional maturation and acquired resistance to E1A oncogene-expressing sarcoma cells.
Authors: Cook J L , Iklé D N , Routes B A 
Published: December 2022

Abstract
Newborn nude rats are NK cell deficient and highly susceptible to tumor induction by NK-susceptible, E1A oncogene-expressing, BHK-21 sarcoma cells, whereas adults have normal NK activity and are tumor resistant. This model of NK cell-related tumor rejection was used to characterize age-related functional maturation of NK cells during nude rat ontogeny. Small numbers of cytolytic incompetent, NKR-P1+ cells were detected in the spleens of newborns. During the first month of life, there was an age-related increase in the numbers of splenic NK cells, followed by a stepwise maturation in their cytolytic competence. Three functional stages in NK cell cytolytic activity were apparent. A nonlytic newborn stage was followed by a transitional stage, during which absent or relatively weak spontaneous cytolytic activity was augmented by prolonged NK cell exposure to susceptible target cells. In the final stage, both spontaneous and augmented cytolytic activity increased toward the adult level that was attained by 4 wk of age. The data suggest the existence of a transient stage in NK cell ontogeny when triggering through the NKR-P1 molecule is functionally immature, and confirm the importance of a cytolytic competent, NK cell response for nude rat rejection of E1A oncogene-expressing tumor cells.
Tumor-associated E6 protein of human papillomavirus type 16 contains an unusual H-2Kb-restricted cytotoxic T cell epitope.
Authors: Gao L , Walter J , Travers P , Stauss H , Chain B M 
Published: December 2022

Abstract
We previously showed that CTL from H-2b mice immunized against the E6 protein of human papilloma virus (HPV) type 16 recognized a 10-mer peptide corresponding to amino acids 131 to 140. We show in this study that the minimal epitope, 130 to 137, is a 8-mer peptide presented by H-2Kb class I molecules. At position P8, the 130 to 137 peptide contains a hydrophobic methionine anchor residue, but P3 and P5 do not contain the typical anchor residues that are frequently found in Kb-bound peptides. Analysis with alanine-substituted peptides indicates that the tryptophan at P3 acts as an alternative anchor mediating Kb binding, while an arginine at P2 is a TCR contact residue. Synthetic 9-mer peptides corresponding to residues 130 to 138 are as efficiently recognized by CTL as 130 to 137 peptides. Analysis of extracts of E6-expressing cells suggests that Ag processing may produce multiple peptides containing the minimal 130 to 137 epitope. In vitro binding studies indicate that Kb binding of peptide 130 to 137 is approximately five orders of magnitude less efficient than Kb binding of previously identified CTL epitopes. In contrast, the E6 protein contains another potential CTL epitope in the region of amino acids 41 to 50. A synthetic peptide spanning this region binds very strongly to Kb and is capable of stimulating a strong peptide-specific CTL response. In the context of the whole protein, however, this epitope remains cryptic.
Surrogate light chain-dependent selection of Ig heavy chain V regions.
Authors: Keyna U , Beck-Engeser G B , Jongstra J , Applequist S E , Jäck H M 
Published: December 2022

Abstract
Bone marrow B cell precursors frequently rearrange the Ig heavy chain variable (VH) gene segment VH81X. It is puzzling, therefore, that mature B cells in adult mice rarely express mu-heavy chains bearing this VH gene segment. We show in this work in transformed pre-B cell lines that two VH81X/mu-chains that differ in their VH-D-JH joining sequences are not assembled covalently with the B cell precursor-specific surrogate light (SL) chain and are not expressed on the cell surface. From these findings, we propose that a B cell precursor clonally expands and proceeds to the next developmental stage only if it expresses a mu-chain with a VH domain that, together with the SL chain, directs the formation of a signal-transducing mu/SL chain membrane complex. Therefore, a checkpoint exists early in B cell development, at which SL chain not only screens B cell precursors for the presence of a full-length mu-chain, but also for a VH domain that promotes the assembly of a mu/SL chain complex.
Breaking immunologic ignorance to an antigenic peptide of simian virus 40 large T antigen.
Authors: Soldevila G , Geiger T , Flavell R A 
Published: December 2022

Abstract
Expression of antigenic proteins in the periphery may result in immunologic tolerance, immunologic ignorance, or autoimmunity. It is not clear why some Ags induce tolerance, whereas others activate Ag-reactive T cells. The physical nature of the Ag, the developmental timing of Ag expression, the priming of reactive lymphocytes, and the level of Ag expression are possible factors determining the immunologic response to extra-thymic Ags. Expression of the whole SV40 large T Ag (SV40-T) induces transformation of T antigen-expressing cells in vivo, and this phenomenon has been postulated to be the triggering event that leads to autoimmunity in some transgenic mouse models. Here we present a model in which a nononcogenic, yet antigenic, fragment of the SV40-T (SV40-Tfrag) is expressed specifically in pancreatic islet beta-cells. In contrast to whole SV40-T transgenic mice, SV40-Tfrag mice that are also transgenic for a TCR specific for the SV40-T are ignorant of Ag in vivo. They do not respond in vivo to the tissue-specific SV40-Tfrag Ag even after priming, but are fully responsive in vitro. This immunologic ignorance cannot be broken after activated SV40-T reactive T cells are transferred into sublethally irradiated mice expressing the islet-specific SV40-Tfrag. However, similar adoptive transfer experiments in mice co-expressing B7-1 and SV40-Tfrag on islet cells specifically lead to Ag recognition and diabetes. This demonstrates that in some circumstances the presence of (primed) reactive T cells is not sufficient to break tolerance; rather, costimulation is additionally required to elicit an autoimmune response. This also suggests that SV40-T-induced cellular transformation is important for the autoimmune response directed against SV40-T in other tissue-specific transgenic models.
In vivo association between p56lck and MAP kinase during IL-2-mediated lymphocyte proliferation.
Authors: Taieb J , Blanchard D A , Auffredou M T , Chaouchi N , Vazquez A 
Published: December 2022

Abstract
We previously reported that p56lck expression is upregulated in human B lymphocytes upon mitogenic stimulation. In this report, we characterized the molecules associated with p56lck in vivo in leukemic B cells costimulated with anti-mu Ab and IL-2 for 72 h. In vitro phosphorylation after p56lck immunoprecipitation indicated that p56lck is associated in vivo with the beta chain of the IL-2 receptor and p42 MAP kinase as well as a number of other proteins. Moreover, p56lck-associated MAP kinase is tyrosine and threonine phosphorylated, suggesting that it is activated. Prevention of DNA synthesis with aphidicolin abrogated this molecular association, and furthermore, cell cycle analysis with IL-2-dependent T cells showed that in cells in G1, MAP kinase was not associated to p56lck, whereas this p56lck-MAP kinase association was observed when cells are in S phase. Thus, p56lck and MAP kinase are only associated during S phase. These data suggest that MAP kinase in association with p56lck is directly involved in the control of IL-2-mediated DNA synthesis of both B and T lymphocytes.
IL-12 promotes enhanced recovery from vesicular stomatitis virus infection of the central nervous system.
Authors: Bi Z , Quandt P , Komatsu T , Barna M , Reiss C S 
Published: December 2022

Abstract
To investigate the role of a cytokine in host defense against the vesicular stomatitis virus (VSV) infection of the central nervous system (CNS), IL-12 was injected i.p. into groups of 10 BALB/c mice on days -1, 0, 1, 2, and 3 postinfection. Four days postinfection, mice were examined. IL-12 strongly enhanced immunity to VSV infection in the CNS as demonstrated by 1) decreased VSV titers in brain homogenate of IL-12-injected mice compared with those of controls; 2) increased expression of inducible nitric oxide synthase in the CNS; 3) enhanced expression of both MHC class I and class II Ags in the CNS; 4) increased T cell infiltration in the CNS, especially in the olfactory bulb; and 5) diminished VSV-induced apoptosis in olfactory bulb. No detrimental effect was observed even with the 200 ng/mouse dose of IL-12. Protective effects of IL-12 were dose dependent. Collectively, these results demonstrate that exogenously added IL-12, even when injected peripherally, significantly enhances recovery from VSV infection of the CNS.
Impact of interferon-gamma receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis.
Authors: Zhao Y X , Tarkowski A 
Published: December 2022

Abstract
The role of IFN-gamma in the regulation of host resistance of Staphylococcus aureus was studied using IFN-gamma receptor-deficient (IFN-gamma R-/-) mice in a model of S. aureus-induced septicemia and arthritis. IFN-gamma R-/- mice and wild-type controls were inoculated intravenously with a toxic shock syndrome toxin-1-producing S. aureus LS-1 strain. IFN-gamma R-/- mice displayed significantly more frequent and more severe arthritis compared with wild-type littermates (p &lt; 0.01) throughout the course of infection. Notably, IFN-gamma R-/- mice developed severe sepsis with high mortality early after the inoculation with staphylococci. However, the mortality of wild-type mice became significantly higher at later stages of the disease compared with IFN-gamma R-/- mice (p &lt; 0.05). This differential outcome of sepsis-related mortality was associated with deficiencies of bacterial elimination from blood and parenchymatous organs and correlated well to serum levels of IL-6 and spleen IL-1 beta and TNF-beta mRNA expression. Thus, bacterial growth and proinflammatory cytokines IL-1 beta, TNF-beta, and IL-6 were higher at the early stage of infection in IFN-gamma-/- mice but increased at the later stage in wild-type littermates. Our data indicate that the absence of IFN-gamma R leads to harmful as well as beneficial effects in S. aureus infection, depending on the stage of the disease and the localization of the infection.
IL-10 is involved in the protective effect of dibutyryl cyclic adenosine monophosphate on endotoxin-induced inflammatory liver injury.
Authors: Arai T , Hiromatsu K , Kobayashi N , Takano M , Ishida H , Nimura Y , Yoshikai Y 
Published: December 2022

Abstract
The effects of exogenous cAMP, dibutyryl cAMP (DBcAMP) on LPS-induced liver injury were examined in mice made hypersensitive to LPS by treatment with i.v. injection of Propionibacterium acnes. In vivo administration of DBcAMP significantly protected P. acnes-treated mice from LPS-induced liver injury, including apoptosis of hepatocytes. DBcAMP significantly increased circulating IL-10 level in correlation with suppression of the TNF-alpha level after LPS challenge in P. acnes-treated mice. Treatment with anti-IL-10 mAb abrogated the protective effect of DBcAMP on LPS-induced liver injury. Similar to in vivo findings, addition to DBcAMP to in vitro culture of liver adherent cells from P. acnes-treated mice enhanced IL-10 synthesis after LPS stimulation. These results suggest that the increment in IL-10 production by liver adherent cells is involved in the protective effect of DBcAMP on LPS-induced inflammatory liver injury.
Subcellular distribution of docking/fusion proteins in neutrophils, secretory cells with multiple exocytic compartments.
Authors: Brumell J H , Volchuk A , Sengelov H , Borregaard N , Cieutat A M , Bainton D F , Grinstein S , Klip A 
Published: December 2022

Abstract
Neutrophils contain at least four distinct types of secretory organelles, which undergo exocytosis during infection and inflammation. The signaling pathways leading to secretion of individual granules and their kinetics of exocytosis vary greatly, causing temporal and regional differences in docking and fusion with the plasma membrane. As a step toward understanding the processes underlying differential granular secretion in neutrophils, we assessed the presence and distribution of a number of proteins reported to be involved in vesicular docking and/or fusion in other systems. Specific Abs were used for immunoblotting of cells fractionated by density gradients and free-flow electrophoresis, and for localization by confocal immunofluorescence and electron microscopy. Syntaxin 1, VAMP (vesicle-associated membrane protein)-1, synaptosome-associated protein-25 (SNAP-25), synaptophysin, and cellubrevin were not detectable in human neutrophils. In contrast, syntaxin 4, VAMP-2, and the 39-kDa isoform of secretory carrier membrane protein (SCAMP) were present. SCAMP was found mainly in secondary and tertiary granules and in a fraction containing secretory vesicles, but was virtually absent from the primary (lysosomal) granules. This profile is consistent with the proposed "post-Golgi" distribution of SCAMP. VAMP-2 was largely absent from primary and secondary granules, but concentrated in tertiary granules and secretory vesicles. This pattern of distribution parallels the increasing sensitivity of these exocytic compartments to intracellular free calcium. Accordingly, ionomycin induced translocation of VAMP-2 toward the plasma membrane. Syntaxin 4 was found almost exclusively in the plasma membrane, and it accumulated in lamellipodia of migrating cells. This regional accumulation may contribute to localized secretion into the phagosomal lumen.
Characterization of mutant forms of recombinant human properdin lacking single thrombospondin type I repeats. Identification of modules important for function.
Authors: Higgins J M , Wiedemann H , Timpl R , Reid K B 
Published: December 2022

Abstract
Properdin is a serum glycoprotein that up-regulates the alternative pathway of complement by stabilizing the C3b-Bb complex. It also binds sulfated glycoconjugates, such as sulfatide, in vitro. Properdin is composed of cyclic dimers, trimers, and tetramers of a 53-kDa monomeric subunit. The monomer contains an N-terminal region of no known homology and six thrombospondin type 1 repeats (TSRs) of approximately 60 amino acids. To identify the regions of properdin important for function, we have expressed human properdin, and mutant forms each lacking a single TSR, in Chinese hamster ovary cells. In addition, limited tryptic digestion yielded "nicked" properdin by the cleavage of one peptide bond in TSR5. The structural and functional properties of these altered forms of properdin were investigated. Properdin "nicked" in TSR5 is unable to bind C3b but retains its overall structure and its ability to bind sulfatide. The removal of TSR5 prevents C3b and sulfatide binding. Properdin lacking TSR4 is unable to stabilize the C3b-Bb complex but is able to bind C3b and sulfatide, and shows the presence of monomers and dimers in an electron microscope. Properdin without TSR3 is able to stabilize the C3b-Bb complex, to bind C3b and sulfatide, and forms dimers, trimers, and tetramers. Properdin lacking TSR6 is unable to form oligomers. The N-linked carbohydrate of properdin is not required for oligomerization or stabilization of the C3b-Bb complex. The results implicate TSR5 in both C3b and sulfatide binding, and suggest that TSR4 may also be involved in stabilization of the C3b-Bb complex.
Autocrine/paracrine involvement of platelet-activating factor and transforming growth factor-beta in the induction of phosphatidylserine recognition by murine macrophages.
Authors: Rose D M , Fadok V A , Riches D W , Clay K L , Henson P M 
Published: December 2022

Abstract
The specific recognition of phosphatidylserine (PS) by macrophages is believed to be one means by which effete and apoptotic cells expressing PS on their outer membrane leaflet are targeted for phagocytosis. The aim of this study was to better understand the autocrine/paracrine factors involved in beta-glucan induction of PS recognition by macrophages. We provide evidence that both platelet-activating factor (PAF) and TGF-beta are involved in beta-glucan induction of PS recognition. This is based on the observations that the PAF receptor antagonist WEB 2086 and Ab against TGF-beta each could partially inhibit beta-glucan-induced PS recognition when used alone and could completely inhibit induction when used in combination. PAF, like TGF-beta, was found to prime macrophages for PS recognition, which could then be triggered by costimulation with a nonspecific phagocytic stimulus, latex particles. We also provide evidence that the priming by PAF and that by TGF-beta can occur independently of each other. This is based on the observations that 1) PAF priming was not blocked by anti-TGF-beta Ab, nor was TGF-beta priming prevented by WEB 2086; and 2) PAF did not increase the steady state level of TGF-beta mRNA, and TGF-beta did not induce PAF synthesis in these cells.
Augmentation or inhibition of IFN-gamma-induced MHC class II expression by lipopolysaccharides. The roles of TNF-alpha and nitric oxide, and the importance of the sequence of signaling.
Authors: Sicher S C , Chung G W , Vazquez M A , Lu C Y 
Published: December 2022

Abstract
MHC class II expression on macrophages is one determinant of Ag presentation and the vigor of CD4+ T cell immunity. We show that LPS may either inhibit or augment IFN-gamma-induced MHC class II on macrophages depending on the sequence of the IFN-gamma and LPS signals. LPS inhibited MHC class II when added simultaneously with IFN-gamma, but augmented class II expression when added after IFN-gamma. Inhibition was due to nitric oxide (NO), which was only produced if LPS was given simultaneously with IFN-gamma. However, even when NO production was inhibited, LPS given simultaneously with IFN-gamma did not augment MHC class II expression. This suggests that LPS delivers different signals when given simultaneously vs after IFN-gamma. LPS augmentation of class II expression was functionally important because it correlated with increased Ag presentation. Augmentation by LPS of IFN-gamma-induced class II expression by macrophages has not been previously reported. We found that TNF-alpha, like LPS, inhibited IFN-gamma-induced class II expression if NO was produced, but augmented it in the absence of NO formation. Studies with a neutralizing anti-TNF-alpha Ab, however, indicate that LPS augmentation of MHC class II did not require TNF-alpha. LPS augmentation involved a different mechanism than IFN-gamma induction of MHC class II. LPS augmentation occurred at a post-transcriptional level, whereas IFN-gamma-induction occurred at the level of gene transcription. LPS augmentation was apparent after 2 h of stimulation by LPS, while IFN-gamma induction of class II expression required more than 8 h.
Matrix metalloproteinases in immunity.
Authors: Goetzl E J , Banda M J , Leppert D 
Published: December 2022

Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-containing endo-proteinases that share structural domains but differ in substrate specificity, cellular sources, and inducibility. Macrophage production and secretion of large quantities of many MMPs, after contact with matrix proteins, is enhanced by surface determinants on activated T cells and suppressed by cytokines from Th1 and Th2 cells. T cells secrete predominantly the gelatinases MMP-2 and -9, after beta 1, integrin- or vascular cell adhesion molecule (VCAM)-1-dependent stimulation by cytokines and inflammatory mediators. MMPs of both T cells and macrophages facilitate secretion of TNF-alpha, by cleavage of the membrane-bound form. T cell MMPs prepare connective tissue matrices for T cell chemotaxis across basement membranes and through tissues. The greater amounts of diverse MMPs from macrophages are capable of degrading connective tissues, which may release stored growth factors. In limited studies of animal models of autoimmunity, specific MMP inhibitors have significantly decreased edema and inflammatory tissue damage, suggesting possible therapeutic benefits.