bluuebunny/crossref_metadata_2025_split huggingface dataset:
Properdin Plays a Protective Role in Polymicrobial Septic Peritonitis
Authors: Stover Cordula M. , Luckett Jeni C. , Echtenacher Bernd , Dupont Aline , Figgitt Sue E. , Brown Jane , Männel Daniela N. , Schwaeble Wilhelm J. 
Published: April 2014

AbstractProperdin is a positive regulator of complement activation so far known to be instrumental in the survival of infections with certain serotypes of Neisseria meningitidis. We have generated a fully backcrossed properdin-deficient mouse line by conventional gene-specific targeting. In vitro, properdin-deficient serum is impaired in alternative pathway-dependent generation of complement fragment C3b when activated by Escherichia coli DH5α. Properdin-deficient mice and wild-type littermates compare in their levels of C3 and IgM. In an in vivo model of polymicrobial septic peritonitis induced by sublethal cecal ligation and puncture, properdin-deficient mice appear immunocompromised, because they are significantly impaired in their survival compared with wild-type littermates. We further show that properdin localizes to mast cells and that properdin has the ability to directly associate with E. coli DH5α. We conclude that properdin plays a significant role in the outcome of polymicrobial sepsis.
Fcγ Receptors Regulate Immune Activation and Susceptibility during Mycobacterium tuberculosis Infection
Authors: Maglione Paul J. , Xu Jiayong , Casadevall Arturo , Chan John 
Published: April 2014

Abstract
The critical role of cellular immunity during tuberculosis (TB) has been extensively studied, but the impact of Abs upon this infection remains poorly defined. Previously, we demonstrated that B cells are required for optimal protection in Mycobacterium tuberculosis-infected mice. FcγR modulate immunity by engaging Igs produced by B cells. We report that C57BL/6 mice deficient in inhibitory FcγRIIB (RIIB−/−) manifested enhanced mycobacterial containment and diminished immunopathology compared with wild-type controls. These findings corresponded with enhanced pulmonary Th1 responses, evidenced by increased IFN-γ-producing CD4+ T cells, and elevated expression of MHC class II and costimulatory molecules B7-1 and B7-2 in the lungs. Upon M. tuberculosis infection and immune complex engagement, RIIB−/− macrophages produced more of the p40 component of the Th1-promoting cytokine IL-12. These data strongly suggest that FcγRIIB engagement can dampen the TB Th1 response by attenuating IL-12p40 production or activation of APCs. Conversely, C57BL/6 mice lacking the γ-chain shared by activating FcγR had enhanced susceptibility and exacerbated immunopathology upon M. tuberculosis challenge, associated with increased production of the immunosuppressive cytokine IL-10. Thus, engagement of distinct FcγR can divergently affect cytokine production and susceptibility during M. tuberculosis infection.
Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response
Authors: van Zoelen Marieke A. D. , Florquin Sandrine , Meijers Joost C. M. , de Beer Regina , de Vos Alex F. , de Boer Onno J. , van der Poll Tom 
Published: April 2014

Abstract
Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR−/−) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR−/− neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR−/− mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.
γδ+ T Cells Involvement in Viral Immune Control of Chronic Human Herpesvirus 8 Infection
Authors: Barcy Serge , De Rosa Stephen C. , Vieira Jeffrey , Diem Kurt , Ikoma Minako , Casper Corey , Corey Lawrence 
Published: April 2014

Abstract
Little is known about what effector populations are associated with the control of human herpesvirus 8 (HHV-8) infection in vivo. We compared T lymphocyte subsets among HIV−HHV-8+ and HIV−HHV-8− infected human individuals. αβ+ T cells from HHV-8-infected individuals displayed a significantly higher percentage of differentiated effector cells among both CD4+ and CD8+ T cell subsets. HHV-8 infection was associated with significant expansion of γδ+ Vδ1 T cells expressing a differentiated effector cell phenotype in peripheral blood. In vitro stimulation of PBMC from HHV-8-infected individuals with either infectious viral particles or different HHV-8 viral proteins resulted in γδ Vδ1 T cell activation. In addition, γδ Vδ1 T cells displayed a strong reactivity against HHV-8-infected cell lines and prevented the release of infectious viral particles following the induction of lyric replication. These data indicate that γδ T cells play a role in both innate and adaptive T cell responses against HHV-8 in immunocompetent individuals.
Mast Cell-Fibroblast Interactions Induce Matrix Metalloproteinase-9 Release from Fibroblasts: Role for IgE-Mediated Mast Cell Activation
Authors: Abel Melanie , Vliagoftis Harissios 
Published: April 2014

Abstract
Mast cells adhere to fibroblasts, but the biological effects of adhesion are not well understood. We hypothesized that these adhesive interactions are important for tissue remodeling through the release of matrix metalloproteinases (MMP). Murine bone marrow cultured mast cells (BMCMC) were cocultured with NIH-3T3 fibroblasts or murine lung fibroblasts (CCL-206) and supernatants analyzed for MMP-9 release by gelatin zymography. Coculture of BMCMC for 24 h with NIH-3T3 or CCL-206 fibroblasts increased the release of MMP-9 from fibroblasts by 1.7 ± 0.2 and 2.0 ± 0.7-fold, respectively. Coculture of BMCMC and fibroblasts in the presence of IgE increased further MMP-9 release, which was released by fibroblasts. MMP-9 release was dependent on TNF released from IgE activated BMCMC and on adhesive interactions between BMCMC and fibroblasts. Increased MMP-9 release was also p44/42-dependent, as was MMP-9 up-regulation during coculture of fibroblasts with resting BMCMC. Finally, IgE injection into the mouse ear increased MMP-9 content of the ear tissue in the absence of Ag, indicating that IgE-mediated remodeling may play a pathogenic role in allergic conditions even in the absence of exposure to allergens. In conclusion, mast cell-fibroblast interactions induce the release of proteases important for tissue remodeling, such as MMP-9. MMP-9 release was further increased in the presence of IgE during coculture, suggesting a role for mast cell-fibroblast interactions in atopic conditions.
IL-4 Is a Critical Determinant in the Generation of Allergic Inflammation Initiated by a Constitutively Active Stat6
Authors: Sehra Sarita , Bruns Heather A. , Ahyi Ayele-Nati N. , Nguyen Evelyn T. , Schmidt Nathan W. , Michels E. Grace , von Bülow Götz-Ulrich , Kaplan Mark H. 
Published: April 2014

Abstract
IL-4 is required for the pathogenesis of atopic diseases and immune regulation. Stat6 is critical for IL-4-induced gene expression and Th cell differentiation. Recently, we have generated mice expressing a mutant Stat6 (Stat6VT) under control of the CD2 locus control region that is transcriptionally active independent of IL-4 stimulation. To determine whether active Stat6 in T cells is sufficient to alter immune regulation in vivo, we mated Stat6VT transgenic mice to IL-4-deficient mice. Stat6VT expression in IL-4-deficient lymphocytes was sufficient to alter lymphocyte homeostasis and promote Th2 differentiation in vitro. HyperTh2 levels in Stat6 transgenic mice correlated with an atopic phenotype that manifested as blepharitis and pulmonary inflammation with a high level of eosinophilic infiltration. In the absence of endogenous IL-4, Stat6VT transgenic mice were protected from allergic inflammation. Thus, in mice with hyperTh2 immune responses in vivo, IL-4 is a critical effector cytokine.
Loss of ABCG1 Results in Chronic Pulmonary Inflammation
Authors: Baldán Ángel , Gomes Aldrin V. , Ping Peipei , Edwards Peter A. 
Published: April 2014

Abstract
ABCG1, a member of the ATP-binding cassette transporter superfamily, is highly expressed in multiple cells of the lung. Loss of ABCG1 results in severe pulmonary lipidosis in mice, with massive deposition of cholesterol in both alveolar macrophages and type 2 cells and the accumulation of excessive surfactant phospholipids. These observations are consistent with ABCG1 controlling cellular sterol metabolism. Herein, we report on the progressive and chronic inflammatory process that accompanies the lipidosis in the lungs of Abcg1−/− mice. Compared with wild-type animals, the lungs of aged chow-fed mice deficient in ABCG1 show distinctive signs of inflammation that include macrophage accumulation, lymphocytic infiltration, hemorrhage, eosinophilic crystals, and elevated levels of numerous cytokines and cytokine receptors. Analysis of bronchoalveolar lavages obtained from Abcg1−/− mice revealed elevated numbers of foamy macrophages and leukocytes and the presence of multiple markers of inflammation including crystals of chitinase-3-like proteins. These data suggest that cholesterol and/or cholesterol metabolites that accumulate in Abcg1−/− lungs can trigger inflammatory signaling pathways. Consistent with this hypothesis, the expression of a number of cytokines was found to be significantly increased following increased cholesterol delivery to either primary peritoneal macrophages or Raw264.7 cells. Finally, cholesterol loading of primary mouse macrophages induced cytokine mRNAs to higher levels in Abcg1−/−, as compared with wild-type cells. These results demonstrate that ABCG1 plays critical roles in pulmonary homeostasis, balancing both lipid/cholesterol metabolism and inflammatory responses.
Cutting Edge: A Naturally Occurring Mutation in CD1e Impairs Lipid Antigen Presentation
Authors: Tourne Sylvie , Maitre Blandine , Collmann Anthony , Layre Emilie , Mariotti Sabrina , Signorino-Gelo François , Loch Caroline , Salamero Jean , Gilleron Martine , Angénieux Catherine , Cazenave Jean-Pierre , Mori Lucia , Hanau Daniel , Puzo Germain , De Libero Gennaro , de la Salle Henri 
Published: April 2014

Abstract
The human CD1a–d proteins are plasma membrane molecules involved in the presentation of lipid Ags to T cells. In contrast, CD1e is an intracellular protein present in a soluble form in late endosomes or lysosomes and is essential for the processing of complex glycolipid Ags such as hexamannosylated phosphatidyl-myo-inositol, PIM6. CD1e is formed by the association of β2-microglobulin with an α-chain encoded by a polymorphic gene. We report here that one variant of CD1e with a proline at position 194, encoded by allele 4, does not assist PIM6 presentation to CD1b-restricted specific T cells. The immunological incompetence of this CD1e variant is mainly due to inefficient assembly and poor transport of this molecule to late endosomal compartments. Although the allele 4 of CD1E is not frequent in the population, our findings suggest that homozygous individuals might display an altered immune response to complex glycolipid Ags.
Non-T Cell Activation Linker Promotes Mast Cell Survival by Dampening the Recruitment of SHIP1 by Linker for Activation of T Cells
Authors: Roget Karine , Malissen Marie , Malbec Odile , Malissen Bernard , Daëron Marc 
Published: April 2014

Abstract
The linker for activation of T cells (LAT) and the non-T cell activation linker (NTAL) are two transmembrane adapters which organize IgE receptor (FcεRI) signaling complexes in mast cells. LAT positively regulates, whereas NTAL negatively regulates mast cell activation. We previously found that the four distal tyrosines of LAT can generate negative signals. We show here that two of these tyrosines provide two binding sites for SHIP1, that LAT recruits SHIP1 in vivo, and that SHIP1 recruitment is enhanced in NTAL-deficient cells. We show that NTAL negatively regulates mast cell activation by decreasing the recruitment, by LAT, of molecules involved in FcεRI-dependent positive signaling. We show that NTAL also decreases the recruitment of SHIP1 by LAT, leading to an increased phosphorylation of the antiapoptotic molecule Akt, and positively regulates mast cell survival. We finally show that the positive effect of NTAL on Akt phosphorylation and mast cell survival requires LAT. Our data thus document the mechanisms by which LAT and NTAL can generate both positive and negative signals which differentially regulate mast cell activation and survival. They also provide molecular bases for the recruitment of SHIP1 in FcεRI signaling complexes. SHIP1 is a major negative regulator of mast cell activation and, hence, of allergic reactions.
E2F4 Modulates Differentiation and Gene Expression in Hematopoietic Progenitor Cells during Commitment to the Lymphoid Lineage
Authors: Enos Megan E. , Bancos Simona A. , Bushnell Timothy , Crispe Ian N. 
Published: April 2014

Abstract
The E2F4 protein is involved in gene repression and cell cycle exit, and also has poorly understood effects in differentiation. We analyzed the impact of E2F4 deficiency on early steps in mouse hematopoietic development, and found defects in early hematopoietic progenitor cells that were propagated through common lymphoid precursors to the B and T lineages. In contrast, the defects in erythromyeloid precursor cells were self-correcting over time. This suggests that E2F4 is important in early stages of commitment to the lymphoid lineage. The E2F4-deficient progenitor cells showed reduced expression of several key lymphoid-lineage genes, and overexpression of two erythromyeloid lineage genes. However, we did not detect effects on cell proliferation. These findings emphasize the significance of E2F4 in controlling gene expression and cell fate.
Allelic and Isotypic Light Chain Inclusion in Peripheral B Cells from Anti-DNA Antibody Transgenic C57BL/6 and BALB/c Mice
Authors: Witsch Esther J. , Bettelheim Eldad 
Published: April 2014

Abstract
Most mature B lymphocytes express one BCR L chain, κ or λ, but recent work has shown that there are exceptions in that some B lymphocytes express both κ and λ and some even bear two different κ L chains. Using the anti-DNA H chain-transgenic mouse, 56R, we find that B cells with pre-existing autoreactivity are especially subject to L chain inclusion. Specifically, we show that isotypic and allelic inclusion enables autoreactive B cells to bypass central tolerance giving rise to B cells that retain dangerous features. One receptor in dual receptor B cells is an editor L chain, i.e., neutralizes or alters self-reactivity of the 56R H chain transgene. We compare the 56R mouse when on the C57/BL/6 background, a strain prone to autoimmunity, with that of 56R when on the BALB/c background, a strain that resists autoimmunity. In the B6.56R mouse, polyreactive B cells with dual L chain move to the follicular B cell compartment. Their localization in the follicular compartment may explain the ease with which B cells in the B6.56R differentiate into autoantibody-producing plasma cells. Likewise, in the BALB/c.56R mouse, dual L chain B cells are found in the follicular B cell compartment. Yet, the lack of autoantibody-producing plasma cells in the BALB/c.56R suggests that postfollicular tolerance checkpoints are intact. The Jκ usage in dual κ L chain B cells suggests increased receptor editing activity and is consistent with the expected distribution of Jκ genes in our computational model for random selection of Jκ.
Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses
Authors: Forsbach Alexandra , Nemorin Jean-Guy , Montino Carmen , Müller Christian , Samulowitz Ulrike , Vicari Alain P. , Jurk Marion , Mutwiri George K. , Krieg Arthur M. , Lipford Grayson B. , Vollmer Jörg 
Published: April 2014

Abstract
The TLRs 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. U-rich RNA sequences were recently discovered that stimulate human TLR7/8-mediated or murine TLR7-mediated immune effects. In this study we identified single-stranded RNA sequences containing defined sequence motifs that either preferentially activate human TLR8-mediated as opposed to TLR7- or TLR7/8-mediated immune responses. The identified TLR8 RNA motifs signal via TLR8 and fail to induce IFN-α from TLR7-expressing plasmacytoid dendritic cells but induce the secretion of Th1-like and proinflammatory cytokines from TLR8-expressing immune cells such as monocytes or myeloid dendritic cells. In contrast, RNA sequences containing the TLR7/8 motif signal via TLR7 and TLR8 and stimulate cytokine secretion from both TLR7- and TLR8-positive immunocytes. The TLR8-specific RNA sequences are able to trigger cytokine responses from human and bovine but not from mouse, rat, and porcine immune cells, suggesting that these species lack the capability to respond properly to TLR8 RNA ligands. In summary, we describe two classes of single-stranded TLR7/8 and TLR8 RNA agonists with diverse target cell and species specificities and immune response profiles.
A Lupus-Suppressor BALB/c Locus Restricts IgG2 Autoantibodies without Altering Intrinsic B Cell-Tolerance Mechanisms
Authors: Tarasenko Tatyana , Kole Hemanta K. , Bolland Silvia 
Published: April 2014

Abstract
FcγR2B-deficient mice develop autoantibodies and glomerulonephritis with a pathology closely resembling human lupus when on the C57BL/6 (B6) background. The same mutation on the BALB/c background does not lead to spontaneous disease, suggesting differences in lupus susceptibility between the BALB/c and B6 strains. An F2 genetic analysis from a B6/BALB cross identified regions from the B6 chromosomes 12 and 17 with positive linkage for IgG autoantibodies. We have generated a congenic strain that contains the suppressor allele from the BALB/c chromosome 12 centromeric region (sbb2a) in an otherwise B6.FcγR2B−/− background. None of the B6.FcγR2B−/−sbb2a/a mice tested have developed IgG autoantibodies in the serum or autoimmune pathology. Mixed bone marrow reconstitution experiments indicate that sbb2a is expressed in non-B bone marrow-derived cells and acts in trans. sbb2a does not alter L chain editing frequencies of DNA Abs in the 3H9H/56R H chain transgenic mice, but the level of IgG2a anti-DNA Abs in the serum is reduced. Thus, sbb2a provides an example of a non-MHC lupus-suppressor locus that protects from disease by restricting the production of pathogenic IgG isotypes even in backgrounds with inefficient Ab editing checkpoints.
Intestinal Epithelial Cell Up-Regulation of LY6 Molecules during Colitis Results in Enhanced Chemokine Secretion
Authors: Flanagan Ken , Modrusan Zora , Cornelius Jennine , Chavali Arvind , Kasman Ian , Komuves Laszlo , Mo Lian , Diehl Lauri 
Published: April 2014

Abstract
In the healthy colon, intestinal epithelial cells (IEC) form a physical barrier separating the myriad of gut Ags from the cells of the immune system. Simultaneously, IEC use several mechanisms to actively maintain immunologic tolerance to nonpathogenic Ags, including commensal bacteria. However, during inflammatory bowel disease (IBD), the line of defense provided by IEC is breached, resulting in uncontrolled immune responses. As IEC are a principal mediator of immune responses in the gut, we were interested in discerning the gene expression pattern of IEC during development and progression of IBD. Laser capture microdissection and microarray analysis were combined to identify the LY6 superfamily as strongly up-regulated genes in inflamed IEC of the colon in two models of murine colitis. Surface expression of LY6A and LY6C on IEC is induced by several cytokines present within the colitic gut, including IL-22 and IFN-γ. Furthermore, cross-linking of LY6C results in production of a number of chemokines which are known to be involved in the immunopathogenesis of IBD. Increased chemokine production was cholesterol dependent, suggesting a role for lipid raft structures in the mechanism. As such, LY6 molecules represent novel targets to down-regulate chemokine expression in the colon and limit subsequent inflammation associated with IBD.
Lipopolysaccharide-Activated IL-10-Secreting Dendritic Cells Suppress Experimental Autoimmune Uveoretinitis by MHCII-Dependent Activation of CD62L-Expressing Regulatory T Cells
Authors: Lau Annie W. T. , Biester Sabine , Cornall Richard J. , Forrester John V. 
Published: April 2014

Abstract
Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic, although there is accumulating evidence that they can also be tolerogenic and induce Ag-specific regulatory T cells (Tregs). However, the mechanism of this Treg induction and the site of Treg action in vivo are yet to be defined. In this study, using the experimental model of interphotoreceptor retinoid-binding protein peptide (1–20)-induced experimental autoimmune uveoretinitis, we show that s.c. inoculation of IRBP-peptide-pulsed IL-10-producing LPS-activated mature DC (IL-10-DC) at one site (the cervical region) suppresses autoimmunity induced at a separate site (the inguinal region). Our data show that s.c. IL-10-DC correlates with an increase in the number of CD4+CD25+Foxp3+ Tregs at the DC-draining lymph nodes (DC-dLN). However, although MHCII−/− IL-10-DC also induces Treg expansion at this DC-dLN, they failed to suppress experimental autoimmune uveoretinitis. Furthermore, unlike wild-type IL-10-DC, MHCII−/− IL-10-DC did not correlate with an increase in the percentage of Tregs expressing CD62L at the DC-dLN, nor did they associate with an increase in Treg number at a distal site. Similar effects were also observed after s.c. hen egg lysozyme-pulsed IL-10-DC, which produced a strong reduction in the number and activation of proliferating Ag-specific CD4+ 3A9 T effector cells. We therefore propose that IL-10-DC require MHCII-dependent Ag presentation, and hence TCR ligation, to promote CD62L-mediated trafficking of Tregs to the site of T effector cell priming, where they suppress autoimmunity.