bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternatively Activated Macrophages in Intestinal Helminth Infection: Effects on Concurrent Bacterial Colitis
Authors: Weng Meiqian , Huntley Deke , Huang I-Fei , Foye-Jackson Ondulla , Wang Lijian , Sarkissian Aliese , Zhou Qingping , Walker W. Allan , Cherayil Bobby J. , Shi Hai Ning 
Published: April 2014

AbstractThe distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, including enteric bacterial infections. To dissect the mechanisms by which helminths modulate the host’s response to enteric bacteria and bacteria-mediated intestinal inflammation, we have recently established a coinfection model and shown that coinfection with the helminth Heligmosomoides polygyrus exacerbates colitis induced by infection with the Gram-negative bacterial pathogen Citrobacter rodentium. The disease severity of the coinfected mice was correlated with high Citrobacter loads in the gut, translocation of the bacteria into mucosal and systemic immune compartments, delayed bacterial clearance, and a significantly enhanced colonic TNF-α response. In the present study, using our in vivo coinfection model as well as in vitro approaches, we test the hypothesis that the phenotypic and functional alterations in macrophages induced by the helminth-driven T cell response may contribute to the observed alterations in the response to C. rodentium. We show that via a STAT6-dependent mechanism H. polygyrus coinfection results in a marked infiltration into the colonic lamina propria of F4/80+ cells that have the phenotype of alternatively activated macrophages. Functional analysis of these macrophages further shows that they are impaired in their killing of internalized bacteria. Yet, these cells produce an enhanced amount of TNF-α in response to C. rodentium infection. These results demonstrate that helminth infection can impair host protection against concurrent enteric bacterial infection and promote bacteria-induced intestinal injury through a mechanism that involves the induction of alternatively activated macrophages.
ASC/PYCARD and Caspase-1 Regulate the IL-18/IFN-γ Axis during Anaplasma phagocytophilum Infection
Authors: Pedra Joao H. F. , Sutterwala Fayyaz S. , Sukumaran Bindu , Ogura Yasunori , Qian Feng , Montgomery Ruth R. , Flavell Richard A. , Fikrig Erol 
Published: April 2014

Abstract
Anaplasma phagocytophilum is an obligate intracellular pathogen that resides within neutrophils and can cause fever, pancytopenia, or death. IFN-γ plays a critical role in the control of A. phagocytophilum; however, the mechanisms that regulate IFN-γ production remain unclear. In this study, we demonstrate that apoptotic specklike protein with a caspase-activating recruiting domain (ASC)/PYCARD, a central adaptor molecule in the Nod-like receptor (NLR) pathway, regulates the IL-18/IFN-γ axis during A. phagocytophilum infection through its effect on caspase-1. Caspase-1- and asc-null mice were more susceptible than control animals to A. phagocytophilum infection due to the absence of IL-18 secretion and reduced IFN-γ levels in the peripheral blood. Moreover, caspase-1 and ASC deficiency reduced CD4+ T cell-mediated IFN-γ after in vitro restimulation with A. phagocytophilum. The NLR family member IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN-γ production in response to A. phagocytophilum. Taken together, our data demonstrate that ASC and caspase-1 are critical for IFN-γ-mediated control of A. phagocytophilum infection.
Activation-Induced Cytidine Deaminase Expression in Follicular Dendritic Cell Networks and Interfollicular Large B Cells Supports Functionality of Ectopic Lymphoid Neogenesis in Autoimmune Sialoadenitis and MALT Lymphoma in Sjögren’s Syndrome
Authors: Bombardieri Michele , Barone Francesca , Humby Frances , Kelly Stephen , McGurk Mark , Morgan Peter , Challacombe Stephen , De Vita Salvatore , Valesini Guido , Spencer Jo , Pitzalis Costantino 
Published: April 2014

Abstract
Demonstration of ectopic germinal center-like structures (GC-LSs) in chronically inflamed tissues in patients with autoimmune disorders is a relatively common finding. However, to what extent ectopic lymphoid structures behave as true GC and are able to support class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig genes is still debated. In addition, no information is available on whether CSR and SHM can take place in the absence of GCs at extrafollicular sites in an ectopic lymphoid tissue. In this study, we show that in salivary glands (SGs) of Sjögren’s syndrome (SS) activation-induced cytidine deaminase (AID), the enzyme responsible for CSR and SHM is invariably expressed within follicular dendritic cell (FDC) networks but is not detectable in SGs in the absence of ectopic GC-LSs, suggesting that FDC networks play an essential role in sustaining the Ag-driven B cell proliferation within SS-SGs. We also show that the recently described population of interfollicular large B cells selectively expresses AID outside ectopic GC in the T cell-rich areas of periductal aggregates. Finally, we report that AID retains its exclusive association with numerous, residual GCs in parotid SS-MALT lymphomas, whereas neoplastic marginal zone-like B cells are consistently AID negative. These results strongly support the notion that ectopic lymphoid structures in SS-SGs express the molecular machinery to support local autoantibody production and B cell expansion and may play a crucial role toward lymphomagenesis.
The Role of Apoptosis in the Ameliorating Effects of a CDR1-Based Peptide on Lupus Manifestations in a Mouse Model
Authors: Sharabi Amir , Luger Dror , Ben-David Hava , Dayan Molly , Zinger Heidey , Mozes Edna 
Published: April 2014

Abstract
Experimental systemic lupus erythematosus (SLE) can be induced in mice following immunization with an anti-DNA mAb expressing a major Id, 16/6Id. Treatment with a peptide, designated human CDR1 (hCDR1; Edratide), that is based on the sequence of CDR1 of the 16/6Id ameliorated disease manifestations. In the present study, we investigated the roles of apoptosis and related molecules in BALB/c mice with induced experimental SLE following treatment with hCDR1. A higher state of activation and increased rate of apoptosis were found in lymphocytes of SLE-afflicted mice as compared with healthy controls. The latter effects were associated with up-regulated caspase-8 and caspase-3, and down-regulated Bcl-xL. The ameliorative effects of hCDR1 were associated with down-regulation of caspase-8 and caspase-3, up-regulation of Bcl-xL, and a reduced rate of apoptosis. Treatment of diseased mice with an apoptosis-reducing compound that inhibited caspases down-regulated the secretion of the pathogenic cytokine IFN-γ and lowered the intensity of glomerular immune complex deposits and the levels of proteinuria. Furthermore, coincubation of Bcl-xL inhibitors with hCDR1-treated cells abrogated the ability of hCDR1 to reduce the activation state of lymphocytes and to down-regulate the secretion of IL-10 and IFN-γ. Moreover, the Bcl-xL-expressing CD4+CD25+ cells from hCDR1-treated mice induced the expression of Bcl-xL in CFSE-labeled CD4+CD25− cells of the SLE-afflicted mice. Thus, the reduction of apoptosis and the up-regulation of Bcl-xL, which plays an apparent role in tolerance induction, contribute to at least part of the beneficial effects of hCDR1 on lupus manifestations.
Unique Features and Distribution of the Chicken CD83+ Cell
Authors: Hansell Chris , Zhu Xing Wu , Brooks Heather , Sheppard Mark , Withanage Sam , Maskell Duncan , McConnell Ian 
Published: April 2014

Abstract
The central importance of dendritic cells (DC) in both innate and acquired immunity is well recognized in the mammalian immune system. By contrast DC have yet to be characterized in avian species despite the fact that avian species such as the chicken have a well-developed immune system. CD83 has proven to be an excellent marker for DC in human and murine immune systems. In this study we identify chicken CD83 (chCD83) as the avian equivalent of the human and murine DC marker CD83. We demonstrate for the first time that unlike human and murine CD83, chCD83 is uniquely expressed in the B cell areas of secondary lymphoid organs and in organs with no human or murine equivalent such as the bursa and Harderian gland. Furthermore through multicolor immunofluorescence, we identify chCD83+ populations that have unique attributes akin to both DC and follicular DC. These attributes include colocalization with B cell microrenvironments, MHC class II expression, dendritic morphology, and distribution throughout peripheral and lymphoid tissues.
Hydrodynamic Vaccination with DNA Encoding an Immunologically Privileged Retinal Antigen Protects from Autoimmunity through Induction of Regulatory T Cells
Authors: Silver Phyllis B. , Agarwal Rajeev K. , Su Shao-Bo , Suffia Isabelle , Grajewski Rafael S. , Luger Dror , Chan Chi-Chao , Mahdi Rashid M. , Nickerson John M. , Caspi Rachel R. 
Published: April 2014

Abstract
The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 μg of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bcl-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8+ cells, IL-10, or TGF-β. In contrast, depletion of CD25+ cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4+CD25high T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3+CD4+CD25+ regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis.
Enhanced Engagement of CTLA-4 Induces Antigen-Specific CD4+CD25+Foxp3+ and CD4+CD25− TGF-β1+ Adaptive Regulatory T Cells
Authors: Li Ruobing , Perez Nicolas , Karumuthil-Melethil Subha , Prabhakar Bellur S. , Holterman Mark J. , Vasu Chenthamarakshan 
Published: April 2014

Abstract
CTLA-4 is a critical negative regulator of T cell response and is instrumental in maintaining immunological tolerance. In this article, we report that enhanced selective engagement of CTLA-4 on T cells by Ag-presenting dendritic cells resulted in the induction of Ag-specific CD4+CD25+Foxp3+ and CD4+CD25−TGF-β1+ adaptive Tregs. These cells were CD62Llow and hyporesponsive to stimulation with cognate Ag but demonstrated a superior ability to suppress Ag-specific effector T cell response compared with their CD62Lhigh counterparts. Importantly, treatment of mice with autoimmune thyroiditis using mouse thyroglobulin (mTg)-pulsed anti-CTLA-4 agonistic Ab-coated DCs, which results in a dominant engagement of CTLA-4 upon self-Ag presentation, not only suppressed thyroiditis but also prevented reemergence of the disease upon rechallenge with mTg. Further, the disease suppression was associated with significantly reduced mTg-specific T cell and Ab responses. Collectively, our results showed an important role for selective CTLA-4 signaling in the induction of adaptive Tregs and suggested that approaches that allow dominant CTLA-4 engagement concomitant with Ag-specific TCR ligation can be used for targeted therapy.
PDL1 Is Required for Peripheral Transplantation Tolerance and Protection from Chronic Allograft Rejection
Authors: Tanaka Katsunori , Albin Monica J. , Yuan Xueli , Yamaura Kazuhiro , Habicht Antje , Murayama Takaya , Grimm Martin , Waaga Ana Maria , Ueno Takuya , Padera Robert F. , Yagita Hideo , Azuma Miyuki , Shin Tahiro , Blazar Bruce R. , Rothstein David M. , Sayegh Mohamed H. , Najafian Nader 
Published: April 2014

Abstract
The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-γ-producing alloreactive T cells and expansion of effector CD8+ T cells in the periphery, and a decline in the percentage of Foxp3+ graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.
Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients
Authors: Nozaki Taiji , Amano Hiroyuki , Bickerstaff Alice , Orosz Charles G. , Novick Andrew C. , Tanabe Kazunari , Fairchild Robert L. 
Published: April 2014

Abstract
Rejected MHC-mismatched cardiac allografts in CCR5−/− recipients have low T cell infiltration, but intense deposition of C3d in the large vessels and capillaries of the graft, characteristics of Ab-mediated rejection. The roles of donor-specific Ab and CD4 and CD8 T cell responses in the rejection of complete MHC-mismatched heart grafts by CCR5−/− recipients were directly investigated. Wild-type C57BL/6 and B6.CCR5−/− (H-2b) recipients of A/J (H-2a) cardiac allografts had equivalent numbers of donor-reactive CD4 T cells producing IFN-γ, whereas CD4 T cells producing IL-4 were increased in CCR5−/− recipients. Numbers of donor-reactive CD8 T cells producing IFN-γ were reduced 60% in CCR5−/− recipients. Day 8 posttransplant serum titers of donor-specific Ab were 15- to 25-fold higher in CCR5−/− allograft recipients, and transfer of this serum provoked cardiac allograft rejection in RAG-1−/− recipients within 14 days, whereas transfer of either serum from wild-type recipients or immune serum from CCR5-deficient recipients diluted to titers observed in wild-type recipients did not mediate this rejection. Wild-type C57BL/6 and B6.CCR5−/− recipients rejected A/J cardiac grafts by day 11, whereas rejection was delayed (day 12–60, mean 21 days) in μMT−/−/CCR5−/− recipients. These results indicate that the donor-specific Ab produced in CCR5−/− heart allograft recipients is sufficient to directly mediate graft rejection, and the absence of recipient CCR5 expression has differential effects on the priming of alloreactive CD4 and CD8 T cells.
All-or-None Activation of CRAC Channels by Agonist Elicits Graded Responses in Populations of Mast Cells
Authors: Chang Wei-Chiao , Di Capite Joseph , Nelson Charmaine , Parekh Anant B. 
Published: April 2014

Abstract
In nonexcitable cells, receptor stimulation evokes Ca2+ release from the endoplasmic reticulum stores followed by Ca2+ influx through store-operated Ca2+ channels in the plasma membrane. In mast cells, store-operated entry is mediated via Ca2+ release-activated Ca2+ (CRAC) channels. In this study, we find that stimulation of muscarinic receptors in cultured mast cells results in Ca2+-dependent activation of protein kinase Cα and the mitogen activated protein kinases ERK1/2 and this is required for the subsequent stimulation of the enzymes Ca2+-dependent phospholipase A2 and 5-lipoxygenase, generating the intracellular messenger arachidonic acid and the proinflammatory intercellular messenger leukotriene C4. In cell population studies, ERK activation, arachidonic acid release, and leukotriene C4 secretion were all graded with stimulus intensity. However, at a single cell level, Ca2+ influx was related to agonist concentration in an essentially all-or-none manner. This paradox of all-or-none CRAC channel activation in single cells with graded responses in cell populations was resolved by the finding that increasing agonist concentration recruited more mast cells but each cell responded by generating all-or-none Ca2+ influx. These findings were extended to acutely isolated rat peritoneal mast cells where muscarinic or P2Y receptor stimulation evoked all-or-none activation of Ca2+entry but graded responses in cell populations. Our results identify a novel way for grading responses to agonists in immune cells and highlight the importance of CRAC channels as a key pharmacological target to control mast cell activation.
Dynamic Changes in Accessibility, Nuclear Positioning, Recombination, and Transcription at the Igκ Locus
Authors: Fitzsimmons Sean P. , Bernstein Ralph M. , Max Edward E. , Skok Jane A. , Shapiro Marjorie A. 
Published: April 2014

Abstract
The 3-megabase Igκ locus undergoes differentially controlled nuclear positioning events and chromatin structural changes during the course of B cell development. The temporal association of chromatin structural changes, transcription, and recombination at the Igκ locus was determined in a murine pre-B cell line that can be induced to recombine at the Igκ locus and in ex vivo-cultured murine pre-B cells. Additionally, the timing of nuclear positioning relative to the temporal order of chromatin structural changes and recombination and transcription was determined. We demonstrate that before induction, the Igκ locus was poised for recombination; both alleles were in a contracted state, and the enrichment of histone modifications and germline transcripts of specific Vκ genes were observed. Histone modifications of the Vκ genes did not vary upon induction but the levels of modifications correlated with the levels of germline Vκ gene transcripts and recombination. Upon induction, but before VκJκ recombination, centromeric recruitment of single Igκ alleles occurred. DNase I sensitivity of the entire locus increased gradually over the course of differentiation while the enrichment of histone modifications downstream of the Vκ genes was increased in the silencer regions upstream of Jκ1, within the Igκ sterile transcript, the κ constant region, the Eκi and Eκ3′ enhancers, and the recombining sequence. The ex vivo pre-B cells showed similar patterns of histone modifications across the locus except at the Vκ genes. In this study, H3 acetylation correlated with levels of germline transcripts while H3 methylation correlated with levels of recombination.
The C/EBPβ Isoform 34-kDa LAP Is Responsible for NF-IL-6-Mediated Gene Induction in Activated Macrophages, but Is Not Essential for Intracellular Bacteria Killing
Authors: Uematsu Satoshi , Kaisho Tsuneyasu , Tanaka Takashi , Matsumoto Makoto , Yamakami Megumi , Omori Hiroko , Yamamoto Masahiro , Yoshimori Tamotsu , Akira Shizuo 
Published: April 2014

Abstract
The C/ebpb gene is translated into three different protein isoforms, two transcriptional activating proteins (38-kDa Full and 34-kDa liver-enriched transcriptional activation protein (LAP)) and one transcriptional inhibitory protein, by alternative use of different AUG initiation codons within the same open reading frame. The isoform 34-kDa LAP is thought to be the most transcriptionally active form of C/EBPβ in macrophages. To assess the function of the 34-kDa LAP in vivo, we generated knock-in mice, in which methionine 20 of C/EBPβ, the start site for the 34-kDa LAP is replaced with an alanine. The expression of the 34-kDa LAP was abolished in C/ebpbM20A/M20A mice. The induction of C/EBPβ target genes, such as inflammatory cytokines, chemokines, prostanoid synthetase, and antimicrobial peptides, was abolished in C/ebpbM20A/M20A macrophages, and C/ebpbM20A/M20A mice were susceptible to Listeria monocytogenes infection. Furthermore, the heat-killed Propionibacterium acnes-induced Th1 response, granuloma formation, and LPS shock were severely impaired. Nevertheless, impairment of intracellular bacteria killing, which is the most prominent phenotype in C/EBPβ-deficient mice, was not observed in C/ebpbM20A/M20A mice. Collectively, we demonstrated that 34-kDa LAP is responsible for NF-IL6-mediated gene induction, but not essential for intracellular bacteria killing in activated macrophages.
Gr-1high Polymorphonuclear Leukocytes and NK Cells Act via IL-15 to Clear Intracellular Haemophilus influenzae in Experimental Murine Peritonitis and Pneumonia
Authors: Miyazaki Shuichi , Ishikawa Fumio , Shimizu Kayo , Ubagai Tsuneyuki , Edelstein Paul H. , Yamaguchi Keizo 
Published: April 2014

Abstract
Polymorphonuclear leukocytes (PMNs) can be divided into Gr-1high and Gr-1low subpopulations, but the differences in the functions of these cells in the host are unknown. This study investigated the roles of these two cell populations in the clearance of an intracellular pathogen (Haemophilus influenzae) causing murine peritonitis and pneumonia. Microarray analysis and quantitative real-time PCR analysis of proteose peptone-elicited peritoneal murine PMNs showed that IL-15 mRNA levels were significantly higher in Gr-1high PMNs than in Gr-1low PMNs. In addition, IL-15 was produced only by Gr-1-positive PMNs, especially Gr-1high PMNs. IL-15 was required for efficient clearance of experimental murine H. influenzae pneumonia, as 4 days postinfection lungs from IL-15 knockout mice contained 50- to 100-fold more bacteria than did wild-type mouse lungs. Gr-1 PMN-depleted C57BL/6 mice were more susceptible to H. influenzae pneumonia than were Gr-1 PMN replete C57BL/6 mice or C57BL/6 nude mice, demonstrating that Gr-1 PMNs are important in the clearance of intracellular bacteria. IL-15-activated NK cells killed H. influenzae in PMNs. Flow cytometry confirmed the expression of CD69 on the cell membrane of IL-15-activated NK cells. Our results show that Gr-1high PMNs produce more IL-15 than Gr-1low PMNs, and that IL-15-activated NK cells protect against early infection by H. influenzae.