bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human IgG2 Can Form Covalent Dimers
Authors: Yoo Esther M. , Wims Letitia A. , Chan Lisa A. , Morrison Sherie L. 
Published: April 2014

Abstract
Unlike IgA and IgM, IgG has not yet been shown to form covalent polymers. However in the presence of specific Ag, murine IgG3 has been shown to polymerize through noncovalent interactions. In contrast to the noncovalent oligomers found with murine IgG3, we have detected covalent dimers in three different recombinant human IgG2 Abs produced in myeloma cells. Both IgG2,κ and IgG2,λ can form dimers. In addition, analysis of pooled human γ globulin and several normal sera revealed the presence of IgG2 dimers. The IgG2 dimers are in contrast to the noncovalent IgG dimers found in pooled sera of multiple donors resulting from idiotype/anti-idiotype (Id/anti-Id) interactions. Cyanogen bromide cleavage analysis suggests that one or more Cys residues in the γ2 hinge are involved in dimer assembly. The potential role of IgG2 dimers in immunity against carbohydrate Ags is discussed.
Perforin-Mediated Effector Function Within the Central Nervous System Requires IFN-γ-Mediated MHC Up-Regulation
Authors: Bergmann Cornelia C. , Parra Beatriz , Hinton David R. , Chandran Ramakrishna , Morrison Maureen , Stohlman Stephen A. 
Published: April 2014

Abstract
CD8+ T cells infiltrating the CNS control infection by the neurotropic JHM strain of mouse hepatitis virus. Differential susceptibility of infected cell types to clearance by perforin or IFN-γ uncovered distinct, nonredundant roles for these antiviral mechanisms. To separately evaluate each effector function specifically in the context of CD8+ T cells, pathogenesis was analyzed in mice deficient in both perforin and IFN-γ (PKO/GKO) or selectively reconstituted for each function by transfer of CD8+ T cells. Untreated PKO/GKO mice were unable to control the infection and died of lethal encephalomyelitis within 16 days, despite substantially higher CD8+ T cell accumulation in the CNS compared with controls. Uncontrolled infection was associated with limited MHC class I up-regulation and an absence of class II expression on microglia, coinciding with decreased CD4+ T cells in CNS infiltrates. CD8+ T cells from perforin-deficient and wild-type donors reduced virus replication in PKO/GKO recipients. By contrast, IFN-γ-deficient donor CD8+ T cells did not affect virus replication. The inability of perforin-mediated mechanisms to control virus in the absence of IFN-γ coincided with reduced class I expression. These data not only confirm direct antiviral activity of IFN-γ within the CNS but also demonstrate IFN-γ-dependent MHC surface expression to guarantee local T cell effector function in tissues inherently low in MHC expression. The data further imply that IFN-γ plays a crucial role in pathogenesis by regulating the balance between virus replication in oligodendrocytes, CD8+ T cell effector function, and demyelination.
Activation of STAT3 by IL-6 and IL-10 in Primary Human Macrophages Is Differentially Modulated by Suppressor of Cytokine Signaling 3
Authors: Niemand Claudia , Nimmesgern Ariane , Haan Serge , Fischer Patrick , Schaper Fred , Rossaint Rolf , Heinrich Peter C. , Müller-Newen Gerhard 
Published: April 2014

Abstract
On human macrophages IL-10 acts as a more potent anti-inflammatory cytokine than IL-6, although both cytokines signal mainly via activation of the transcription factor STAT3. In this study we compare IL-10 and IL-6 signaling in primary human macrophages derived from blood monocytes. Pretreatment of macrophages with PMA or the proinflammatory mediators LPS and TNF-α blocks IL-6-induced STAT3 activation, whereas IL-10-induced activation of STAT3 remains largely unaffected. Although LPS induces the feedback inhibitor suppressor of cytokine signaling 3 (SOCS3) in macrophages, inhibition of IL-6 signal transduction by LPS occurs rapidly and does not depend on gene transcription. We also found that pretreatment of macrophages with IL-10 inhibits subsequent STAT3 activation by IL-6, whereas IL-10-induced STAT3 activation is not affected by preincubation with IL-6. This cross-inhibition is dependent on active transcription and might therefore be explained by different sensitivities of IL-10 and IL-6 signaling toward the feedback inhibitor SOCS3, which is induced by both cytokines. In contrast to the IL-6 signal transducer gp130, which has been previously shown to recruit SOCS3 to one of its phosphotyrosine residues (Y759), peptide precipitation experiments suggest that SOCS3 does not interact with phosphorylated tyrosine motifs of the IL-10R. Taken together, different sensitivities of IL-10 and IL-6 signaling toward mechanisms that inhibit the Janus kinase/STAT pathway define an important mechanism that contributes to the different anti-inflammatory potencies of these two cytokines.
Monocytes Are Potent Facilitators of Alveolar Neutrophil Emigration During Lung Inflammation: Role of the CCL2-CCR2 Axis
Authors: Maus Ulrich A. , Waelsch Katharina , Kuziel William A. , Delbeck Tim , Mack Matthias , Blackwell Timothy S. , Christman John W. , Schlöndorff Detlef , Seeger Werner , Lohmeyer Jürgen 
Published: April 2014

Abstract
Coordinated neutrophil and monocyte recruitment is a characteristic feature of acute lung inflammatory responses. We investigated the role of monocyte chemotactic protein-1 (CCL2, JE) and the chemokine receptor CCR2 in regulating alveolar leukocyte traffic. Groups of wild-type (WT) mice, CCR2-deficient mice, lethally irradiated CCR2-deficient and WT mice that were reciprocally bone marrow transplanted (chimeric CCR2 deficient and WT, respectively), chimeric CCR2-deficient mice with an enriched CCR2+ alveolar macrophage population, and CCR2-deficient mice transfused with CCR2+ mononuclear cells were treated with intratracheal CCL2 and/or Escherichia coli endotoxin. Our data show that alveolar monocyte recruitment is strictly dependent on CCR2. LPS-induced neutrophil migration to the lungs is CCR2 independent. However, when CCR2-bearing blood monocytes are present, alveolar neutrophil accumulation is accelerated and drastically amplified. We suggest that this hitherto unrecognized cooperativity between monocytes and neutrophils contributes to the strong, coordinated leukocyte efflux in lung inflammation.
Secretory Phospholipases A2 Activate Selective Functions in Human Eosinophils
Authors: Triggiani Massimo , Granata Francescopaolo , Balestrieri Barbara , Petraroli Angelica , Scalia Giulia , Del Vecchio Luigi , Marone Gianni 
Published: April 2014

Abstract
Secretory phospholipases A2 (sPLA2s) are released in large amounts in the blood of patients with systemic inflammatory diseases and accumulate at sites of chronic inflammation, such as the airways of patients with bronchial asthma. Blood eosinophils or eosinophils recruited in inflammatory areas therefore can be exposed in vivo to high concentrations of sPLA2. We have examined the effects of two structurally different sPLA2s (group IA and group IIA) on several functions of eosinophils isolated from normal donors and patients with hypereosinophilia. Both group IA and IIA sPLA2 induced a concentration-dependent release of β-glucuronidase, IL-6, and IL-8. Release of the two cytokines was associated with the accumulation of their specific mRNA. In addition, sPLA2s induced the surface expression of CD44 and CD69, two major activation markers of eosinophils. In contrast, none of the sPLA2s examined induced the production of IL-5, the de novo synthesis of leukotriene C4 and platelet-activating factor, or the generation of superoxide anion from human eosinophils. Incubation of eosinophils with the major enzymatic products of the sPLA2s (arachidonic acid, lysophosphatidylcholine, or lysophosphatidic acid) did not reproduce any of the enzymes’ effects. In addition, inactivation of sPLA2 enzymatic activity by bromophenacyl bromide did not influence the release of β-glucuronidase or of cytokines. Stimulation of eosinophils by sPLA2s was associated with activation of extracellular signal-regulated kinases 1/2. These results indicate that sPLA2s selectively activate certain proinflammatory and immunoregulatory functions of human eosinophils through mechanism(s) independent from enzymatic activity and from the generation of arachidonic acid.
Engineered Recombinant Peanut Protein and Heat-Killed Listeria monocytogenes Coadministration Protects Against Peanut-Induced Anaphylaxis in a Murine Model
Authors: Li Xiu-Min , Srivastava Kamal , Huleatt James W. , Bottomly Kim , Burks A. Wesley , Sampson Hugh A. 
Published: April 2014

Abstract
Peanut allergy (PNA) is the major cause of fatal and near-fatal anaphylactic reactions to foods. Traditional immunotherapy using peanut (PN) protein is not an option for PNA therapy because of the high incidence of adverse reactions. We investigated the effects of s.c. injections of engineered (modified) recombinant PN proteins and heat-killed Listeria monocytogenes (HKLM) as an adjuvant on anaphylactic reactions in a mouse model of PN allergy. PN-allergic C3H/HeJ mice were treated s.c. with a mixture of the three major PN allergens and HKLM (modified (m)Ara h 1–3 plus HKLM). The effects on anaphylactic reactions following PN challenge and the association with Ab levels and cytokine profiles were determined. Although all mice in the sham-treated groups exhibited anaphylactic symptoms with a median symptom score of 3, only 31% of mice in the mAra h 1–3 plus HKLM group developed mild anaphylaxis, with a low median symptom score of 0.5. Alterations in core body temperature, bronchial constriction, plasma histamine, and PN-specific IgE levels were all significantly reduced. This protective effect was markedly more potent than in the mAra h 1–3 protein alone-treated group. HKLM alone did not have any protective effect. Reduced IL-5 and IL-13, and increased IFN-γ levels were observed only in splenocytes cultures from mAra h 1–3 plus HKLM-treated mice. These results show that immunotherapy with modified PN proteins and HKLM is effective for treating PN allergy in this model, and may be a potential approach for treating PNA.
Neutrophils Promote Mononuclear Cell Infiltration During Viral-Induced Encephalitis
Authors: Zhou Jiehao , Stohlman Stephen A. , Hinton David R. , Marten Norman W. 
Published: April 2014

Abstract
Neutrophils are the first infiltrating cell population to appear within the CNS during infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). To determine whether neutrophils play a role in limiting acute JHMV infection, mice were depleted of neutrophils. Infection of neutropenic animals resulted in increased levels of virus replication and mortality compared with control mice. Furthermore, neutropenia resulted in significantly reduced mononuclear leukocyte infiltration possibly due to reduced loss of blood brain barrier integrity during acute JHMV infection. These data suggest that infiltrating neutrophils are crucial for limiting virus replication during acute JHMV infection, contribute to the loss of blood brain barrier integrity and play a role in shaping adaptive immunity within the CNS.
The Cytokine Macrophage Migration Inhibitory Factor Reduces Pro-Oxidative Stress-Induced Apoptosis
Authors: Nguyen Mai Tuyet , Lue Hongqi , Kleemann Robert , Thiele Michael , Tolle Gabriele , Finkelmeier Doris , Wagner Eva , Braun Andrea , Bernhagen Jürgen 
Published: April 2014

Abstract
The cytokine macrophage migration inhibitory factor (MIF) exhibits pro- and anti-inflammatory activities and regulates cell proliferation and survival. We investigated the effects of MIF on apoptosis. As MIF exhibits oxidoreductase activity and participates in regulating oxidative cell stress, we studied whether MIF could affect oxidative stress-induced apoptosis. We demonstrated that MIF exhibits antiapoptotic activity in various settings. MIF suppressed camptothecin-induced apoptosis in HeLa and Kym cells and HL-60 promyeloblasts. Both exogenous MIF and endogenous MIF, induced following overexpression through tetracycline (tet) gene induction, led to significant suppression of apoptosis. Apoptosis reduction by MIF was also observed in T cells. A role for MIF in redox stress-induced apoptosis was addressed by comparing the effects of rMIF with those of the oxidoreductase mutant C60SMIF. Endogenous overexpression of C60SMIF was similar to that of MIF, but C60SMIF did not suppress apoptosis. Exogenous rC60SMIF inhibited apoptosis. A role for MIF in oxidative stress-induced apoptosis was directly studied in HL-60 leukocytes and tet-regulated HeLa cells following thiol starvation or diamide treatment. MIF protected these cells from redox stress-induced apoptosis and enhanced cellular glutathione levels. As overexpressed C60SMIF did not protect tet-regulated HeLa cells from thiol starvation-induced apoptosis, it seems that the redox motif of MIF is important for this function. Finally, overexpression of MIF inhibited phosphorylation of endogenous c-Jun induced by thiol starvation, indicating that MIF-based suppression of apoptosis is mediated through modulation of c-Jun N-terminal kinase activity. Our findings show that MIF has potent antiapoptotic activities and suggest that MIF is a modulator of pro-oxidative stress-induced apoptosis.
Role of the Chemokine Stromal Cell-Derived Factor 1 in Autoantibody Production and Nephritis in Murine Lupus
Authors: Balabanian Karl , Couderc Jacques , Bouchet-Delbos Laurence , Amara Ali , Berrebi Dominique , Foussat Arnaud , Baleux Françoise , Portier Alain , Durand-Gasselin Ingrid , Coffman Robert L. , Galanaud Pierre , Peuchmaur Michel , Emilie Dominique 
Published: April 2014

Abstract
In normal mice, stromal cell-derived factor 1 (SDF-1/CXCL12) promotes the migration, proliferation, and survival of peritoneal B1a (PerB1a) lymphocytes. Because these cells express a self-reactive repertoire and are expanded in New Zealand Black/New Zealand White (NZB/W) mice, we tested their response to SDF-1 in such mice. PerB1a lymphocytes from NZB/W mice were exceedingly sensitive to SDF-1. This greater sensitivity was due to the NZB genetic background, it was not observed for other B lymphocyte subpopulations, and it was modulated by IL-10. SDF-1 was produced constitutively in the peritoneal cavity and in the spleen. It was also produced by podocytes in the glomeruli of NZB/W mice with nephritis. The administration of antagonists of either SDF-1 or IL-10 early in life prevented the development of autoantibodies, nephritis, and death in NZB/W mice. Initiation of anti-SDF-1 mAb treatment later in life, in mice with established nephritis, inhibited autoantibody production, abolished proteinuria and Ig deposition, and reversed morphological changes in the kidneys. This treatment also counteracted B1a lymphocyte expansion and T lymphocyte activation. Therefore, PerB1a lymphocytes are abnormally sensitive to the combined action of SDF-1 and IL-10 in NZB/W mice, and SDF-1 is key in the development of autoimmunity in this murine model of lupus.
Prothrombin Binds to the Surface of Apoptotic, But Not Viable, Cells and Serves as a Target of Lupus Anticoagulant Autoantibodies
Authors: D’Agnillo Paolo , Levine Jerrold S. , Subang Rebecca , Rauch Joyce 
Published: April 2014

Abstract
Anti-phospholipid Ab (aPL) are a heterogeneous group of autoantibodies directed against various combinations of phospholipids (PL) and PL-binding proteins. Lupus anticoagulant (LA) Ab, a subset of aPL, exhibit anticoagulant properties in vitro, but are procoagulant in vivo. Most LA Ab are specific for either β2-glycoprotein I (β2GPI) or prothrombin (PT), two PL-binding proteins. We have previously shown that β2GPI and β2GPI-dependent aPL bind specifically to apoptotic, but not viable, thymocytes. In this study, we demonstrate that PT, like β2GPI, binds selectively to the surface of apoptotic, but not viable, Jurkat cells. Furthermore, PT supports the binding of systemic lupus erythematosus-derived polyclonal and murine monoclonal LA Ab to apoptotic cells. Two LA mAb, which differed dramatically in their relative affinities for PT, were studied. Although one mAb (29J3-62) had a high affinity for PT alone, the other (29I4-24) showed minimal reactivity with PT alone and required PL for elevated binding. Monovalent fragments of 29I4-24 reacted with PL-bound PT with high affinity, suggesting that this mAb recognizes a PL-dependent epitope. Despite these differences, PT-dependent binding of both mAb to apoptotic cells was 30-fold greater than that to viable cells. Moreover, binding of PT to apoptotic cells was, itself, increased in the presence of bivalent, but not monovalent, forms of either mAb. In summary, our data demonstrate the following: 1) specific binding of PT to apoptotic cells, an effect enhanced by PT-dependent LA Ab; 2) heterogeneity of PT-dependent LA Ab; and 3) potential pathogenicity of Ab of either low or high affinity for PT.
Cytokine Polymorphisms Play a Role in Susceptibility to Ultraviolet B-Induced Modulation of Immune Responses after Hepatitis B Vaccination
Authors: Sleijffers Annemarie , Yucesoy Berran , Kashon Michael , Garssen Johan , De Gruijl Frank R. , Boland Greet J. , Van Hattum Jan , Luster Michael I. , Van Loveren Henk 
Published: April 2014

Abstract
UVB exposure can alter immune responses in experimental animals and humans. In an earlier human volunteer study, we demonstrated that hepatitis B-specific humoral and cellular immunity after vaccination on average were not significantly affected by UVB exposure. However, it is known that individuals differ in their susceptibility to UVB-induced immunomodulation, and it was hypothesized that polymorphisms in specific cytokines may play a role in this susceptibility. In this respect, we previously demonstrated that immune responses after hepatitis B vaccination are influenced by the minor allelic variant of IL-1β in the general population. For all volunteers, single nucleotide polymorphisms were determined for the following UV response-related cytokines: IL-1 receptor antagonist (+2018), IL-1α (+4845), IL-1β (+3953), TNF-α (−308), and TNF-α (−238). Exposure to UVB significantly suppressed Ab responses to hepatitis B in individuals with the minor variant for the IL-1β polymorphism. Increased minimal erythema dose values (just perceptible), which resulted in higher absolute UVB exposures, were observed in the same individuals. There were no associations observed between UVB-induced immunomodulation and the other cytokine polymorphisms examined. This study indicates that individual susceptibility to UVB radiation needs to be considered when studying the effects of UVB in humans.
CD4+ T Cells Pass Through an Effector Phase During the Process of In Vivo Tolerance Induction
Authors: Huang Ching-Tai , Huso David L. , Lu Zhenbing , Wang Tianhong , Zhou Gang , Kennedy Eugene P. , Drake Charles G. , Morgan David J. , Sherman Linda A. , Higgins Amy D. , Pardoll Drew M. , Adler Adam J. 
Published: April 2014

Abstract
An important process in the generation of tolerance to peripheral self-Ags is the induction of unresponsiveness in mature specific T cells. Although the end stage of this process, termed anergy, is well defined, the pathway by which naive T cells become anergic remains to be elucidated. Using an in vivo self-tolerance model, we demonstrate that CD4+ T cells pass through a significant effector stage on their way to an anergic state. This stage is characterized by production of effector cytokines, provision of help for CD8+ T cells, and induction of in vivo pathology within organs that express cognate Ag. These results suggest that the initial activation stage in T cell tolerance is similar to that seen in memory induction. They also suggest that autoimmune pathology can result during the natural process of tolerance induction rather than requiring that tolerance be broken.
T Cell Tolerance to a Neo-Self Antigen Expressed by Thymic Epithelial Cells: The Soluble Form Is More Effective Than the Membrane-Bound Form
Authors: Zhang Meifen , Vacchio Melanie S. , Vistica Barbara P. , Lesage Sylvie , Egwuagu Charles E. , Yu Cheng-Rong , Gelderman Monique P. , Kennedy Michael C. , Wawrousek Eric F. , Gery Igal 
Published: April 2014

Abstract
We have previously shown that transgenic (Tg) mice expressing either soluble or membrane-bound hen egg lysozyme (sHEL or mHEL, respectively) under control of the αA-crystallin promoter develop tolerance due to thymic expression of minuscule amounts of HEL. To further address the mechanisms by which this tolerance develops, we mated these two lines of Tg mice with the 3A9 line of HEL-specific TCR Tg mice, to produce double-Tg mice. Both lines of double-Tg mice showed deletion of HEL-specific T cells, demonstrated by reduction in numbers of these cells in the thymus and periphery, as well as by reduced proliferative response to HEL in vitro. In addition, the actual deletional process in thymi of the double-Tg mice was visualized in situ by the TUNEL assay and measured by binding of Annexin V. Notably, the apoptosis localized mainly in the thymic medulla, in line with the finding that the populations showing deletion and increased Annexin V binding consisted mainly of single- and double-positive thymocytes. Interestingly, the thymic deletional effect of sHEL was superior to that of mHEL in contrast to the opposite differential tolerogenic effects of these HEL forms on B cells specific to this Ag. Analysis of bone marrow chimeras indicates that both forms of HEL are produced by irradiation-resistant thymic stromal cells and the data suggest that sHEL is more effective in deleting 3A9 T cells due mainly to its higher accessibility to cross-presentation by dendritic APC.
Cross-Linking of CD32 Induces Maturation of Human Monocyte-Derived Dendritic Cells Via NF-κB Signaling Pathway
Authors: Bánki Zoltán , Kacani Laco , Müllauer Brigitte , Wilflingseder Doris , Obermoser Gerlinde , Niederegger Harald , Schennach Harald , Sprinzl Georg M. , Sepp Norbert , Erdei Anna , Dierich Manfred P. , Stoiber Heribert 
Published: April 2014

AbstractDendritic cells (DC) represent a unique set of APCs that initiate immune responses through priming of naive T cells. Maturation of DC is a crucial step during Ag presentation and can be induced by triggering a broad spectrum of DC surface receptors. Although human DC express several receptors for the Fc portion of IgG which were described to play an important role in Ag internalization, little is known about the effects of IgG or immune complexes on DC maturation. In this study, we show that cross-linking of FcγR-type II (CD32) with immobilized IgG (imIgG) can induce maturation of human monocyte-derived DC via the NF-κB signaling pathway. IgG-mediated maturation was accompanied by a moderate increase of IL-10 secretion, whereas no IL-12 production was observed. Involvement of CD32 was further supported by experiments with the anti-CD32 mAb, which blocked IgG-triggered DC maturation and cytokine secretion significantly. Furthermore, DC cultivated in the presence of imIgG induced allogeneic T cell proliferation. Because this imIgG-induced maturation was considerably impaired in monocyte-derived DC from systemic lupus erythematosus patients, we suggest that DC, which matured in the presence of immune complexes, may contribute to prevention of pathological immune responses.