bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasmacytoid Dendritic Cells Regulate Breach of Self-Tolerance in Autoimmune Arthritis
Authors: Jongbloed Sarah L. , Benson Robert A. , Nickdel Mohammed B. , Garside Paul , McInnes Iain B. , Brewer James M.
Published: April 2014

Achieving remission in rheumatoid arthritis (RA) remains elusive despite current biological therapeutics. Consequently, interest has increased in strategies to re-establish immune tolerance to provide long-term disease suppression. Although dendritic cells (DC) are prime candidates in initiating autoreactive T cell responses, and their presence within the synovial environment suggests a role in generation and maintenance of autoreactive, synovial T cell responses, their functional importance remains unclear. We investigated the contribution made by plasmacytoid DCs (pDCs) in the spontaneous breach of tolerance to arthritis-related self proteins, including rheumatoid factor, citrullinated peptide, and type II collagen observed in a novel arthritis model. Selective pDC depletion in vivo enhanced the severity of articular pathology and enhanced T and B cell autoimmune responses against type II collagen. pDC may offer a net anti-inflammatory function in the context of articular breach of tolerance. Such data will be vital in informing DC modulatory/therapeutic approaches.
Critical Role for the Transcription Regulator CCCTC-Binding Factor in the Control of Th2 Cytokine Expression
Authors: Ribeiro de Almeida Claudia , Heath Helen , Krpic Sanja , Dingjan Gemma M. , van Hamburg Jan Piet , Bergen Ingrid , van de Nobelen Suzanne , Sleutels Frank , Grosveld Frank , Galjart Niels , Hendriks Rudi W.
Published: April 2014

Differentiation of naive CD4+ cells into Th2 cells is accompanied by chromatin remodeling at the Th2 cytokine locus allowing the expression of the IL-4, IL-5, and IL-13 genes. In this report, we investigated the role in Th2 differentiation of the transcription regulator CCCTC-binding factor (CTCF). Chromatin immunoprecipitation analysis revealed multiple CTCF binding sites in the Th2 cytokine locus. Conditional deletion of the Ctcf gene in double-positive thymocytes allowed development of peripheral T cells, but their activation and proliferation upon anti-CD3/anti-CD28 stimulation in vitro was severely impaired. Nevertheless, when TCR signaling was circumvented with phorbol ester and ionomycin, we observed proliferation of CTCF-deficient T cells, enabling the analysis of Th2 differentiation in vitro. We found that in CTCF-deficient Th2 polarization cultures, transcription of IL-4, IL-5, and IL-13 was strongly reduced. By contrast, CTCF deficiency had a moderate effect on IFN-γ production in Th1 cultures and IL-17 production in Th17 cultures was unaffected. Consistent with a Th2 cytokine defect, CTCF-deficient mice had very low levels of IgG1 and IgE in their serum, but IgG2c was close to normal. In CTCF-deficient Th2 cultures, cells were polarized toward the Th2 lineage, as substantiated by induction of the key transcriptional regulators GATA3 and special AT-rich binding protein 1 (SATB1) and down-regulation of T-bet. Also, STAT4 expression was low, indicating that in the absence of CTCF, GATA3 still operated as a negative regulator of STAT4. Taken together, these findings show that CTCF is essential for GATA3- and SATB1-dependent regulation of Th2 cytokine gene expression.
Cutting Edge: Histamine Receptor H4 Activation Positively Regulates In Vivo IL-4 and IFN-γ Production by Invariant NKT Cells
Authors: Leite-de-Moraes Maria C. , Diem Séverine , Michel Marie-Laure , Ohtsu Hiroshi , Thurmond Robin L. , Schneider Elke , Dy Michel
Published: April 2014

Histamine (HA) is a biogenic amine with multiple activities in the immune system. In this study we demonstrate that histamine-free histidine decarboxylase-deficient (HDC−/−) mice present a numerical and functional deficit in invariant NK T (iNKT) cells as evidenced by a drastic decrease of IL-4 and IFN-γ production. This deficiency was established both by measuring cytokine levels in the serum and intracellularly among gated iNKT cells. It resulted from the lack of HA, because a single injection of this amine into HDC−/− mice sufficed to restore normal IL-4 and IFN-γ production. HA-induced functional recovery was mediated mainly through the H4 histamine receptor (H4R), as assessed by its abrogation after a single injection of a selective H4R antagonist and the demonstration of a similar iNKT cell deficit in H4R−/− mice. Our findings identify a novel function of HA through its H4R and suggest that it might become instrumental in modulating iNKT cell functions.
Autoimmunity in Dry Eye Is Due to Resistance of Th17 to Treg Suppression
Authors: Chauhan Sunil K. , El Annan Jaafar , Ecoiffier Tatiana , Goyal Sunali , Zhang Qiang , Saban Daniel R. , Dana Reza
Published: April 2014

Dry eye disease (DED), an inflammatory autoimmune disorder affecting the ocular surface, degrades visual performance and the quality of life of >10 million people in the United States alone. The primary limitation in the effective treatment of DED is an incomplete understanding of its specific cellular and molecular pathogenic elements. Using a validated mouse model of DED, herein we functionally characterize the different T cell subsets, including regulatory T cells (Tregs) and pathogenic effector T cells, and determine their contribution to the pathogenesis of DED. Our data demonstrate the presence of dysfunctional Tregs and the resistance of pathogenic T cells, particularly Th17 cells, to Treg suppression in DED. In addition, we clearly show that in vivo blockade of IL-17 significantly reduces the severity and progression of disease, which is paralleled by a reduction in the expansion of Th17 cells and restoration of Treg function. Our findings elucidate involvement of a previously unknown pathogenic T cell subset (Th17) in DED that is associated specifically with Treg dysfunction and disease pathogenesis and suggest a new target for dry eye therapy.
Targeting Antigen to MHC Class II Molecules Promotes Efficient Cross-Presentation and Enhances Immunotherapy
Authors: Dickgreber Nina , Stoitzner Patrizia , Bai Yan , Price Kylie M. , Farrand Kathryn J. , Manning Kristy , Angel Catherine E. , Dunbar P. Rod , Ronchese Franca , Fraser John D. , Bäckström B. Thomas , Hermans Ian F.
Published: April 2014

An efficient pathway of cross-presentation common to a range of dendritic cell (DC) populations was identified by targeting Ag to MHC class II molecules. This finding was achieved by conjugating Ag to M1, which is a modified version of the superantigen streptococcal mitogenic exotoxin Z-2 that binds to MHC class II molecules but cannot directly stimulate T cells. M1 conjugates were efficiently presented to CD4+ and CD8+ T cells by bone marrow-derived DC and Langerhans cells in vitro. Whereas nonconjugated Ag was preferentially cross-presented by splenic CD8α+ DC in vivo, M1-conjugated Ag was cross-presented by all dendritic subtypes assessed. Potent effector T cell responses with antitumor activity were elicited when M1 conjugates were injected together with an adjuvant. This method of Ag delivery has significant potential in therapeutic applications.
Chemokine-Enhanced Chemotaxis of Lymphangioleiomyomatosis Cells with Mutations in the Tumor Suppressor TSC2 Gene
Authors: Pacheco-Rodriguez Gustavo , Kumaki Fumiyuki , Steagall Wendy K. , Zhang Yi , Ikeda Yoshihiko , Lin Jing-Ping , Billings Eric M. , Moss Joel
Published: April 2014

Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction caused by LAM cells (smooth-muscle-like cells) that have mutations in the tumor suppressor genes tuberous sclerosis complex (TSC) 1 or 2 and have the capacity to metastasize. Since chemokines and their receptors function in chemotaxis of metastatic cells, we hypothesized that LAM cells may be recruited by chemokine(s) in the lung. Quantification of 25 chemokines in bronchoalveolar lavage fluid from LAM patients and healthy volunteers revealed that concentrations of CCL2, CXCL1, and CXCL5 were significantly higher in samples from LAM patients than those from healthy volunteers. In vitro, CCL2 or MCP-1 induced selective migration of cells, showing loss of heterozygosity of TSC2 from a heterogeneous population of cells grown from explanted LAM lungs. Additionally, the frequencies of single-nucleotide polymorphisms in the CCL2 gene promoter region differed significantly in LAM patients and healthy volunteers (p = 0.018), and one polymorphism was associated significantly more frequently with the decline of lung function. The presence (i.e., potential functionality) of chemokine receptors was evaluated using immunohistochemistry in lung sections from 30 LAM patients. Expression of chemokines and these receptors varied among LAM patients and differed from that seen in some cancers (e.g., breast cancer and melanoma cells). These observations are consistent with the notion that chemokines such as CCL2 may serve to determine mobility and specify the site of metastasis of the LAM cell.
Differentiated Human Alveolar Type II Cells Secrete Antiviral IL-29 (IFN-λ1) in Response to Influenza A Infection
Authors: Wang Jieru , Oberley-Deegan Rebecca , Wang Shuanglin , Nikrad Mrinalini , Funk C. Joel , Hartshorn Kevan L. , Mason Robert J.
Published: April 2014

Alveolar type II epithelial cells (ATIIs) are one of the primary targets for influenza A pneumonia. The lack of a culture system for maintaining differentiated ATIIs hinders our understanding of pulmonary innate immunity during viral infection. We studied influenza A virus (IAV)-induced innate immune responses in differentiated primary human ATIIs and alveolar macrophages (AMs). Our results indicate that ATIIs, but not AMs, support productive IAV infection. Viral infection elicited strong inflammatory chemokine and cytokine responses in ATIIs, including secretion of IL-8, IL-6, MCP-1, RANTES, and MIP-1β, but not TNF-α, whereas AMs secreted TNF-α as well as other cytokines in response to infection. Wild-type virus A/PR/8/34 induced a greater cytokine response than reassortant PR/8 virus, A/Phil/82, despite similar levels of replication. IAV infection increased mRNA expression of IFN genes IFN-β, IL-29 (IFN-λ1), and IL-28A (IFN-λ2). The major IFN protein secreted by type II cells was IL-29 and ATIIs appear to be a major resource for production of IL-29. Administration of IL-29 and IFN-β before infection significantly reduced the release of infectious viral particles and CXC and CC chemokines. IL-29 treatment of type II cells induced mRNA expression of antiviral genes MX1, OAS, and ISG56 but not IFN-β. IL-29 induced a dose-dependent decrease of viral nucleoprotein and an increase of antiviral genes but not IFN-β. These results suggest that IL-29 exerts IFN-β-independent protection in type II cells through direct activation of antiviral genes during IAV infection.
Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells
Authors: Flores-Langarica Adriana , Sebti Yasmine , Mitchell Daniel A. , Sim Robert B. , MacPherson Gordon G.
Published: April 2014

Mice lacking complement components show delayed development of prion disease following peripheral inoculation. The delay could relate to reduced scrapie prion protein (PrPSc) accumulation on follicular dendritic cells (DCs). However conventional DCs (cDCs) play a crucial role in the early pathogenesis of prion diseases and complement deficiency could result in decreased PrPSc uptake by cDCs in the periphery. To explore this possibility, we cultured murine splenic or gut-associated lymph node cDCs with scrapie-infected whole brain homogenate in the presence or absence of complement. Uptake decreased significantly if the serum in the cultures was heat-inactivated. Because heat inactivation primarily denatures C1q, we used serum from C1q−/− mice and showed that PrPSc uptake was markedly decreased. PrPSc internalization was saturable and temperature-dependent, suggesting receptor-mediated uptake. Furthermore, uptake characteristics differed from fluid-phase endocytosis. Immunofluorescence showed colocalization of C1q and PrPSc, suggesting interaction between these molecules. We evaluated the expression of several complement receptors on cDCs and confirmed that cDCs that take up PrPSc express one of the C1q receptors, calreticulin. Our results show that C1q participates in PrPSc uptake by cDCs, revealing a critical role for cDCs in initial prion capture, an event that takes place before the PrPSc accumulation within the follicular DC network.
IL-12 Enhances CTL Synapse Formation and Induces Self-Reactivity
Authors: Markiewicz Mary A. , Wise Erica L. , Buchwald Zachary S. , Cheney Elizabeth E. , Hansen Ted H. , Suri Anish , Cemerski Saso , Allen Paul M. , Shaw Andrey S.
Published: April 2014

Immunological synapse formation between T cells and target cells can affect the functional outcome of TCR ligation by a given MHC-peptide complex. Although synapse formation is usually induced by TCR signaling, it is not clear whether other factors can affect the efficiency of synapse formation. Here, we tested whether cytokines could influence synapse formation between murine CTLs and target cells. We found that IL-12 enhanced synapse formation, whereas TGFβ decreased synapse formation. The enhanced synapse formation induced by IL-12 appeared to be functional, given that IL-12-treated cells could respond to weak peptides, including self-peptides, to which the T cells were normally unresponsive. These responses correlated with expression of functionally higher avidity LFA-1 on IL-12-treated CTLs. These findings have implications for the function of IL-12 in T cell-mediated autoimmunity.
The Epigenetic Profile of Ig Genes Is Dynamically Regulated during B Cell Differentiation and Is Modulated by Pre-B Cell Receptor Signaling
Authors: Xu Cheng-Ran , Feeney Ann J.
Published: April 2014

Ag receptor loci poised for V(D)J rearrangement undergo germline transcription (GT) of unrearranged genes, and the accessible gene segments are associated with posttranslational modifications (PTM) on histones. In this study, we performed a comprehensive analysis of the dynamic changes of four PTM throughout B and T cell differentiation in freshly isolated ex vivo cells. Methylation of lysines 4 and 79 of histone H3, and acetylation of H3, demonstrated stage and lineage specificity, and were most pronounced at the J segments of loci poised for, or undergoing, rearrangement, except for dimethylation of H3K4, which was more equally distributed on V, D, and J genes. Focusing on the IgL loci, we demonstrated there are no active PTM in the absence of pre-BCR signaling. The κ locus GT and PTM on Jκ genes are rapidly induced following pre-BCR signaling in large pre-B cells. In contrast, the λ locus shows greatly delayed onset of GT and PTM, which do not reach high levels until the immature B cell compartment, the stage at which receptor editing is initiated. Analysis of MiEκ−/− mice shows that this enhancer plays a key role in inducing not only GT, but PTM. Using an inducible pre-B cell line, we demonstrate that active PTM on Jκ genes occur after GT is initiated, indicating that histone PTM do not make the Jκ region accessible, but conversely, GT may play a role in adding PTM. Our data indicate that the epigenetic profile of IgL genes is dramatically modulated by pre-BCR signaling and B cell differentiation status.
Tim-1 Signaling Substitutes for Conventional Signal 1 and Requires Costimulation to Induce T Cell Proliferation
Authors: Mariat Christophe , Degauque Nicolas , Balasubramanian Savithri , Kenny James , DeKruyff Rosemarie H. , Umetsu Dale T. , Kuchroo Vijay , Zheng Xin Xiao , Strom Terry B.
Published: April 2014

Differentiation and clonal expansion of Ag-activated naive T cells play a pivotal role in the adaptive immune response. T cell Ig mucin (Tim) proteins influence the activation and differentiation of T cells. Tim-3 and Tim-2 clearly regulate Th1 and Th2 responses, respectively, but the precise influence of Tim-1 on T cell activation remains to be determined. We now show that Tim-1 stimulation in vivo and in vitro induces polyclonal activation of T cells despite absence of a conventional TCR-dependent signal 1. In this model, Tim-1-induced proliferation is dependent on strong signal 2 costimulation provided by mature dendritic cells. Ligation of Tim-1 upon CD4+ T cells with an agonist anti-Tim-1 mAb elicits a rise in free cytosolic calcium, calcineurin-dependent nuclear translocation of NF-AT, and transcription of IL-2. Because Tim-4, the Tim-1 ligand, is expressed by mature dendritic cells, we propose that interaction between Tim-1+ T cells and Tim-4+ dendritic cells might ensure optimal stimulation of T cells, when TCR-derived signals originating within an inflamed environment are weak or waning.
Macrophages Activated by C-Reactive Protein through FcγRI Transfer Suppression of Immune Thrombocytopenia
Authors: Marjon Kristopher D. , Marnell Lorraine L. , Mold Carolyn , Du Clos Terry W.
Published: April 2014

C-reactive protein (CRP) is an acute-phase protein with therapeutic activity in mouse models of systemic lupus erythematosus and other inflammatory and autoimmune diseases. To determine the mechanism by which CRP suppresses immune complex disease, an adoptive transfer system was developed in a model of immune thrombocytopenic purpura (ITP). Injection of 200 μg of CRP 24 h before induction of ITP markedly decreased thrombocytopenia induced by anti-CD41. CRP-treated splenocytes also provided protection from ITP in adoptive transfer. Splenocytes from C57BL/6 mice were treated with 200 μg/ml CRP for 30 min, washed, and injected into mice 24 h before induction of ITP. Injection of 106 CRP-treated splenocytes protected mice from thrombocytopenia, as did i.v. Ig-treated but not BSA-treated splenocytes. The suppressive cell induced by CRP was found to be a macrophage by depletion, enrichment, and the use of purified bone marrow-derived macrophages. The induction of protection by CRP-treated cells was dependent on FcRγ-chain and Syk activation, indicating an activating effect of CRP on the donor cell. Suppression of ITP by CRP-treated splenocytes required FcγRI on the donor cell and FcγRIIb in the recipient mice. These findings suggest that CRP generates suppressive macrophages through FcγRI, which then act through an FcγRIIb-dependent pathway in the recipient to decrease platelet clearance. These results provide insight into the mechanism of CRP regulatory activity in autoimmunity and suggest a potential new therapeutic approach to ITP.
B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells
Authors: Hu Yi-Ling , Metz Daniela P. , Chung James , Siu Gerald , Zhang Ming
Published: April 2014

Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (TFH cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of TFH cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F1 mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in TFH cells and GC B cells as well as an overall decrease in the frequency of ICOS+ T cells. Coculture experiments of Ag-primed B cells with CXCR5+ or CXCR5− T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the TFH cell pool is an important mechanism by which ICOS regulates Ab production.
Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway
Authors: Chen Taoyong , Guo Jun , Han Chaofeng , Yang Mingjin , Cao Xuetao
Published: April 2014

Extracellular heat shock proteins (HSP) can activate dendritic cells (DC) and monocytes/macrophages, and HSP derived from tumor cells have been regarded as potent adjuvant facilitating presentation of tumor Ags and induction of antitumor immunity. However, the roles and the underlying mechanisms of releasable HSP in the induction of antitumor immunity have not been fully elucidated. In this study, we report that heat stress can induce the release of various HSP from tumor cells, which, in turn, activate tumor cells to produce chemokines for chemoattraction of DC and T cells via TLR4 signaling pathway. In vivo, we find that the infiltration and function of DC and T cells within tumor after local hyperthermia are increased significantly. We also provide evidence that HSP70 proteins released by tumor cells and TLR4 expressed by tumor cells/DC are essential for the chemoattraction of DC/T cells and for the subsequent induction of tumor-specific antitumor immunity. Therefore, our study suggests that heat stress-induced releasable HSP70 proteins from tumor cells play important roles in the initiation of antitumor immunity by inducing tumor cell production of chemokines and by activating the chemoattracted DC via TLR4 pathway.
T Cell Leukemia/Lymphoma 1 and Galectin-1 Regulate Survival/Cell Death Pathways in Human Naive and IgM+ Memory B Cells through Altering Balances in Bcl-2 Family Proteins
Authors: Tabrizi Siamak Jabbarzadeh , Niiro Hiroaki , Masui Mariko , Yoshimoto Goichi , Iino Tadafumi , Kikushige Yoshikane , Wakasaki Takahiro , Baba Eishi , Shimoda Shinji , Miyamoto Toshihiro , Hara Toshiro , Akashi Koichi
Published: April 2014

BCR signaling plays a critical role in purging the self-reactive repertoire, or in rendering it anergic to establish self-tolerance in the periphery. Differences in self-reactivity between human naive and IgM+ memory B cells may reflect distinct mechanisms by which BCR signaling dictates their survival and death. Here we demonstrate that BCR stimulation protected naive B cells from apoptosis with induction of prosurvival Bcl-2 family proteins, Bcl-xL and Mcl-1, whereas it rather accelerated apoptosis of IgM+ memory B cells by inducing proapoptotic BH3-only protein Bim. We found that BCR-mediated PI3K activation induced the expression of Mcl-1, whereas it inhibited Bim expression in B cells. Phosphorylation of Akt, a downstream molecule of PI3K, was more sustained in naive than IgM+ memory B cells. Abundant expression of T cell leukemia/lymphoma 1 (Tcl1), an Akt coactivator, was found in naive B cells, and enforced expression of Tcl1 induced a high level of Mcl-1 expression, resulting in prolonged B cell survival. In contrast, Galectin-1 (Gal-1) was abundantly expressed in IgM+ memory B cells, and inhibited Akt phosphorylation, leading to Bim up-regulation. Enforced expression of Gal-1 induced accelerated apoptosis in B cells. These results suggest that a unique set of molecules, Tcl1 and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM+ memory B cells.
Methylation Status of CpG Islands Flanking a cAMP Response Element Motif on the Protein Phosphatase 2Acα Promoter Determines CREB Binding and Activity
Authors: Sunahori Katsue , Juang Yuang-Taung , Tsokos George C.
Published: April 2014

Protein phosphatase 2A (PP2A) is a major serine/threonine protein phosphatase in eukaryotic cells and is involved in many essential aspects of cell function. The catalytic subunit of the enzyme (PP2Ac), a part of the core enzyme, has two isoforms, α (PP2Acα) and β (PP2Acβ), of which PP2Acα is the major form expressed in vivo. Deregulation of PP2A expression has been linked to several diseases, but the mechanisms that control the expression of this enzyme are still unclear. We conducted experiments to decipher molecular mechanisms involved in the regulation of the PP2Acα promoter in human primary T cells. After preparing serially truncated PP2Acα promoter luciferase constructs, we found that the region stretching around 240 bases upstream from the translation initiation site was of functional significance and included a cAMP response element motif flanked by three GC boxes. Shift assays revealed that CREB/phosphorylated CREB and stable protein 1 could bind to the region. Furthermore, we demonstrated that methylation of deoxycytosine in the CpG islands limited binding of phosphorylated CREB and the activity of the PP2Acα promoter. In contrast, the binding of stable protein 1 to a GC box within the core promoter region was not affected by DNA methylation. Primary T cells treated with 5-azacitidine, a DNA methyltransferase inhibitor, showed increased expression of PP2Acα mRNA. We propose that conditions associated with hypomethylation of CpG islands, such as drug-induced lupus, permit increased PP2Ac expression.
A Novel Activating Chicken IgY FcR Is Related to Leukocyte Receptor Complex (LRC) Genes but Is Located on a Chromosomal Region Distinct from the LRC and FcR Gene Clusters
Authors: Viertlboeck Birgit C. , Schmitt Ramona , Hanczaruk Matthias A. , Crooijmans Richard P. M. A. , Groenen Martien A. M. , Göbel Thomas W.
Published: April 2014

FcRs have multifaceted roles in the immune system. Chicken FcRs were demonstrated on macrophages decades ago; however, only recently the chicken Ig-like receptor AB1, encoded in the leukocyte receptor complex, was molecularly identified as a high-affinity FcR. The present study was initiated to identify additional receptors with the capability to bind chicken immunoglobulins. Based on database searches, we cloned a novel chicken FcR, designated gallus gallus FcR (ggFcR), which was shown to bind selectively chicken IgY. The receptor consists of four extracellular C2-set Ig domains, followed by a transmembrane region containing arginine as a positively charged amino acid and a short cytoplasmic tail. ggFcR associates with the common γ-chain, indicative for an activating receptor, and real-time RT-PCR revealed high expression on PBMC, thrombocytes, and macrophages. The genomic organization is similar to most Ig-like receptor genes, where each Ig domain is encoded by a separate exon. Additionally, the ggFcR signal peptide is encoded by two exons, the second of which is 36 bp, a hallmark for genes encoded in the leukocyte receptor complex. Phylogenetic analysis also showed a relationship to genes encoded in the leukocyte receptor complex. Surprisingly, ggFcR is not encoded in the leukocyte receptor complex, but it is located as a single isolated gene at the extremity of chicken chromosome 20.
Surfactant Protein A Enhances Production of Secretory Leukoprotease Inhibitor and Protects It from Cleavage by Matrix Metalloproteinases
Authors: Ramadas Ravisankar A. , Wu Lizhen , LeVine Ann Marie
Published: April 2014

Mice lacking surfactant protein A (SP-A) are susceptible to bacterial infection associated with an excessive inflammatory response in the lung. To determine mechanisms by which SP-A is antiinflammatory in the lung during bacterial infection, SP-A regulation of secretory leukoprotease inhibitor (SLPI), an inhibitor of serine proteases, was assessed. SLPI protein expression and antineutrophil elastase activity were reduced in bronchoalveolar fluid of SP-A−/− compared with SP-A+/+ mice. Intratracheal administration of SP-A to SP-A−/− mice enhanced SLPI protein expression and antineutrophil elastase activity in the lung. SLPI mRNA was similar in whole lung and alveolar type II cells; however, it was significantly reduced in alveolar macrophages from SP-A−/− compared with SP-A+/+ mice. In vitro, SP-A enhanced SLPI production by macrophage THP-1 cells but not respiratory epithelial A549 cells. SP-A inhibited LPS induced IκB-α degradation in THP-1 cells, which was partially reversed with knockdown of SLPI. Matrix metalloproteinase (MMP)-12 cleaved SLPI and incubation with SP-A reduced MMP-12-mediated SLPI cleavage. The collagen-like region of SP-A conferred protection of SLPI against MMP mediated cleavage. SP-A plays an important role in the lung during bacterial infection regulating protease and antiprotease activity.
The Adaptor Protein CIKS/Act1 Is Essential for IL-25-Mediated Allergic Airway Inflammation
Authors: Claudio Estefania , Sønder Søren Ulrik , Saret Sun , Carvalho Gabrielle , Ramalingam Thirumalai R. , Wynn Thomas A. , Chariot Alain , Garcia-Perganeda Antonio , Leonardi Antonio , Paun Andrea , Chen Amy , Ren Nina Y. , Wang Hongshan , Siebenlist Ulrich
Published: April 2014

IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c+ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.
The Critical Role of Epithelial-Derived Act1 in IL-17- and IL-25-Mediated Pulmonary Inflammation
Authors: Swaidani Shadi , Bulek Katarzyna , Kang Zizhen , Liu Caini , Lu Yi , Yin Weiguo , Aronica Mark , Li Xiaoxia
Published: April 2014

IL-25 initiates, promotes, and augments Th2 immune responses. In this study, we report that Act1, a key component in IL-17-mediated signaling, is an essential signaling molecule for IL-25 signaling. Although Act1-deficient mice showed reduced expression of KC (CXCL1) and neutrophil recruitment to the airway compared with wild-type mice in response to IL-17 stimulation, Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1 (CCL11), and pulmonary eosinophilia. Using a mouse model of allergic pulmonary inflammation, we observed diminished Th2 responses and lung inflammation in Act1-deficient mice compared with wild-type mice. Importantly, Act1 deficiency in epithelial cells reduced the phenotype of allergic pulmonary inflammation due to loss of IL-17-induced neutrophilia and IL-25-induced eosinophilia, respectively. These results demonstrate the essential role of epithelial-derived Act1 in allergic pulmonary inflammation through the distinct impact of the IL-17R-Act1 and IL-25R-Act1 axes. Such findings are crucial for the understanding of pathobiology of atopic diseases, including allergic asthma, which identifies Act1 as a potential therapeutic target.
Myeloid-Specific Expression of Api6/AIM/Spα Induces Systemic Inflammation and Adenocarcinoma in the Lung
Authors: Qu Peng , Du Hong , Li Yuan , Yan Cong
Published: April 2014

To study the functional role of apoptosis inhibition of myeloid lineage cells in tumor formation, apoptosis inhibitor 6 (Api6/AIM/Spα) was overexpressed in a myeloid-specific c-fms-rtTA/(TetO)7-CMV-Api6 bitransgenic mouse model under the control of the c-fms promoter/intron 2. In this bitransgenic system, the Api6-Flag fusion protein was expressed in myeloid lineage cells after doxycycline treatment. Induction of Api6 abnormally elevated levels of macrophages, neutrophils, and dendritic cells in the bone marrow, blood, and lung in vivo. BrdU incorporation and annexin V binding studies showed systemically increased cell proliferation and inhibition of apoptosis in myeloid lineage cells. Api6 overexpression activated oncogenic signaling pathways, including Stat3, Erk1/2, and p38 in myeloid lineage cells in multiple organs of the bitransgenic mice. In the lung, severe inflammation and massive tissue remodeling were observed in association with increased expression of procancer cytokines/chemokines, decreased expression of proapoptosis molecule genes, and increased expression of matrix metalloproteinase genes as a result of Api6 overexpression. Oncogenic CD11b+/Gr-1+ myeloid-derived suppressor cells were systemically increased. After Api6 overexpression, lung adenocarcinoma was observed in bitransgenic mice with a 35% incidence rate. These studies suggest that dysregulation of myeloid cell populations by extracellular Api6 signaling leads to abnormal myelopoiesis and lung cancer.
A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris
Authors: Takahashi Hayato , Kuwana Masataka , Amagai Masayuki
Published: April 2014

The development of naive B cells into IgG-producing memory B cells requires cognate T cell-B cell interaction in Ag-specific immune responses. It is unknown whether a single T cell clone is sufficient or whether multiple clones are necessary to induce polyclonal IgG production in vivo. We addressed this issue using a mouse model of pemphigus vulgaris, a fatal autoimmune blistering skin disease caused by IgG autoantibodies against desmoglein (Dsg) 3. We previously isolated several Dsg3-reactive T cell clones from Dsg3−/− mice. Among these, two pathogenic T cell clones induced anti-Dsg3 IgG production and the development of a pemphigus phenotype when adoptively transferred with unprimed B cells from Dsg3−/− mice. IgG Abs harvested from recipient mice reacted with at least three parts of the extracellular domain of Dsg3, as determined using domain-swapped Dsg3/Dsg1 molecules. The anti-Dsg3 IgGs included at least two subclasses among IgG1, IgG2a, IgG2b, and IgG3 in each mouse. The anti-Dsg3 IgG induced by Dsg3-reactive T cell clones with primed B cells from Dsg3−/− mice also showed reactivity against different parts of the molecule, with a similar epitope distribution. Together, these results indicate that a single potent Dsg3-reactive T cell is sufficient to commit polyclonal naive B cells to produce pathogenic anti-Dsg3 IgG Abs and induce the PV phenotype. These findings provide an important framework for examining immunological mechanisms in Ab-mediated autoimmune diseases.
In en uit de praktijk - Kroniek van het Nederlands als vreemde taal
Authors: van Kalsbeek Alice
Published: April 2014

Het is bekend dat docenten graag zelf materiaal ontwikkelen. Naast bestaande leergangen hebben de meesten een map met favoriete teksten en werkvormen om een cursus nog meer af te stemmen op de wensen en behoeften van de cursisten. Soms is er een verzamelmap voor het hele team. Auteurs en producenten van leergangen zien dat graag: hoe meer materiaal er om een leergang heen is gemaakt, des te steviger de leergang in het curriculum is verankerd. Hoe dikker de mappen, hoe beter, zou je zeggen. Maar er is een kritische grens, zo blijkt uit een aantal recente publicaties. Als de map te dik wordt en van goede kwaliteit is, weekt het materiaal zich los van de leergang. De geïnteresseerde uitgever doet de rest. Zo ontstaan weer nieuwe leermiddelen of naslagwerken met het label ‘in de praktijk ontstaan’. Er zijn ook mappen die niet speciaal naast een leergang zijn ontwikkeld, maar als zelfstandig cursusmateriaal – bijvoorbeeld omdat de doelgroep zo specifiek is – die ook resulteren in een uitgave. Ten slotte worden leermiddelen en naslagwerken in opdracht van een uitgever ontwikkeld volgens een bepaald concept dat bij meer talen wordt toegepast. De publicaties die hier worden besproken zijn exponenten van deze drie ontwikkelingspatronen. In de vorige kroniek kondigde ik aan deze keer meer aandacht te besteden aan Vlaamse producten omdat er een aantal op stapel stond. Die zijn intussen allemaal verschenen.
Romanschrijvers en de maatschappelijke actualiteit - Kroniek van het proza
Authors: Goedegebuure Jaap
Published: April 2014

Sinds het einde van de jaren tachtig zijn Nederlandse en Vlaamse romanciers zich in toenemende mate bezig gaan houden met de maatschappelijke actualiteit. In zijn veelbesproken boek De revanche van de roman (2009) zag Thomas Vaessens, hoogleraar aan de Universiteit van Amsterdam, er zelfs een terugkeer van het engagement in.
Kroniek van de taalkunde 2009
Authors: Hüning Matthias
Published: April 2014

Even leek het erop dat de Europese meertaligheid een net zo serieus onderwerp zou kunnen zijn als het verkeer, het klimaat of misschien zelfs als de visserij. Vanaf 2007 had de EU immers een heuse ‘commissaris voor meertaligheid’, de Roemeen Leonard Orban. Voor die tijd maakte dit onderwerp altijd deel uit van de portefeuille van de commissaris voor onderwijs en cultuur. En, meer nog, de commissie maakte in het kader van haar ‘Framework Programme 6’ ook veel geld vrij voor twee reusachtige onderzoeksprojecten over het belang van meertaligheid voor Europa: het ‘integrated project’ DYLAN (www.dylan-project.org) en het ‘network of excellence’ LINEE (www.linee.info).
Smeltende torens
Authors: Missinne Lut
Published: April 2014

The poem ‘Een psalm voor het smelten’ which Leo Vroman (° 1915) wrote as a reaction to the attack on the New York Twin Towers, illustrates his particular way of writing poetry, his playful and unpretentious use of the language, the surprising combination of a scientifical perspective and human emotion, and a lively tone, offering the reader comfort for his anxieties and fear of death. ‘Een psalm voor het smelten’ was published in the volume Tweede verschiet (2003). It is one of a series of psalms that Vroman wrote in this period and in which he addresses a ‘System’, his particular designation of an ordering principle in life. Vroman’s poem strikes us – and this all the more when compared with other poems on 9/11 – by its unusual perspective, its deliberate refraining from each form of drama, its concentration on the transformation of materials as if describing a physical process and its almost shockingly peaceful depiction of the drama, ending up in a simple statement of complete helplessness. In this way Vroman’s poem avoids the direct melodrama that characterizes many verses on 9/11.
Oranje bloed? Eerste Wereldoorlog-poëzie in vergelijkend perspectief
Authors: Buelens Geert
Published: April 2014

All too often researchers and teachers of literary texts assume that their audiences share a body of knowledge which they cannot possibly share because of its cultural specificity. In this article Great War poetry by Jacob Israel de Haan, Ber Horowitz, Edward Słoński, René de Clercq, Jozef Simons, Albert Verwey and Herman Gorter is used to illustrate how the authors' notions of nationhood and (inter)nationalism are determined by the way in which they are politically, linguistically and geographically situated. By making this explicit, it both facilitates and enriches our understanding of their work.
Cultuurtekst als middel voor interculturele reflectie
Authors: Quist Gerdi
Published: April 2014

This article posits that language teaching methods which implicitly assume a direct link between one particular national culture and one particular language cannot address the changing needs of language learners in contemporary multicultural societies, which are characterized by increased mobility and cultural complexity. It further charts different views of intercultural communication and, along with Kumaravadivelu (2008), takes a view of language and culture pedagogy as leading to cultural ‘transformation’ rather than providing cultural information. An example of an approach in the field of teaching Dutch as a foreign language is provided. This cultuurtekst approach encourages learners to reflect on the multiplicity of discourses in texts – global as well as nationally articulated ones. It is the self-reflexivity of students in considering these discourses and relating them to their own experiences which sets a step towards the pedagogic aim of cultural transformation.
Lingua receptiva als bouwsteen voor de transnationale neerlandistiek
Authors: ten Thije Jan D.
Published: April 2014

This paper discusses a new concept of multilingual communication in the Netherlands, i.e. receptive multilingualism or so-called lingua receptiva (LaRa). ‘LaRa is the ensemble of those linguistic, mental, interactional as well as intercultural competences which are creatively activated when listeners are receiving linguistic actions in their ‘passive’ language or variety. In order to monitor and process ‘passive knowledge activation in hearers’, speakers make use of subsidiary competences and control communicative asymmetries as soon as these become manifested in interaction (Rehbein et al., in preparation).’ The paper discusses studies concerning institutional practices of lingua receptiva in German-Dutch transnational communication. Subsequently, European traditions with regard to receptive multilingualism in Scandinavia, the Habsburg Empire and Switzerland are presented. Finally, the paper suggests further research concerning academic applications of Lingua Receptiva in transnational Dutch Studies.
Kijken en bekeken worden - De avonden als stripverhaal
Authors: Hermann Christine
Published: April 2014

‘Comic version offers new insights’ – with these words the Stichting Beeldverhaal Nederland acclaimed the publication of Dick Matena’s comic version of De avonden, incorporating the complete text of the novel. But what actually is the benefit of Matena’s approach? In this paper I will investigate how the comic artist has translated Reve’s style into images, paying special attention to visual focalisation techniques. Several examples shall illustrate by which techniques certain themes (monotony, isolation, repressed sexuality) are evoked without being actually depicted. What the text leaves unsaid, is evoked on the panels by means of e.g. layout, colouring, pictorial composition, camera angle, field size, absence of mimicry and (physical as well as eye) contact.

There is, however, one theme which is indeed depicted, namely vision. Whereas the novel can only describe observation, in the comic it can be actually shown. The reader is at the same time a viewer: he watches the protagonist and at the same time literally shares his view. In this way the viewer gets himself involved in the story and thus in a way satisfies the desire of the protagonist to be ‘seen’. The images thus not only repeat or supplement the message of the text, but also provide an additional semantic value.
Research Note: Analysing Tourism Demand in Tourist Districts — The Case of Sicily
Authors: Asero Vincenzo , Tomaselli Venera
Published: April 2014

This paper analyses tourism demand in the tourist districts in Sicily to study the relationship between the characteristics of tourists, types of tourism and expenditure. The data were obtained from a survey of tourists leaving the island after a holiday. The likelihood of choosing a type of holiday is estimated by means of a multinomial logistic model. The findings highlight the importance of the seaside, cultural, and food and wine/nature segments. The analysis of the distribution of per capita per day expenditure shows higher average values for the cultural holiday. The research provides insights for decision makers concerning the implementation of destination market strategies.
Markets versus Regulation: The Efficiency and Distributional Impacts of U.S. Climate Policy Proposals
Authors: Rausch Sebastian , Karplus Valerie J.
Published: April 2014

Regulatory measures have proven the favored approach to climate change mitigation in the U.S., while market-based policies have gained little traction. Using a model that resolves the U.S. economy by region, income category, and sector-specific technology deployment opportunities, this paper studies the magnitude and distribution of economic impacts under regulatory versus market-based approaches. We quantify heterogeneity in the national response to regulatory policies, including a fuel economy standard and a clean or renewable electricity standard, and compare these to a cap-and-trade system targeting carbon dioxide or all greenhouse gases. We find that the regulatory policies substantially exceed the cost of a cap-and-trade system at the national level. We further show that the regulatory policies yield large cost disparities across regions and income groups, which are exaggerated by the difficulty of implementing revenue recycling provisions under regulatory policy designs.
Overview of EMF 24 Policy Scenarios
Authors: Fawcett Allen A. , Clarke Leon E. , Rausch Sebastian , Weyant John P.
Published: April 2014

The Energy Modeling Forum 24 study included a set of policy scenarios designed to compare economy wide market-based and sectoral regulatory approaches of potential U.S. climate policy. Models from seven teams participated in this part of the study assessing economy-wide cap-and-trade climate policy and sectoral policies in the transportation and electric sector in terms of potential greenhouse gas emissions reductions, economic cost, and energy systems implications. This paper presents an overview of the results from the U.S. policy scenarios, and provides insights into the comparison of results from the participating models. In particular, various metrics were used to compare the model results including allowance price, the efficient frontier, consumption loss, GDP loss, and equivalent variation. We find that the choice of economic metric is an important factor in the comparison of model results. Among the insights, we note that the carbon price should cautiously be considered when other non-cap sectoral policies affecting emissions are assumed in tandem. We also find that a transportation sector policy is consistently shown to be inefficient compared to an economy-wide cap-and-trade policy with a comparable level of emissions reductions.
Technology Assumptions and Climate Policy: The Interrelated Effects of U.S. Electricity and Transport Policy
Authors: Jaccard Mark , Goldberg Suzanne
Published: April 2014

Although economists prefer a unique, economy-wide carbon price, climate policies are likely to continue to combine technology- and sector-specific regulations with, at best, some degree of carbon pricing. A hybrid energy-economy model that combines technological details with partial macro-economic feedbacks offers a means of estimating the likely effects of this kind of policy mix, especially under different scenarios of technological innovation. We applied such a model, called CIMS-US, in a model comparison project directed by the Energy Modeling Forum at Stanford University (EMF 24) and present here the interrelated effects of policies focused separately on electricity and transportation. We find that technological innovation encouraged by transportation regulation can inadvertently increase emissions from electricity generation and ethanol production to the extent that abatement from the regulation itself is effectively neutralized. When, however, regulation of electricity generation is combined with transportation policy or there is economy-wide carbon pricing, substantial abatement occurs.
Factors Affecting the Rise of Renewable Energy in the U.S.: Concern over Environmental Quality or Rising Unemployment?
Authors: Ohler Adrienne M.
Published: April 2014

This paper studies the development of renewable energy (RE) in the U.S. by examining the capacity to generate electricity from renewable sources. RE capacity exhibits a U-shaped relationship with per capita income, similar to other metrics for environmental quality (EQ). To explain this phenomenon, I consider several of the environmental Kuznets curve theories that describe the relationship between income and environmental quality (Y-EQ), including evolving property rights, increased demand for improved EQ, and changing economic composition. The results fail to provide support for the Y-EQ theories. I further consider the alternative hypothesis that increases in unemployment lead to increases in relative RE capacity, suggesting that promoting RE projects as a potential job creator is one of the main drivers of RE projects. The results imply that lagged unemployment is a significant predictor of relative RE capacity, particularly for states with a large manufacturing share of GDP.