bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Endothelial Cell Expression of ICAM-1 and VCAM-1 at the Onset of Eliciting Contact Hypersensitivity in Mice: Evidence for a Dominant Role of TNF-α
Authors: McHale Julie F. , Harari Olivier A. , Marshall Diane , Haskard Dorian O. 
Published: December 2022

AbstractWe have studied vascular endothelial activation and increased expression of ICAM-1 and VCAM-1 at the onset of the elicitation phase of oxazolone contact hypersensitivity in mice. By measuring the local uptake of i.v. administered radiolabeled anti-ICAM-1 and anti-VCAM-1 mAb, we found that endothelial ICAM-1 and VCAM-1 was increased by 4 h after challenge, 2 h later than the first peak of ear swelling and 125I-labeled human serum albumen uptake. Increased expression of endothelial ICAM-1 and VCAM-1 was significantly greater in sensitized animals than in naive animals. Anti-TNF-α antiserum significantly inhibited both the increase in ear thickness (p &lt; 0.01), and the up-regulation of ICAM-1 and VCAM-1 expression (p &lt; 0.01 for both) at 4 h. In contrast, the combination of anti-IL-1α and IL-1β had only a small inhibitory effect on ICAM-1 expression (p &lt; 0.05) and no significant effect on increased ear thickness or on VCAM-1 expression. A mixture of anti-TNF-α, anti-IL-1α, and IL-1β was no more inhibitory for endothelial ICAM-1 and VCAM-1 expression than anti-TNF-α alone. ICAM-1 and VCAM-1 expression at 4 h was unaffected by a combination of mAb against α4 and β2 integrins, whereas expression at 24 h was significantly inhibited (p &lt; 0.05), suggesting that the release of TNF-α and other cytokines involved in the initiation of the response may not require leukocyte traffic or other leukocyte functions involving these integrins. We conclude that the early up-regulation of endothelial ICAM-1 and VCAM-1 during the elicitation of contact hypersensitivity is primarily due to the immune-dependent local release of TNF-α.
Role of p38-Mitogen-Activated Protein Kinase in Spontaneous Apoptosis of Human Neutrophils
Authors: Aoshiba Kazutetsu , Yasui Shuji , Hayashi Mitsutoshi , Tamaoki Jun , Nagai Atsushi 
Published: December 2022

Abstract
Neutrophils constitutively undergo apoptosis at both normal and inflamed sites: an important process that limits the toxic potential of the neutrophil. However, the signal pathway for neutrophil apoptosis is currently unknown. In this study, we evaluated the role of p38-mitogen-activated protein kinase (MAPK) in the spontaneous apoptosis of neutrophils in vitro. We found that p38-MAPK was constitutively tyrosine phosphorylated and activated during spontaneous apoptosis of neutrophils. Inhibition of p38-MAPK by SB203580 and an antisense oligonucleotide delayed apoptosis by approximately 24 h. The antioxidants catalase and N-acetylcysteine delayed neutrophil apoptosis, but failed to inhibit phosphorylation and activation of p38-MAPK. Granulocyte-macrophage CSF and anti-Fas Ab, which altered the rate of apoptosis, did not affect phosphorylation and activation of p38-MAPK. These results suggest that the constitutive phosphorylation and activation of p38-MAPK are involved in the program of spontaneous apoptosis in neutrophils.
Negative Feedback Between Prostaglandin and α- and β-Chemokine Synthesis in Human Microglial Cells and Astrocytes
Authors: Janabi Nazila , Hau Isabelle , Tardieu Marc 
Published: December 2022

AbstractThe understanding of immune surveillance and inflammation regulation in cerebral tissue is essential in the therapy of neuroimmunological disorders. We demonstrate here that primary human glial cells were able to produce α- and β-chemokines (IL-8 &gt; growth related protein α (GROα) ≫ RANTES &gt; microphage inflammatory protein (MIP)-1α and MIP-1β) in parallel to PGs (PGE2 and PGF2α) after proinflammatory cytokine stimulation: TNF-α + IL-1β induced all except RANTES, which was induced by TNF-α + IFN-γ. Purified cultures of astrocytes and microglia were also induced by the same combination of cytokines, to produce all these mediators except MIP-1α and MIP-1β, which were produced predominantly by astrocytes. The inhibition of PG production by indomethacin led to a 37–60% increase in RANTES, MIP-1α, and MIP-1β but not in GROα and IL-8 secretion. In contrast, inhibition of IL-8 and GRO activities using neutralizing Abs resulted in a specific 6-fold increase in PGE2 but not in PGF2α production by stimulated microglial cells and astrocytes, whereas Abs to β-chemokines had no effect. Thus, the production of PGs in human glial cells down-regulates their β-chemokine secretion, whereas α-chemokine production in these cells controls PG secretion level. These data suggest that under inflammatory conditions, the intraparenchymal production of PGs could control chemotactic gradient of β-chemokines for an appropriate effector cell recruitment or activation. Conversely, the elevated intracerebral α-chemokine levels could reduce PG secretion, preventing the exacerbation of inflammation and neurotoxicity.
A Transgenic Model to Analyze the Immunoregulatory Role of IL-10 Secreted by Antigen-Presenting Cells
Authors: Groux Hervé , Cottrez Françoise , Rouleau Matthieu , Mauze Smita , Antonenko Svetlana , Hurst Stephen , McNeil Tom , Bigler Mike , Roncarolo Maria-Grazia , Coffman Robert L. 
Published: December 2022

AbstractIL-10 is a cytokine secreted by a wide variety of cells type that has pleiotropic stimulatory and suppressive activities on both lymphoid and myeloid cells in vitro. To analyze the consequences of high IL-10 secretion by APCs in immune responses, we produced transgenic mice expressing human IL-10 directed by the MHC class II Ea promoter. Despite alterations in the development of T and B cells, no gross abnormalities were detected in peripheral lymphocyte populations or serum Ig levels. However, when immunized using conditions that give either a Th2-type or a Th1-type response, IL-10 transgenic mice failed to mount a significant T or B cell immune response to OVA. IL-10 transgenic mice were also highly susceptible to infection with intracellular pathogens like Listeria monocytogenes or Leishmania major, in contrast to IL-10 transgenic mice, where the transgene was express in T cells. Finally, the recently described stimulatory effect of IL-10 on CD8+ T cells was confirmed by the ability of IL-10 transgenic mice to limit the growth of immunogenic tumors by a CTL-mediated mechanism. These results demonstrate, that, depending on the type of immune response, IL-10 can mediate immunosuppressive or immunostimulatory activities in vivo.
A hsp70-2 Mutation Recognized by CTL on a Human Renal Cell Carcinoma
Authors: Gaudin Catherine , Kremer Florence , Angevin Eric , Scott Véronique , Triebel Frédéric 
Published: December 2022

AbstractWe performed T cell cloning experiments with a tumor-infiltrating lymphocyte subpopulation derived from a renal cell carcinoma tumor site (RCC-7) in which the TCR clonotypic repertoire had been analyzed in terms of TCRBV complementarity-determining region 3 size distribution. We report in this work the characterization of one of the five RCC-specific MHC class I-restricted CTL clones isolated in RCC-7. This TCRBV6J1S1 CTL recognized only the autologous RCC-7 tumor cell line in the context of HLA-A*0201, and the Ag is encoded by a mutated form of the hsp70-2 gene found in the tumor cells, but not in autologous PBLs nor in 47 other tumors. The identification of this gene was achieved by cotransfecting into COS cells a cDNA library of RCC-7 together with HLA-A*0201. Transfectants expressing the Ag were identified by their ability to stimulate TNF release by the CTL clone. The antigenic peptide is a decamer with a mutated residue at position 8. Half-maximal lysis was obtained with only 5 × 10−11 M of decapeptide in target sensitization assays compared with 5 × 10−8 M for the wild-type decapeptide. This difference in recognition was not related to difference in binding HLA-A*0201-presenting molecules, as assessed in an immunofluorescence-based peptide-binding assay using T2 cells. Constitutive hsp70 expression in various tumors suggests that this stress-induced protein may be recognized in situ by tumor-infiltrating lymphocytes. The finding in the tumor of a mutated form of the stress-induced hsp70-2 gene whose product is specifically recognized by TILs with high avidity is discussed in view of the present use of mycobacteria or heterologous heat-shock proteins as immunomodulators or as subunit vaccine candidates.
Integrin Engagement Regulates Proliferation and Collagenase Expression of Rheumatoid Synovial Fibroblasts
Authors: Sarkissian Madathia , Lafyatis Robert 
Published: December 2022

AbstractGrowth of and metalloproteinase production by fibroblast-like synoviocytes (FLSs) in patients with rheumatoid arthritis (RA) contribute to cartilage and bone destruction associated with development of the expanding inflammatory tissue referred to as pannus. Increased levels of extracellular matrix (ECM) proteins in the pannus suggest that intracellular signals generated through integrin receptors might control these processes. We developed a cell culture system permitting accurate assessment of the effect of cell adhesion to various ECM proteins on FLS phenotype. We show that FLS proliferation to platelet-derived growth factor requires a second signal provided by adhesion to an ECM protein. Fibronectin, vitronectin, collagen, or laminin could provide the second signal and was similarly required for the proliferation of FLSs from RA or osteoarthritis patients. Adhesion to fibronectin, collagen, or Arg-Gly-Asp peptide down-regulated collagenase expression. Primarily αv integrin receptors mediated this down-regulation upon adhesion to fibronectin. Loss of cell adhesion and TNF-α stimulation synergistically increased collagenase expression. Increased collagenase expression upon nonadherence was mimicked by treatment with cytochalasin B, suggesting that the loss of cytoskeletal structure associated with a change in cell shape mediates increased collagenase in nonadherent cells. Thus, although increased fibronectin in the lining layer in RA might be expected to inhibit collagenase expression, the change in cell shape associated with this multilayer structure might actually lead to increased collagenase expression.
Mimicry Between the Hepatitis B Virus DNA Polymerase and the Antigenic Targets of Nuclear and Smooth Muscle Antibodies in Chronic Hepatitis B Virus Infection
Authors: Gregorio Germana V. , Choudhuri Kaushik , Ma Yun , Vegnente Angela , Mieli-Vergani Giorgina , Vergani Diego 
Published: December 2022

Abstract
Autoantibodies to nuclear and smooth muscle are common in hepatitis B virus (HBV) infection. To understand their origin, we scanned protein databases and found that HBV-DNA polymerase (HBV-pol) shares 7–9 amino acid sequences with nuclear (MHC II trans-activator, nuclear pore core protein, nuclear mitotic apparatus, and polymyositis sclerosis Ag) and smooth muscle proteins (caldesmon and myosin). Twenty-mer peptides with relevant homologues and an irrelevant control peptide were constructed and ELISAs were established. Sixty-five children with chronic HBV infection, 104 patients with other chronic liver diseases (CLD), 36 patients with extrahepatic autoimmune diseases, and 24 healthy controls were investigated. Double reactivity to HBV-pol peptides and corresponding self homologues was observed in 40% of HBV-positive patients as compared with four (4%) with other chronic liver diseases, two (6%) with extrahepatic autoimmune diseases, and in none of the healthy controls (p &lt; 0.001 for all). Double reactivity to myosin or caldesmon peptides and their HBV-pol homologues was associated with anti-smooth muscle Ab positivity by immunofluorescence (p &lt; 0.05 for both). HBV-positive sera double reactive for myosin or caldesmon and their homologous HBV-pol peptides also reacted with the native proteins on immunoblot. Fifty to ninety percent Ab inhibition to individual HBV-pol and HBV-pol99–118 peptides was noted by preincubation with individual HBV-pol/self homologue peptide and native proteins, respectively, but not with control peptide. Our results show that cross-reactive immunity targeting homologous sequences of viral and self proteins may partly account for autoantibody production in HBV infection.
Engagement of B Cell Receptor Regulates the Invariant Chain-Dependent MHC Class II Presentation Pathway
Authors: Zimmermann Valérie S. , Rovere Patrizia , Trucy Jeannine , Serre Karine , Machy Patrick , Forquet Frédérique , Leserman Lee , Davoust Jean 
Published: December 2022

AbstractThe intracellular sites in which Ags delivered by the B cell receptor (BCR) are degraded and loaded onto class II molecules remain poorly defined. To address this issue, we generated wild-type and invariant chain (Ii)-deficient H-2k mice bearing BCR specific for hen egg lysozyme. Our results show that, 1) unlike Ags taken up from the fluid phase, Ii is required for presentation of hen egg lysozyme internalized through the BCR in a manner independent of the peptide analyzed; 2) BCR ligation induces intracellular accumulation of MHC class II molecules only in Ii-positive B cells; and 3) these class II molecules reach intracellular compartments where BCR targets exogenous Ag. No differences in expression of adhesion and costimulatory molecules or in the presentation of soluble peptides were detectable between Ii-positive and -negative B cells. Therefore, the BCR delivers its ligand to compartments containing MHC class II-Ii complexes and bypasses the Ii-independent presentation pathway. The linked roles of Ag internalization and B cell activation of the BCR leads to potent Ii-dependent presentation in splenic B cells.
B Cell Response After MMTV Infection: Extrafollicular Plasmablasts Represent the Main Infected Population and Can Transmit Viral Infection
Authors: Ardavín Carlos , Martín Pilar , Ferrero Isabel , Azcoitia Iñigo , Anjuère Fabienne , Diggelmann Heidi , Luthi Frédéric , Luther Sanjiv , Acha-Orbea Hans 
Published: December 2022

Abstract
The immune response to mouse mammary tumor virus (MMTV) relies on the presentation of an MMTV-encoded superantigen by infected B cells to superantigen-specific T cells. The initial extrafollicular B cell differentiation involved the generation of B cells expressing low levels of B220. These B220low B cells corresponded to plasmablasts that expressed high levels of CD43 and syndecan-1 and were CD62 ligand− and IgD−. Viral DNA was detected nearly exclusively in these B220low B cells by PCR, and retroviral type-A particles were observed in their cytoplasm by electron microscopy. An MMTV transmission to the offspring was also achieved after transfer of B220low CD62 ligand− CD43+ plasmablasts into noninfected females. These data suggest that B220low plasmablasts, representing the bulk of infected B cells, are capable of sustaining viral replication and may be involved in the transmission of MMTV.
Overlapping Roles for L-Selectin and P-Selectin in Antigen-Induced Immune Responses in the Microvasculature
Authors: Kanwar Samina , Steeber Douglas A. , Tedder Thomas F. , Hickey Michael J. , Kubes Paul 
Published: December 2022

AbstractAlthough L-selectin mediates lymphocyte attachment to endothelial venules of peripheral lymph nodes, its role in leukocyte recruitment into tissues following Ag challenge is less well established. The objective of this study was to systematically examine the role of L-selectin in leukocyte rolling in the peripheral microvasculature during the first 24 h of an immune response. A type I hypersensitivity response was elicited in wild-type (C57BL/6) and L-selectin-deficient mice by systemic (i.p.) sensitization and intrascrotal challenge with chicken egg OVA. The cremaster microcirculation was observed in untreated and sensitized mice 4, 8, and 24 h post-Ag challenge by intravital microscopy. Leukocyte recruitment in L-selectin-deficient mice and wild-type mice treated with an L-selectin function-blocking mAb was examined at each time point. Ag challenge induced a significant increase in leukocyte rolling (60 cells/min/venule to ∼300 cells/min/venule) in wild-type mice at 4–24 h. This response was reduced by approximately 60–70% in L-selectin-deficient mice and in wild-type mice treated with an L-selectin-blocking mAb. P-selectin blockade by Ab completely inhibited leukocyte rolling at 4–24 h in wild-type animals and also blocked the residual rolling seen in L-selectin-deficient mice. Blocking E-selectin function had no effect on leukocyte rolling flux at any time point in wild-type or L-selectin-deficient mice. Despite reduced rolling, leukocyte adhesion and emigration were not measurably reduced in the L-selectin-deficient mice in this vascular bed. In conclusion, leukocyte rolling is L-selectin-dependent post-Ag challenge with L-selectin and P-selectin sharing overlapping functions.
Lymphocyte Activation Gene-3, a MHC Class II Ligand Expressed on Activated T Cells, Stimulates TNF-α and IL-12 Production by Monocytes and Dendritic Cells
Authors: Avice Marie-Noëlle , Sarfati Marika , Triebel Frederic , Delespesse Guy , Demeure Christian E. 
Published: December 2022

AbstractLymphocyte activation gene-3 (LAG-3) is an MHC class II ligand structurally and genetically related to CD4. Although its expression is restricted to activated T cells and NK cells, the functions of LAG-3 remain to be elucidated. Here, we report on the expression and function of LAG-3 on proinflammatory bystander T cells that are activated in the absence of TCR engagement. LAG-3 is expressed at high levels on human T cells cocultured with autologous monocytes and IL-2 and synergizes with the low levels of CD40 ligand (CD40L) expressed on these cells to trigger TNF-α and IL-12 production by monocytes. Indeed, anti-LAG-3 mAb inhibits both IL-12 and IFN-γ production in IL-2-stimulated cocultures of T cells and autologous monocytes. Soluble LAG-3Ig fusion protein markedly enhances IL-12 production by monocytes stimulated with infra-optimal concentrations of sCD40L, whereas it directly stimulates monocyte-derived dendritic cells (DC) for the production of TNF-α and IL-12, unravelling an enhanced responsiveness to MHC class II engagemenent in DC as compared with activated monocytes. Thus similar to CD40L, LAG-3 may be involved in the proinflammatory activity of cytokine-activated bystander T cells and most importantly it may directly activate DC.
γδ T Cells Contribute to Control of Chronic Parasitemia inPlasmodium chabaudiInfections in Mice
Authors: Seixas Elsa M. G. , Langhorne Jean 
Published: December 2022

AbstractDuring a primary infection of mice with Plasmodium chabaudi, γδ T cells are stimulated and their expansion coincides with recovery from the acute phase of infection in normal mice or with chronic infections in B cell-deficient mice (μ-MT). To determine whether the large γδ T cell pool observed in female B cell-deficient mice is responsible for controlling the chronic infection, studies were done using double-knockout mice deficient in both B and γδ cells (μ-MT × δ−/−TCR) and in γδ T cell-depleted μ-MT mice. In both types of γδ T cell-deficient mice, the early parasitemia following the peak of infection was exacerbated, and the chronic parasitemia was maintained at significantly higher levels in the absence of γδ T cells. The majority of γδ T cells in C57BL/6 and μ-MT mice responding to infection belonged predominantly to a single family of γδ T cells with TCR composed of Vγ2Vδ4 chains and which produced IFN-γ rather than IL-4.
IL-5 and Eosinophils Are Essential for the Development of Airway Hyperresponsiveness Following Acute Respiratory Syncytial Virus Infection
Authors: Schwarze Jürgen , Cieslewicz Grzegorz , Hamelmann Eckard , Joetham Anthony , Shultz Leonard D. , Lamers Marinus C. , Gelfand Erwin W. 
Published: December 2022

AbstractViral respiratory infections can cause bronchial hyperresponsiveness and exacerbate asthma. In mice, respiratory syncytial virus (RSV) infection, which induces an immune response dominated by IFN-γ, results in airway hyperresponsiveness (AHR) and eosinophil influx into the airways, both of which are prevented by pretreatment with anti-IL-5 Ab. To delineate the role of IL-5, IL-4, and IFN-γ in the development of RSV-induced AHR and lung eosinophilia, we tested the ability of mice deficient in each of these cytokines to develop these symptoms of RSV infection. Mice deficient in either IL-5, IL-4, or IFN-γ were administered infectious RSV intranasally, and 6 days later, airway responsiveness to inhaled methacholine was assessed by barometric body plethysmography, and numbers of lung eosinophils and production of IFN-γ, IL-4, and IL-5 by mononuclear cells from peribronchial lymph nodes were monitored. RSV infection resulted in airway eosinophilia and AHR in both IL-4- and IFN-γ-deficient mice, but not in IL-5-deficient mice. Reconstitution of IL-5-deficient mice with IL-5 restored these responses and enhanced the responses in IL-4-deficient mice. Anti-VLA-4 (very late Ag-4) treatment prevented lung eosinophilia and AHR following RSV infection and IL-5 reconstitution. We conclude that in response to RSV, IL-5 is essential for the influx of eosinophils into the lung and that eosinophils in turn are critical for the development of AHR. IFN-γ and IL-4 are not essential for these responses to RSV infection.
HIV-1-Specific CTL Responses Primed In Vitro by Blood-Derived Dendritic Cells and Th1-Biasing Cytokines
Authors: Wilson Cara C. , Olson Walter C. , Tuting Thomas , Rinaldo Charles R. , Lotze Michael T. , Storkus Walter J. 
Published: December 2022

AbstractVaccine strategies designed to elicit strong cell-mediated immune responses to HIV Ags are likely to lead to protective immunity against HIV infection. Dendritic cells (DC) are the most potent APCs capable of priming both MHC class I- and II-restricted, Ag-specific T cell responses. Utilizing a system in which cultured DC from HIV-seronegative donors were used as APC to present HIV-1 Ags to autologous T cells in vitro, the strength and specificity of primary HIV-specific CTL responses generated to exogenous HIV-1 Nef protein as well as intracellularly expressed nef transgene product were investigated. DC expressing the nef gene were able to stimulate Nef-specific CTL, with T cells from several donors recognizing more than one epitope restricted by a single HLA molecule. Primary Nef-specific CTL responses were also generated in vitro using DC pulsed with Nef protein. T cells primed with Nef-expressing DC (via protein or transgene) were able to lyse MHC class I-matched target cells pulsed with defined Nef epitope peptides as well as newly identified peptide epitopes. The addition of Th1-biasing cytokines IL-12 or IFN-α, during priming with Nef-expressing DC, enhanced the Nef-specific CTL responses generated using either Ag-loading approach. These results suggest that this in vitro vaccine model may be useful in identifying immunogenic epitopes as vaccine targets and in evaluating the effects of cytokines and other adjuvants on Ag-specific T cell induction. Successful approaches may provide information important to the development of prophylactic HIV vaccines and are envisioned to be readily translated into clinical DC-based therapeutic vaccines for HIV-1.