bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence That Langerhans Cells in Adult Pulmonary Langerhans Cell Histiocytosis Are Mature Dendritic Cells: Importance of the Cytokine Microenvironment
Authors: Tazi Abdellatif , Moreau Joelle , Bergeron Anne , Dominique Stéphane , Hance Allan J. , Soler Paul 
Published: December 2022

Abstract
Because Langerhans cells (LC) in peripheral tissues are generally “immature” cells with poor lymphostimulatory activity, the contribution of immune responses initiated by LC to the pathogenesis of pulmonary LC histiocytosis (LCH) has been uncertain. In this study we demonstrate that LC accumulating in LCH granulomas are phenotypically similar to mature lymphostimulatory dendritic cells present in lymphoid organs. LC in LCH granulomas intensely expressed B7-1 and B7-2 molecules, whereas normal pulmonary LC and LC accumulating in other pathologic lung disorders did not express these costimulatory molecules. The presence of B7+ LC in LCH granulomas was associated with the expression in these lesions, but not at other sites in the lung, of a unique profile of cytokines (presence of GM-CSF, TNF-α, and IL-1β and the absence of IL-10) that is known to promote the in vitro differentiation of LC into cells expressing a lymphostimulatory phenotype. Finally, LCH granulomas were the only site where CD154-positive T cells could be identified in close contact with LC intensely expressing CD40 Ags. Taken together, these results strongly support the idea that an abnormal immune response initiated by LC may participate in the pathogenesis of pulmonary LCH, and suggest that therapeutic strategies aimed at modifying the lymphostimulatory phenotype of LC may be useful in the treatment of this disorder.
Induction and Visualization of Mucosal Memory CD8 T Cells Following Systemic Virus Infection
Authors: Kim Sung-Kwon , Schluns Kimberly S. , Lefrançois Leo 
Published: December 2022

AbstractWhether CD8 T cell memory exists outside secondary lymphoid organs is unclear. Using an adoptive transfer system that enables tracking of OVA-specific CD8 T cells, we explored the antigenic requirements for inducing CD8 T cell memory and identified intestinal mucosa memory cells. Although systemic immunization with soluble OVA induced clonal expansion, memory CD8 cells were not produced. In contrast, infection with virus-encoding OVA induced memory CD8 cells in the periphery and the lamina propria and intraepithelial compartments of the intestinal mucosa. Mucosal memory cells expressed a distinct array of adhesion molecules as compared with secondary lymphoid memory cells, suggesting that there may be separate mucosal and systemic memory pools. Mucosal CD8 memory cells rapidly produced IFN-γ after Ag stimulation. Reactivation of memory cells by Ag feeding resulted in increased cell size and up-regulation of CD28 and CD11c. CD8 mucosal memory cells exhibited ex vivo lytic activity that was up-regulated dramatically following Ag reencounter in vivo. Interestingly, reactivation of memory cells did not require CD28-mediated costimulation. The ability of the intestinal mucosa to maintain CD8 memory cells provides a potential mechanism for effective mucosal vaccination.
Nitric Oxide Suppresses Human T Lymphocyte Proliferation Through IFN-γ-Dependent and IFN-γ-Independent Induction of Apoptosis
Authors: Allione Alessandra , Bernabei Paola , Bosticardo Marita , Ariotti Silvia , Forni Guido , Novelli Francesco 
Published: December 2022

AbstractHuman normal and malignant T cells cease to proliferate, down-modulate Bcl-2 expression, and undergo apoptosis when cultured in the presence of NO-donor compounds (sodium nitroprusside and NOC12) for 48 h. At 72 h, cells that evade apoptosis start to proliferate again, overexpress both chains of the IFN-γR, and thus become susceptible to apoptosis in the presence of IFN-γ. By contrast, in the presence of IFN-γ, no apoptosis, but an increase of proliferation was displayed by control cultures of T cells not exposed to NO and not overexpressing IFN-γR chains. The NO-induced cell surface overexpression of IFN-γR chains did not affect the transduction of IFN-γ-mediated signals, as shown by the expression of the transcription factor IFN regulatory factor 1 (IRF-1). However, transduction of these signals was quantitatively modified, because IFN-γ induces enhanced levels of caspase-1 effector death in NO-treated cells. These findings identify NO as one of the environmental factors that critically govern the response of T cells to IFN-γ. By inducing the overexpression of IFN-γR chains, NO decides whether IFN-γ promotes cell proliferation or the induction of apoptosis.
Systemic Expression of Rat Soluble Retinal Antigen Induces Resistance to Experimental Autoimmune Uveoretinitis
Authors: McPherson Scott W. , Roberts Josh P. , Gregerson Dale S. 
Published: December 2022

AbstractTo assess the role of sequestration in the maintenance of the immune privilege of the retina, retrovirally mediated gene transfer was used to express a defined, specific retinal autoantigen, rat soluble retinal Ag (S-Ag), in a systemic, nonsequestered manner. In this study we report the stable, long term transduction of rat retinal S-Ag into PBMC. Tolerance to S-Ag was assayed by challenging the S-Ag chimeric animals with S-Ag peptides in CFA and monitoring the time course and severity of experimental autoimmune uveoretinitis (EAU). The resulting data showed a correlation between the incidence of S-Ag chimerism and the loss of susceptibility to EAU. The development of resistance to EAU induction supports the hypothesis that Ag sequestration contributes to retinal immune privilege.
Comparing the Relative Role of Perforin/Granzyme Versus Fas/Fas Ligand Cytotoxic Pathways in CD8+ T Cell-Mediated Insulin-Dependent Diabetes Mellitus
Authors: Kreuwel Huub T. C. , Morgan David J. , Krahl Troy , Ko Alice , Sarvetnick Nora , Sherman Linda A. 
Published: December 2022

AbstractCD8+ cytotoxic T cells play a critical role in initiating insulin-dependent diabetes mellitus. The relative contribution of each of the major cytotoxic pathways, perforin/granzyme and Fas/Fas ligand (FasL), in the induction of autoimmune diabetes remains controversial. To evaluate the role of each lytic pathway in β cell lysis and induction of diabetes, we have used a transgenic mouse model in which β cells expressing the influenza virus hemagglutinin (HA) are destroyed by HA-specific CD8+ T cells from clone-4 TCR-transgenic mice. Upon adoptive transfer of CD8+ T cells from perforin-deficient clone-4 TCR mice, there was a 30-fold increase in the number of T cells required to induce diabetes. In contrast, elimination of the Fas/FasL pathway of cytotoxicity had little consequence. When both pathways of cytolysis were eliminated, mice did not become diabetic. Using a model of spontaneous diabetes, which occurs in double transgenic neonates that express both clone-4 TCR and Ins-HA transgenes, mice deficient in either the perforin or FasL/Fas lytic pathway become diabetic soon after birth. This indicates that, in the neonate, large numbers of autoreactive CD8+ T cells can lead to destruction of islet β cells by either pathway.
Amplitude and Frequency Modulation of Metabolic Signals in Leukocytes: Synergistic Role of IFN-γ in IL-6- and IL-2-Mediated Cell Activation
Authors: Adachi Yoshiyuki , Kindzelskii Andrei L. , Ohno Naohito , Yadomae Toshiro , Petty Howard R. 
Published: December 2022

AbstractMany stimuli cause intracellular concentration oscillations of second messengers or metabolites, which, in turn, may encode information in their amplitudes and frequencies. We now test the hypothesis that synergistic cellular responses to dual cytokine exposure correlate with cross-talk between metabolic signaling pathways of leukocytes. Polarized RAW264.7 macrophages and human neutrophils and monocytes exhibited NAD(P)H autofluorescence oscillation periods of ≅20 s. IFN-γ tripled the NAD(P)H oscillatory amplitude for these cells. Although IL-6 had no effect, incubation of cells with IFN-γ and IL-6 increased both oscillatory amplitude and frequency. Parallel changes were noted after treatment with IFN-γ and IL-2. However, IL-1β and TNF-α did not display frequency doubling with or without IFN-γ exposure. To determine whether frequency doubling required complete IFN-γ signaling or simply metabolic amplitude modulation, an electric field was applied to cells at NAD(P)H troughs, which has been shown to enhance NAD(P)H amplitudes. Electric field application led to frequency doubling in the presence of IL-6 or IL-2 alone, suggesting that amplitude modulation is crucial to synergism. Because NADPH participates in electron trafficking to NO, we tested NO production during cytokine exposure. Although IL-6 and IL-2 alone had no effect, IFN-γ plus IL-6 and IFN-γ plus IL-2 enhanced NO release in comparison to IFN-γ treatment alone. When NO production was examined for single cells, it incrementally increased with the same phase and period as NAD(P)H. We suggest that amplitude and frequency modulation of cellular metabolic oscillations contribute to intracellular signaling synergy and entrain NO production.
A Recurrent Breakpoint in the Most Common Deletion of the Ig Heavy Chain Locus (del A1-GP-G2-G4-E )
Authors: Brusco Alfredo , Saviozzi Silvia , Cinque Fernanda , Bottaro Andrea , DeMarchi Mario 
Published: December 2022

Abstract
Human Ig heavy chain constant regions are encoded by a cluster of genes, the IGHC locus, on 14q32.3. Several forms of IGHC deletions and duplications spanning one to five genes have been described in different populations, with frequencies of 1.5–3.5% and 4.5–44%, respectively. Despite the common occurrence of these gene rearrangements, little is known about the breakpoint sites; evidence obtained from deletions in the IGHC locus and in other regions of the human genome suggests that they preferentially occur in highly homologous regions and might be favored by a variety of recombinogenic signals. We present here a detailed study of three homozygotes for the most common type of IGHC multiple gene deletion, spanning the A1-GP-G2-G4-E genes. Using a combination of Southern blotting, long-range PCR, and automated sequencing, the unequal crossover events of all of the six studied haplotypes have been mapped to a region of ∼2 kb with almost complete homology between EP1-A1 and E-A2, flanked by two minisatellites. These results are consistent with the hypothesis that segments of complete homology may be required for efficient homologous recombination in humans. The possible role of minisatellites as recombination signals is inferred, in agreement with current knowledge.
Surfactant Protein A Down-Regulates Proinflammatory Cytokine Production Evoked byCandida albicansin Human Alveolar Macrophages and Monocytes
Authors: Rosseau Simone , Hammerl Peter , Maus Ulrich , Günther Andreas , Seeger Werner , Grimminger Friedrich , Lohmeyer Jürgen 
Published: December 2022

AbstractSurfactant protein A (SP-A) has been implicated in the regulation of pulmonary host defense and inflammatory events. We analyzed the impact of SP-A on the Candida albicans-induced cytokine response in human alveolar macrophages (AM) and its precursor cells, the monocytes, which rapidly expand the alveolar mononuclear phagocyte pool under inflammatory conditions. Both recombinant human SP-A and natural canine SP-A were employed. SP-A dose-dependently down-regulated the proinflammatory cytokine response of AM and monocytes to both viable and nonviable Candida, including TNF-α, IL-1β, macrophage inflammatory protein-1α, and monocyte chemoattractant protein-1. In contrast, SP-A did not affect the baseline liberation of these cytokines. The release of the antiinflammatory cytokines IL-1 receptor antagonist and IL-6 was not inhibited by SP-A under baseline conditions and in response to fungal challenge. The inhibitory effect of SP-A on proinflammatory cytokine release was retained upon reassembly of the apoprotein with natural surfactant lipids and in the presence of serum constituents, for mimicry of plasma leakage into the alveolar space. It was not reproduced by the homologous proteins complement component C1q and type IV collagen. It was independent of Candida-SP-A binding and phagocyte C1q receptor occupancy, but apparently demanded SP-A internalization by the mononuclear phagocytes, effecting down-regulation of proinflammatory cytokine synthesis at the transcriptional level. We conclude that SP-A limits excessive proinflammatory cytokine release in AM and monocytes confronted with fungal challenge in the alveolar compartment. These data lend further credit to an important physiological role of SP-A in regulating alveolar host defense and inflammation.
Paired Stat6 C-Terminal Transcription Activation Domains Required Both for Inhibition of an IFN-Responsive Promoter andTrans-Activation
Authors: Goenka Shreevrat , Youn Jeehee , Dzurek Linda M. , Schindler Ulrike , Yu-Lee Li-yuan , Boothby Mark 
Published: December 2022

AbstractThe cytokines IL-4 and IFN-γ exert biologically antagonistic effects that in part reflect opposing influences on gene transcription. While the molecular mechanisms for IL-4-mediated transcription activation have been extensively studied, little is known about molecular mechanisms required for IL-4 inhibition of IFN-γ signaling. We have investigated IL-4 inhibition of the IFN-γ-inducible promoter for IFN regulatory factor-1 (IRF-1). In a cell line with low endogenous Stat6, increasing levels of activated Stat6 at constant doses of IFN-γ and IL-4 leads to inhibition of the IRF-1 promoter. The Stat1-dependent IFN-γ activation sequence element of the IRF-1 promoter is a target for Stat6-mediated inhibition despite apparently normal Stat1 DNA binding. However, our data are inconsistent with competition between Stat1 and Stat6 for access to the IRF-1 IFN-γ activation sequence or for an essential coactivator as a mechanism for this Stat6-mediated inhibition. Instead, the data demonstrate that a threshold of Stat6 transcription activation domains is required for IL-4-dependent inhibition. The findings provide evidence of a novel mechanism in which the Stat6 transcription activation domains play a critical role in the IL-4-mediated inhibition of an IFN-γ-inducible promoter.
Presence of CpG DNA and the Local Cytokine Milieu Determine the Efficacy of Suppressive DNA Vaccination in Experimental Autoimmune Encephalomyelitis
Authors: Lobell Anna , Weissert Robert , Eltayeb Sana , Svanholm Cecilia , Olsson Tomas , Wigzell Hans 
Published: December 2022

AbstractWe here study the adjuvant properties of immunostimulatory DNA sequences (ISS) and coinjected cytokine-coding cDNA in suppressive vaccination with DNA encoding an autoantigenic peptide, myelin basic protein peptide 68–85, against Lewis rat experimental autoimmune encephalomyelitis (EAE). EAE is an autoaggressive, T1-mediated disease of the CNS. ISS are unmethylated CpG motifs found in bacterial DNA, which can induce production of type 1 cytokines in vertebrates through the innate immune system. Because ISS in the plasmid backbone are necessary for efficient DNA vaccination, we studied the effect of one such ISS, the 5′-AACGTT-3′ motif, in our system. Treatment with a DNA vaccine encoding myelin basic protein peptide 68–85 and containing three ISS of 5′-AACGTT-3′ sequence suppressed clinical signs of EAE, while a corresponding DNA vaccine without such ISS had no effect. We further observed reduced proliferative T cell responses in rats treated with the ISS-containing DNA vaccine, compared with controls. We also studied the possible impact of coinjection of plasmid DNA encoding rat cytokines IL-4, IL-10, GM-CSF, and TNF-α with the ISS-containing DNA vaccine. Coinjection of IL-4-, IL-10-, or TNF-α-coding cDNA inhibited the suppressive effect of the DNA vaccine on EAE, whereas GM-CSF-coding cDNA had no effect. Coinjection of cytokine-coding cDNA with the ISS-deficient DNA vaccine failed to alter clinical signs of EAE. We conclude that the presence of ISS and induction of a local T1 cytokine milieu is decisive for specific protective DNA vaccination in EAE.
A “Stealth Effect”: Adenocarcinoma Cells Engineered to Express TRAIL Elude Tumor-Specific and Allogeneic T Cell Reactions
Authors: Giovarelli Mirella , Musiani Piero , Garotta Gianni , Ebner Reinhard , Di Carlo Emma , Kim Yunsoo , Cappello Paola , Rigamonti Laura , Bernabei Paola , Novelli Francesco , Modesti Andrea , Coletti Anna , Ferrie Ann Kim , Lollini Pier-Luigi , Ruben Steve , Salcedo Theodora , Forni Guido 
Published: December 2022

AbstractBALB/c mammary adenocarcinoma cells engineered to express TNF-related apoptosis-inducing ligand (TRAIL)/APO-2 ligand (APO-2L) on their membrane (TSA-TRAIL) grow with kinetics similar to that of parental cells (TSA-pc) in vitro and in nu/nu mice. In contrast, TSA-TRAIL cells grow faster than TSA-pc in normal BALB/c mice. In DBA/2 mice, which differ from BALB/c mice at minor histocompatibility Ags, they also grow faster and display a higher percentage of tumor takes than TSA-pc. In fully histoincompatible C57BL/6 (B6) mice, TSA-TRAIL cells form evident tumors that are slowly rejected by most mice, but outgrow in a few. In contrast, TSA-pc cells are rejected at once by B6 mice. Since TRAIL/APO-2L induces apoptosis by interacting with a variety of specific receptors, this rapid growth in both syngeneic and allogeneic mice may be the result of an immunosuppressive mechanism. The following evidence supports this hypothesis: 1) TSA-TRAIL cells overcome the strong immunity against TSA-pc cells elicited in BALB/c mice by preimmunization with TSA cells engineered to release IL-4; 2) their rejection by B6 mice does not prime a CTL-mediated memory; 3) thymidine uptake by T lymphocytes unstimulated or stimulated by allogeneic cells is inhibited when TSA-TRAIL cells are added as third party cells; 4) CTL kill TSA-pc but not TSA-TRAIL cells in 48-h assays; and 5) activated lymphocytes interacting with TSA-TRAIL cells in vivo and in vitro undergo apoptosis.
Cloning and Characterization of a Novel Activating Ly49 Closely Related to Ly49A
Authors: Makrigiannis Andrew P. , Gosselin Pierre , Mason Llewellyn H. , Taylor Lynn S. , McVicar Daniel W. , Ortaldo John R. , Anderson Stephen K. 
Published: December 2022

AbstractThe majority of the known Ly49 family members have been isolated from either C57BL/6 (B6) or BALB/c mice. Interestingly, the anti-Ly49 Ab reactivities observed in 129/J mice are different from those of B6 mice. Furthermore, immunoprecipitation of 129/J NK cell lysates with YE1/32 and YE1/48, Abs specific for the inhibitory Ly49A in B6, resulted in detection of the activation-associated DAP12 molecule. These results indicated a need for a more detailed study of this strain. Therefore, a cloning strategy was devised to isolate Ly49 cDNAs from 129/J mice. An immunoreceptor tyrosine-based inhibitory motif-containing, Ly49D-related clone was discovered that we have named Ly49O, and one immunoreceptor tyrosine-based inhibitory motif-lacking, Ly49A-related clone was discovered that we have named Ly49P. No anti-Ly49 mAb reacted with Ly49O, whereas the molecule encoded by the Ly49P cDNA was found to react with YE1/32 and YE1/48. Ly49P was found to associate with mouse DAP12, and Ab-mediated cross-linking of Ly49P resulted in mouse DAP12 phosphorylation and Ca2+ mobilization, indicating that Ly49P is a competent activation receptor. Ly49P, therefore, represents a novel member of the Ly49 activating receptor subfamily.
Nitric Oxide and the Th2 Response Combine to Prevent Severe Hepatic Damage DuringSchistosoma mansoniInfection
Authors: Brunet L. Rosa , Beall M. , Dunne D. W. , Pearce E. J. 
Published: December 2022

AbstractDuring infection with Schistosoma mansoni, NO production increases following the deposition of parasite eggs in the liver. In wild-type C57BL/6 mice, NO levels peak during the sixth week of infection and are subsequently down-regulated. Inducible NO synthase (iNOS) mRNA was found in diseased liver tissue along with TNF-α and IFN-γ, which are known promoters of iNOS expression. Mice treated with aminoguanidine, a selective inhibitor of iNOS, exhibited cachexia and exacerbated liver pathology, suggesting that NO limits hepatocyte damage when the liver is first exposed to eggs. Hepatic iNOS is up-regulated in SCID mice, indicating that NO production is part of an innate response. Studies with infected highly susceptible IL-4−/− mice revealed that prolonged NO production is in itself deleterious and that a major function of the Th2 response, which is severely compromised in the absence of IL-4, is to regulate NO production. In these animals, plasma NO levels are high compared with those in infected wild-type mice and remain elevated until death. Nevertheless, the underlying importance of NO is illustrated by the finding that aminoguanidine treatment leads to more severe liver disease and reduced time to death in infected IL-4−/− mice.
Neutralization of Endogenous Granulocyte-Macrophage Colony-Stimulating Factor Subverts the Protective Immune Response toHistoplasma capsulatum
Authors: Deepe George S. , Gibbons Reta , Woodward Erin 
Published: December 2022

AbstractWe examined the influence of endogenous GM-CSF on the course of primary and secondary pulmonary histoplasmosis. A high proportion (≥75%) of C57BL/6 mice given mAb to GM-CSF did not survive primary infection, whereas 88–94% of infected controls survived. Analysis of leukocytes revealed significantly fewer CD4+ and CD8+ cells in lungs, but not airways, of anti-GM-CSF-treated mice as compared with infected controls. However, the histopathology was similar between the two groups. Lungs of mice given mAb to GM-CSF manifested depressed levels of TNF-α, IFN-γ, and reactive nitrogen intermediates and elevated levels of IL-4 and IL-10. Administration of mAb to IL-4, to IL-10, or both restored protective immunity in GM-CSF-neutralized mice. In secondary infection, administration of mAb to GM-CSF exacerbated infection but did not alter survival over 30 days. The character of the inflammatory response was similar, and no differences were detected in Th1 or Th2 cytokine production between the two groups. Thus, endogenous GM-CSF is essential for survival in primary but not secondary infection, and blockade perturbs protective immunity. These findings reveal a new mechanism whereby GM-CSF contributes to host protection and demonstrate differences in control of primary and secondary histoplasmosis.
C1q and C4b Bind Simultaneously to CR1 and Additively Support Erythrocyte Adhesion
Authors: Tas Sander W. , Klickstein Lloyd B. , Barbashov Sergei F. , Nicholson-Weller Anne 
Published: December 2022

AbstractPreviously, we showed that soluble C1q bound specifically to CR1 on transfected cells. If the CR1-C1q interaction were to participate in immune complex clearance, then this interaction should support E adhesion. Using a tip plate adhesion assay, we found that immobilized C1q mediated adhesion of human E. E binding to C1q was specifically inhibited by polyclonal anti-CR1 Fab fragments. Intact C1 was not efficient as an adherence ligand until it was treated with EDTA or the C1 inhibitor to remove the C1r2C1s2 complex from C1, leaving C1q. Titration of C1q alone, C4b alone, and C1q + C4b indicated that the two complement ligands were additive in their ability to support CR1-mediated adhesion of E. Analysis of binding to immobilized CR1 using a BIAcore instrument documented that C1q, C4b, and C3b binding were independent events. Additionally, C1q-dependent binding of immune complexes and heat-aggregated IgG to E was documented. These experiments confirm that the immune adherence receptor in humans, CR1, is the single receptor for all of the opsonic ligands of complement, provide evidence for a single C1q binding site on LHR-D of CR1, and suggest that C1q may participate in immune clearance.