bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocyte-Derived Dendritic Cells Induce a House Dust Mite-Specific Th2 Allergic Inflammation in the Lung of Humanized SCID Mice: Involvement of CCR7
Authors: Hammad Hamida , Lambrecht Bart N. , Pochard Pierre , Gosset Philippe , Marquillies Philippe , Tonnel André-Bernard , Pestel Joël 
Published: April 2014

AbstractIn rodents, airway dendritic cells (DCs) capture inhaled Ag, undergo maturation, and migrate to the draining mediastinal lymph nodes (MLN) to initiate the Ag-specific T cell response. However, the role of human DCs in the pathogenesis of the Th2 cell-mediated disease asthma remains to be clarified. Here, by using SCID mice engrafted with T cells from either house dust mite (HDM)-allergic patients or healthy donors, we show that DCs pulsed with Der p 1, one of the major allergens of HDM, and injected intratracheally into naive animals migrated into the MLN. In the MLN, Der p 1-pulsed DCs from allergic patients induced the proliferation of IL-4-producing CD4+ T cells, whereas those from healthy donors induced IFN-γ-secreting cells. In reconstituted human PBMC-reconstituted SCID mice primed with pulsed DCs from allergic patients, repeated exposure to aerosols of HDM induced 1) a strong pulmonary inflammatory reaction rich in T cells and eosinophils, 2) an increase in IL-4 and IL-5 production in the lung lavage fluid, and 3) increased IgE production compared with that in mice primed with unpulsed DCs. All these effects were reduced following in vivo neutralization of the CCR7 ligand secondary lymphoid tissue chemokine. These data in human PBMC-reconstituted SCID mice show that monocyte-derived DCs might play a key role in the pathogenesis of the pulmonary allergic response by inducing Th2 effector function following migration to the MLN.
Activation of Toll-Like Receptor 2 in Acne Triggers Inflammatory Cytokine Responses
Authors: Kim Jenny , Ochoa Maria-Teresa , Krutzik Stephan R. , Takeuchi Osamu , Uematsu Satoshi , Legaspi Annaliza J. , Brightbill Hans D. , Holland Diana , Cunliffe William J. , Akira Shizuo , Sieling Peter A. , Godowski Paul J. , Modlin Robert L. 
Published: April 2014

Abstract
One of the factors that contributes to the pathogenesis of acne is Propionibacterium acnes; yet, the molecular mechanism by which P. acnes induces inflammation is not known. Recent studies have demonstrated that microbial agents trigger cytokine responses via Toll-like receptors (TLRs). We investigated whether TLR2 mediates P. acnes-induced cytokine production in acne. Transfection of TLR2 into a nonresponsive cell line was sufficient for NF-κB activation in response to P. acnes. In addition, peritoneal macrophages from wild-type, TLR6 knockout, and TLR1 knockout mice, but not TLR2 knockout mice, produced IL-6 in response to P. acnes. P. acnes also induced activation of IL-12 p40 promoter activity via TLR2. Furthermore, P. acnes induced IL-12 and IL-8 protein production by primary human monocytes and this cytokine production was inhibited by anti-TLR2 blocking Ab. Finally, in acne lesions, TLR2 was expressed on the cell surface of macrophages surrounding pilosebaceous follicles. These data suggest that P. acnes triggers inflammatory cytokine responses in acne by activation of TLR2. As such, TLR2 may provide a novel target for treatment of this common skin disease.
Bystander CD8 T Cell-Mediated Demyelination After Viral Infection of the Central Nervous System
Authors: Haring Jodie S. , Pewe Lecia L. , Perlman Stanley 
Published: April 2014

AbstractMultiple sclerosis, a chronic inflammatory disease of the CNS, is characterized by immune-mediated demyelination. Many patients have a remitting-relapsing course of disease with exacerbations often following unrelated microbial illnesses. The relationship between the two events remains obscure. One possibility is that T cells specific for the inciting microbial pathogen are able to effect demyelination at a site of ongoing inflammation within the CNS. This possibility was examined in mice infected with mouse hepatitis virus, a well-described model of virus-induced demyelination. Using transgenic TCR/recombination activation gene 2−/− mice with only non-mouse hepatitis virus-specific T cells, we show that CD8 T cells are able to cause demyelination in the absence of cognate Ag in the CNS, but only if specifically activated. These findings demonstrate a novel mechanism for immune-mediated neuropathology and show that activated CD8 T cells may serve as important mediators of bystander demyelination during times of infection, including in patients with multiple sclerosis.
V75R576 IL-4 Receptor α Is Associated with Allergic Asthma and Enhanced IL-4 Receptor Function
Authors: Risma Kimberly A. , Wang Ning , Andrews Ryan P. , Cunningham Christie M. , Ericksen Mark B. , Bernstein Jonathan A. , Chakraborty Ranajit , Hershey Gurjit K. Khurana 
Published: April 2014

AbstractAsthma is a complex polygenic disease. Many studies have implicated the importance of IL-4Rα in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4Rα allelic variants that have been found to associate with asthma and atopy. We examined the effects of each variant alone and in combination on IL-4-dependent gene induction. We found that neither the Q576R nor the I75V variants affected IL-4-dependent CD23 expression. However, the combination of V75R576 resulted in expression of an IL-4Rα with enhanced sensitivity to IL-4. We next examined the genetics of five of the known IL-4Rα allelic variants in asthmatic and nonatopic populations. Strikingly, the association of V75/R576 with atopic asthma was greater than either allele alone and the association of R576 with atopic asthma was dependent on the coexistence of V75. A haplotype analysis revealed a single IL-4Rα haplotype that was associated with allergic asthma, VACRS, further confirming the importance of the V75 and R576 combination in the genetics of asthma. This is the first report demonstrating that a functional alteration in IL-4Rα requires the coexistence of two naturally occurring single nucleotide polymorphisms (snps) in combination; neither snp alone is sufficient. These data illustrate the importance of studying snps in combination, because the functional significance of a given snp may only be evident in a specific setting of additional snps in the same or different genes.
Detection and Induction of CTLs Specific for SYT-SSX-Derived Peptides in HLA-A24+ Patients with Synovial Sarcoma
Authors: Sato Yuriko , Nabeta Yuki , Tsukahara Tomohide , Hirohashi Yoshihiko , Syunsui Rong , Maeda Akiko , Sahara Hiroeki , Ikeda Hideyuki , Torigoe Toshihiko , Ichimiya Shingo , Wada Takuro , Yamashita Toshihiko , Hiraga Hiroaki , Kawai Akira , Ishii Takeshi , Araki Nobuhito , Myoui Akira , Matsumoto Seiichi , Umeda Tohru , Ishii Seiichi , Kawaguchi Satoshi , Sato Noriyuki 
Published: April 2014

AbstractTo investigate the immunogenic property of peptides derived from the synovial sarcoma-specific SYT-SSX fusion gene, we synthesized four peptides according to the binding motif for HLA-A24. The peptides, SS391 (PYGYDQIMPK) and SS393 (GYDQIMPKK), were derived from the breakpoint of SYT-SSX, and SS449a (AWTHRLRER) and SS449b (AWTHRLRERK) were from the SSX region. These peptides were tested for their reactivity with CTL precursors (CTLps) in 16 synovial sarcoma patients using HLA-A24/SYT-SSX peptide tetramers and also for induction of specific CTLs from four HLA-A24+ synovial sarcoma patients. Tetramer analysis indicated that the increased CTLp frequency to the SYT-SSX was associated with pulmonary metastasis in synovial sarcoma patients (p &lt; 0.03). CTLs were induced from PBLs of two synovial sarcoma patients using the peptide mixture of SS391 and SS393, which lysed HLA-A24+ synovial sarcoma cells expressing SYT-SSX as well as the peptide-pulsed target cells in an HLA class I-restricted manner. These findings suggest that aberrantly expressed SYT-SSX gene products have primed SYT-SSX-specific CTLps in vivo and increased their frequency in synovial sarcoma patients. The identification of SYT-SSX peptides may offer an opportunity to design peptide-based immunotherapeutic approaches for HLA-A24+ patients with synovial sarcoma.
Role of the Passive Apoptotic Pathway in Graft-Versus-Host Disease
Authors: Drobyski William R. , Komorowski Richard , Logan Brent , Gendelman Maria 
Published: April 2014

AbstractDonor T cells have been shown to undergo apoptosis during graft-vs-host disease (GVHD). Although active apoptosis mediated through Fas/Fas ligand interactions has been implicated in GVHD, little is known about the role of the passive apoptotic pathway. To examine this question, we compared the ability of normal donor T cells and T cells overexpressing the antiapoptotic protein, Bcl-xL, to mediate alloreactive responses in vitro and lethal GVHD in vivo. In standard MLCs, T cells that overexpressed Bcl-xL had significantly higher proliferative responses but no difference in cytokine phenotype. Overexpression of Bcl-xL prolonged survival of both resting and alloactivated CD4+ and CD8+ T cells as assessed by quantitative flow cytometry, accounting for the higher proliferative responses. Analysis of engraftment in murine transplantation experiments demonstrated an increase in donor T cell chimerism in animals transplanted with Bcl-xL T cells, suggesting that overexpression of Bcl-xL prolonged T cell survival in vivo as well. Notably, transplantation of Bcl-xL T cells into nonirradiated F1 recipients also significantly exacerbated GVHD as assessed by mortality and pathological damage in the gastrointestinal tract. However, when mice were irradiated no difference in GVHD mortality was observed between animals transplanted with wild-type and Bcl-xL T cells. These data demonstrate that the passive apoptotic pathway plays a role in the homeostatic survival of transplanted donor T cells. Moreover, the susceptibility of donor T cells to undergo passive apoptosis is a significant factor in determining GVHD severity under noninflammatory but not inflammatory conditions.
Transfection of Macrophage Inflammatory Protein 1α into B16 F10 Melanoma Cells Inhibits Growth of Pulmonary Metastases But Not Subcutaneous Tumors
Authors: van Deventer Hendrik W. , Serody Jonathon S. , McKinnon Karen P. , Clements Casey , Brickey W. June , Ting Jenny P.-Y. 
Published: April 2014

AbstractMacrophage inflammatory protein 1α (MIP-1α), a CC chemokine, is a chemoattractant for T cells and immature dendritic cells. Plasmacytoma cells expressing MIP-1α generate a cytotoxic T cell response without affecting tumor growth. To understand this discrepancy, we compared a local tumor model with a metastatic one using MIP-1α-transfected B16 F10 melanoma cells. Clonal idiosyncrasies were controlled by selecting three lipotransfected tumor clones and two pcDNA vector transfected control clones with equivalent in vitro proliferative capacities. No significant differences were seen between the MIP-1α-producing and control melanoma cells after s.c. injection in the hind leg. All animals had a leg diameter of 10 cm in 18.5–21.5 days. However, after i.v. injection the number of pulmonary foci was significantly reduced in the MIP-1α-producing clones. Injection of 106 control transfected cells resulted in a median of 98.5 tumor foci in 2 wk, whereas the injection of the MIP-1α-producing clones resulted in 89.5, 26.5, and 0 foci. The number of metastatic foci was inversely proportional to the amount of MIP-1α produced by the clone in vitro. Flow cytometry showed a significant increase in CD8+ cells in lungs of mice with MIP-1α-transfected tumors 3 days after injection. This increase was not maintained 10 days later despite continued production of MIP-1α. The protection offered by transfection with MIP-1α was significantly impaired in β2-microglobulin−/− mice. Our findings suggest that MIP-1α is effective in preventing the initiation of metastasis, but not at sustaining an effective antitumor response.
Cutting Edge: A Novel Role for Fas Ligand in Facilitating Antigen Acquisition by Dendritic Cells
Authors: Tada Yuji , O-Wang Jiyang , Takiguchi Yuichi , Tatsumi Koichiro , Kuriyama Takayuki , Okada Seiji , Tokuhisa Takeshi , Sakiyama Shigeru , Tagawa Masatoshi 
Published: April 2014

AbstractFas ligand (FasL)-expressing tumor cells are found to effectively mediate rejection of the coinoculated FasL negative parental cells while having no effect on the growth of histologically distinct tumor cells. These observations indicate that FasL induces a specific immune response against Ag derived from FasL-bearing tumors and suggest a possible role for FasL in tumor Ag presentation. Indeed, tumor cells expressing FasL can efficiently interact with dendritic cells (DCs) and this interaction requires the expression of membrane-bound FasL on tumors and Fas on DCs. Moreover, DCs cocultured with FasL-expressing tumors are able to elicit a tumor-specific immune response in vivo, suggesting that DCs acquire tumor Ag during the Fas/FasL-mediated DC-tumor contact. These results identify a novel role for FasL in augmenting tumor-DC interactions and subsequent tumor Ag acquisition by DCs, and suggest that FasL-expressing tumor cells could be used to generate tumor-specific DC vaccines.
Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10
Authors: Lang Roland , Patel Divyen , Morris John J. , Rutschman Robert L. , Murray Peter J. 
Published: April 2014

AbstractIL-10 regulates inflammation by reducing cytokine and chemokine production from activated macrophages. We performed microarray experiments to identify possible effector molecules of IL-10 and to investigate the global effect of IL-10 on the transcriptional response induced in LPS-activated macrophages. To exclude background effects of endogenous IL-10, macrophages from IL-10-deficient mice were used. IL-10 up-regulated expression of a small number of genes (26 and 37 after 45 min and 3 h, respectively), including newly identified and previously documented targets such as suppressor of cytokine signaling-3 and IL-1 receptor antagonist. However, the activation program triggered by LPS was profoundly affected by IL-10. IL-10 repressed 62 and further increased 15 of 259 LPS-induced genes. For all genes examined, the effects of IL-10 were determined to be STAT3-dependent. These results suggest that IL-10 regulates STAT3-dependent pathways that selectively target a broad component of LPS-induced genes at the mRNA level.
Follicular Dendritic Cell-Mediated Up-Regulation of CXCR4 Expression on CD4 T Cells and HIV Pathogenesis
Authors: Estes Jacob D. , Keele Brandon F. , Tenner-Racz Klara , Racz Paul , Redd Michael A. , Thacker Tyler C. , Jiang Yongjun , Lloyd Michael J. , Gartner Suzanne , Burton Gregory F. 
Published: April 2014

AbstractFollicular dendritic cells (FDCs) represent a major reservoir of HIV, and active infection occurs surrounding these cells, suggesting that this microenvironment is highly conducive to virus transmission. Because CD4 T cells around FDCs in germinal centers express the HIV coreceptor, CXCR4, whereas CD4 lymphocytes in many other sites do not, it prompted the hypothesis that FDCs may increase CXCR4 expression on CD4 T cells, thereby facilitating infection. To test this, HIV receptor/coreceptor expression was determined on CD4 T cells cultured with or without FDCs, and its consequence to infection was assessed by measuring virus binding and entry. FDCs had little effect on CCR5 or CD4 expression but increased CXCR4 expression on CD4 T cells. FDC-mediated up-regulation of CXCR4 on CD4 T cells occurred by 24 h and was sustained for at least 96 h in vitro, and FDC-CD4 T cell contact was necessary. Importantly, increased CXCR4 expression directly correlated with increased binding and entry of HIV-1 X4 isolates. Furthermore, CD4+CD57+ germinal center T cells expressed high levels of CXCR4 and supported enhanced entry of X4 HIV compared with other CD4 T cells from the same tissue. Thus, in addition to serving as a reservoir of infectious virus, FDCs render surrounding germinal center T cells highly susceptible to infection with X4 isolates of HIV-1.
Murine Malaria Is Exacerbated by CTLA-4 Blockade
Authors: Jacobs Thomas , Graefe Sebastian E. B. , Niknafs Sonja , Gaworski Iris , Fleischer Bernhard 
Published: April 2014

AbstractCytolytic T lymphocyte-associated Ag-4 (CD152) is a negatively regulating molecule, which is primarily expressed on T cells following their activation. In this study, we have examined the role of CTLA-4 expression in experimental blood-stage malaria. Similar to human malaria, CTLA-4 is expressed on CD4+ T cells of C57BL/6 mice after infection with Plasmodium berghei. A kinetic analysis revealed that CTLA-4 expression was increased on day 5 postinfection and reached a peak on day 9 postinfection, when almost 10% of splenic CD4+ T cells expressed CTLA-4. Blockade of CTLA-4 in vivo by a specific mAb and subsequent challenge with P. berghei caused neurological signs reminiscent of murine cerebral malaria and earlier death. Histologic examination of brain sections from anti-CTLA-4-treated mice revealed pathologic changes such as hemorrhages and edema, which were absent in control mice. Furthermore, treatment with anti-CTLA-4 also reversed the extensive loss of CD4+ T cells and the suppressed T cell response occurring during blood-stage malaria. Our data suggest that CTLA-4 expression prevents immune pathology by restricting T cell activation during malaria. They also indicate that the development of cerebral malaria is mediated by a failure to down-regulate T cell activation.
Requirement for RhoA Kinase Activation in Leukocyte De-Adhesion
Authors: Liu Li , Schwartz Barbara R. , Lin Nancy , Winn Robert K. , Harlan John M. 
Published: April 2014

AbstractLeukocyte migration from bloodstream to tissue requires rapid coordinated regulation of integrin-dependent adhesion and de-adhesion. Whether de-adhesion is an active process mediated by a distinct signaling pathway(s) or a passive decay of initial adhesion remains undetermined. We found that blockade of RhoA with C3 exoenzyme or inhibition of RhoA kinase by the specific inhibitor Y-27632 enhanced phorbol ester-stimulated α4β1-dependent adhesion of Jurkat cells at 30 min. Similarly, Y-27632 treatment increased stimulated β2 integrin-dependent neutrophil adhesion at 30 min but not at 5 min. Because reduced de-adhesion could mimic augmentation of adhesion at later time points, we developed an assay to measure de-adhesion specifically. Treatment of phorbol ester—or bacterial chemoattractant peptide—but not Mn2+-stimulated neutrophils adherent to serum-coated plastic or endothelial cells with Y-27632 or C3 exoenzyme markedly reduced the rate of de-adhesion, while markedly increasing their spreading. RhoA kinase inhibitor effects on de-adhesion and spreading were reversed by treatment with the cytoskeletal-disrupting agent cytochalasin D. Treatment with Y-27632 influenced neither integrin activation epitope nor integrin clustering. We conclude that activation of RhoA kinase promotes leukocyte de-adhesion by inhibiting cytoskeletal-dependent spreading, and that these effects of RhoA kinase constitute a new mechanism for regulation of integrin receptor avidity.
CCR6 Colocalizes with CD18 and Enhances Adhesion to Activated Endothelial Cells in CCR6-Transduced Jurkat T Cells
Authors: Maki Wusi , Morales Romeo E. , Carroll Virginia A. , Telford William G. , Knibbs Randall N. , Stoolman Lloyd M. , Hwang Sam T. 
Published: April 2014

AbstractCCR6 is expressed by memory T cells (mTC) and is a requirement for efficient arrest of a subset of mTC to activated human dermal microvascular endothelial cells (HDMEC) under physiologic shear stress. We now address whether CCR6 alone is sufficient to induce arrest of a model T cell line (Jurkat) that shows low expression of all CCRs tested (CCR1–10). Herein, we transduced Jurkat (JK) T cells expressing fucosyltransferase VII with a chimeric chemokine receptor consisting of CCR6 fused to enhanced green fluorescent protein. In contrast to the starting JK lines, the resulting cell line (JK fucosyltransferase VII-CCR6) migrated 6-fold better to CCL20 in chemotaxis assays, arrested in response to CCL20 that was immobilized to plastic, and demonstrated a 2.5-fold increase in adhesion to activated HDMEC (p = 0.001). Adhesion was blocked by anti-CD18 mAb (p = 0.005) but not by anti-CD49d mAb (p = 0.3). After arrest on recombinant substrates, CCR6 clustered on the surface as detected by real-time observation of enhanced green fluorescent protein fluorescence. Dual-label confocal microscopy revealed that LFA-1 (CD18 and CD11a), but not CXCR4, colocalized with clustered CCR6 in the presence of immobilized CCL20. Thus, the functional expression of CCR6 is sufficient to provide the chemokine signaling necessary to induce arrest of a JK T cell line to activated HDMEC. Clustering of CCR6 and coassociation with critical integrins may serve to strengthen adhesion between T cells and activated endothelial cells.
Endogenous H/K ATPase β-Subunit Promotes T Cell Tolerance to the Immunodominant Gastritogenic Determinant
Authors: Laurie Karen L. , van Driel Ian R. , Zwar Tricia D. , Barrett Simon P. , Gleeson Paul A. 
Published: April 2014

Abstract
A CD4+ T cell response to the gastric H/K ATPase β-subunit (H/Kβ) is required for the onset of experimental autoimmune gastritis in BALB/c mice. The extent to which endogenous H/Kβ contributes toward the tolerance of the H/Kβ-specific T cell repertoire in normal individuals is not known. By comparison of T cell responses in H/Kβ-deficient (o/o) and H/Kβ-expressing BALB/c mice, in this work we show that the endogenous H/Kβ autoantigen plays a major role in the tolerance of pathogenic H/Kβ-specific T cells. First, T cell-dependent Ab responses to the H/Kβ Ag were enhanced in H/K ATPase-immunized H/Kβ-deficient mice compared with wild-type mice. Second, peptide immunization experiments indicated that immune responses to the major gastritogenic epitope of the H/K ATPase, namely H/Kβ253–277, were significantly more vigorous in H/Kβ-deficient mice compared with wild-type mice. Third, unfractionated splenocytes from H/Kβ-deficient mice, but not H/Kβ-expressing mice, induced autoimmune gastritis after adoptive transfer to BALB/c nude mice. The enhanced responses to H/Kβ in H/Kβ-deficient mice were shown to be intrinsic to CD4+CD25− T cells rather than a change in status of CD4+CD25+ regulatory T cells. We conclude from these studies that the H/Kβ-specific T cells in wild-type mice represent the residue of a T cell repertoire, directed toward a single determinant, that has been subjected to partial tolerance induction.
Distinct Response of Human B Cell Subpopulations in Recognition of an Innate Immune Signal, CpG DNA
Authors: Jung Jaeho , Yi Ae-Kyung , Zhang Xin , Choe Jongseon , Li Li , Choi Yong Sung 
Published: April 2014

AbstractInnate immunity has recently gained renewed interest in its ability to regulate adaptive immunity. Among the innate immune signals, CpG DNA has revealed its potential as a vaccine adjuvant. However, the cellular mechanism for the effect of CpG DNA on the humoral immune response is not well understood. Here, we investigated the effects of CpG DNA on human B cell differentiation using highly purified B cell subsets: naive, germinal center (GC), and memory B cells. In the in vitro culture system that mimics the primary or secondary immune response in vivo, CpG DNA markedly augmented the proliferation and generation of plasma cells from naive and memory B cells. CpG DNA dramatically increased plasma cell generation from GC B cells. However, CpG DNA did not have effect on memory B cell generation from GC B cells. These results suggest that CpG DNA potentiates the B cell adaptive immune response by enhancing terminal differentiation, but does not affect the generation of memory B cells.