bluuebunny/crossref_metadata_2025_split huggingface dataset:
MyD88 Signaling Is Not Essential for Induction of Antigen-Specific B Cell Responses but Is Indispensable for Protection against Streptococcus pneumoniae Infection following Oral Vaccination with Attenuated Salmonella Expressing PspA Antigen
Authors: Park Sung-Moo , Ko Hyun-Jeong , Shim Doo-Hee , Yang Jin-Young , Park Yong-Ho , Curtiss Roy , Kweon Mi-Na 
Published: April 2014

Abstract
TLRs directly induce innate host defense responses, but the mechanisms of TLR-mediated adaptive immunity remain subject to debate. In this study, we clarified a role of TLR-mediated innate immunity for induction of adaptive immunity by oral vaccination with a live recombinant attenuated Salmonella enteric serovar Typhimurium vaccine (RASV) strain expressing Streptococcus pneumoniae surface protein A (PspA) Ag. Of note, oral or intranasal vaccination with RASV expressing PspA resulted in identical or even significantly higher levels of PspA-specific IgG and IgA responses in the systemic and mucosal compartments of MyD88−/− mice of either BALB/c or C57BL/6 background when compared with those of wild-type mice. Although PspA-specific CD4+ T cell proliferation in the MyD88−/− mice was minimal, depletion of CD4+ T cells abolished PspA-specific IgG and IgA responses in the MyD88−/− mice of BALB/c background. Of the greatest interest, MyD88−/− mice that possessed high levels of PspA-specific IgG and IgA responses but minimal levels of CD4+ T cell responses died earlier than nonvaccinated and vaccinated wild-type mice following i.v. or intranasal challenge with virulent S. pneumoniae. Taken together, these results suggest that innate immunity activated by MyD88 signals might not be necessary for Ag-specific Ab induction in both systemic and mucosal sites but is critical for protection following oral vaccination with attenuated Salmonella expressing PspA.
Functional Dichotomy of Dendritic Cells following Interaction withLeishmania braziliensis: Infected Cells Produce High Levels of TNF-α, whereas Bystander Dendritic Cells Are Activated to Promote T Cell Responses
Authors: Carvalho Lucas P. , Pearce Edward J. , Scott Phillip 
Published: April 2014

AbstractLeishmania braziliensis infections are often associated with exaggerated immune responses that can sometimes lead to severe disease associated with high levels of IFN-γ and TNF-α. To explore the role played by dendritic cells (DCs) in these responses, we characterized DCs that were exposed to L. braziliensis. We found that DCs cultured with L. braziliensis parasites up-regulated DC activation markers and produced IL-12 and TNF-α. However, not all DCs in the culture became infected, and an analysis of infected and uninfected DCs demonstrated that the up-regulation of activation markers and IL-12 production was primarily confined to the uninfected (bystander) DCs. Further studies with Transwell chambers and parasite fractions indicated that the activation of bystander DCs was mediated by a soluble parasite product, in a type 1 IFN- and MyD88-independent, but TNF-α-dependent fashion, and that the activated DCs were more efficient at presenting Ag than control DCs. In contrast, L. braziliensis-infected DCs failed to up-regulate activation markers, but exhibited a dramatic enhancement in their ability to produce TNF-α in response to LPS as compared with uninfected DCs. These findings uncover a dual role for DCs in L. braziliensis infection: T cell activation by bystander DCs due to enhanced Ag-presenting capacity following exposure to soluble parasite products, and increased production of TNF-α by infected cells that may contribute to the local control of the parasites, but concomitantly induce immunopathology.
Zinc Signals Are Essential for Lipopolysaccharide-Induced Signal Transduction in Monocytes
Authors: Haase Hajo , Ober-Blöbaum Julia L. , Engelhardt Gabriela , Hebel Silke , Heit Antje , Heine Holger , Rink Lothar 
Published: April 2014

Abstract
Cytosolic alterations of calcium ion concentrations are an integral part of signal transduction. Similar functions have been hypothesized for other metal ions, in particular zinc (Zn2+), but this still awaits experimental verification. Zn2+ is important for multiple cellular functions, especially in the immune system. Among other effects, it influences formation and secretion of pro-inflammatory cytokines, including TNF-α. Here we demonstrate that these effects are due to a physiological signaling system involving intracellular Zn2+ signals. An increase of the intracellular zinc ion concentration occurs upon stimulation of human leukocytes with Escherichia coli, LPS, Pam3CSK4, TNF-α, or insulin, predominantly in monocytes. Chelating this zinc signal with the membrane permeable zinc-specific chelator TPEN (N,N,N′,N′-tetrakis-(2-pyridyl-methyl)ethylenediamine) completely blocks activation of LPS-induced signaling pathways involving p38 MAPK, ERK1/2, and NF-κB, and abrogates the release of proinflammatory cytokines, including TNF-α. This function of Zn2+ is not limited to monocytes or even the immune system, but seems to be another generalized signaling system based on intracellular fluctuations of metal ion concentrations, acting parallel to Ca2+.
IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia
Authors: Shimizu Eisuke , Kawahara Kohichi , Kajizono Makoto , Sawada Makoto , Nakayama Hitoshi 
Published: April 2014

Abstract
A hallmark of immunopathology associated with Alzheimer’s disease is the presence of activated microglia (MG) surrounding senile plaque deposition of β-amyloid (Aβ) peptides. Aβ peptides are believed to be potent activators of MG, which leads to Alzheimer’s disease pathology, but the role of MG subtypes in Aβ clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Aβ1–42 (o-Aβ1–42). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Aβ-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Aβ clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of 125I-labeled o-Aβ1–42 compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Aβ1–42 in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Aβ1–42, because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Aβ1–42 were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Aβ-overproducing brain. Thus, selective o-Aβ1–42 clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer’s disease.
Human Plasmacytoid Dendritic Cells Interact with gp96 via CD91 and Regulate Inflammatory Responses
Authors: De Filippo AnnaMaria , Binder Robert J. , Camisaschi Chiara , Beretta Valeria , Arienti Flavio , Villa Antonello , Della Mina Pamela , Parmiani Giorgio , Rivoltini Licia , Castelli Chiara 
Published: April 2014

Abstract
Glucose-regulated stress protein gp96 is known to be involved in the host response to pathogens and to cancer. Our study explored the relationships between gp96 and human blood plasmacytoid dendritic cells (pDC) and proved that gp96 directly targets pDC by a receptor-dependent interaction. Competition studies identified CD91 as a gp96 receptor on pDC, and laser confocal imaging indicated that CD91 triggering was followed by gp96 endocytosis and trafficking into early endosomes and later into the endoplasmic reticulum compartment. Using two alternative Abs, we showed that human blood pDC reproducibly expressed CD91, although different levels of expression were detectable among the analyzed donors. Moreover, CpG-matured pDC displayed CD91 receptor up-regulation that correlated with an increased gp96 binding. Functionally, gp96-pDC interaction activated the NF-κB pathway, leading to the nuclear translocation of the NF-κB complex. gp96-treated pDC maintained an immature phenotype, while they down-modulated the release of IL-8, suggesting an anti-inflammatory role of this pathway, and they strongly up-regulated the cell surface expression of the gp96 receptor CD91. CpG-matured or gp96-treated pDC, expressing high levels of the gp96 receptor CD91, antagonized the gp96-induced activation of monocyte-derived dendritic cells in terms of cell surface phenotype and cytokine production. Altogether, these results suggest that gp96-pDC interaction might represent an active mechanism controlling the strength of the immune response to free, extracellular available gp96; this mechanism could be particularly relevant in wounds and chronic inflammation.
CCR5 Deficiency Aggravates Crescentic Glomerulonephritis in Mice
Authors: Turner Jan-Eric , Paust Hans-Joachim , Steinmetz Oliver M. , Peters Anett , Meyer-Schwesinger Catherine , Heymann Felix , Helmchen Udo , Fehr Susanne , Horuk Richard , Wenzel Ulrich , Kurts Christian , Mittrücker Hans-Willi , Stahl Rolf A. K. , Panzer Ulf 
Published: April 2014

Abstract
The chemokine receptor CCR5 is predominantly expressed on monocytes and Th1-polarized T cells, and plays an important role in T cell and monocyte recruitment in inflammatory diseases. To investigate the functional role of CCR5 in renal inflammation, we induced a T cell-dependent model of glomerulonephritis (nephrotoxic serum nephritis) in CCR5−/− mice. Induction of nephritis in wild-type mice resulted in up-regulation of renal mRNA expression of the three CCR5 chemokine ligands, CCL5 (15-fold), CCL3 (4.9-fold), and CCL4 (3.4-fold), in the autologous phase of the disease at day 10. The up-regulated chemokine expression was paralleled by infiltration of monocytes and T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Nephritic CCR5−/− mice showed a 3- to 4-fold increased renal expression of CCL5 (61.6-fold vs controls) and CCL3 (14.1-fold vs controls), but not of CCL4, in comparison with nephritic wild-type mice, which was accompanied by augmented renal T cell and monocyte recruitment and increased lethality due to uremia. Furthermore, CCR5−/− mice showed an increased renal Th1 response, whereas their systemic humoral and cellular immune responses were unaltered. Because the CCR5 ligands CCL5 and CCL3 also act via CCR1, we investigated the effects of the pharmacological CCR1 antagonist BX471. CCR1 blockade in CCR5−/− mice significantly reduced renal chemokine expression, T cell infiltration, and glomerular crescent formation, indicating that increased renal leukocyte recruitment and consecutive tissue damage in nephritic CCR5−/− mice depended on functional CCR1. In conclusion, this study shows that CCR5 deficiency aggravates glomerulonephritis via enhanced CCL3/CCL5-CCR1-driven renal T cell recruitment.
Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils
Authors: Tamassia Nicola , Le Moigne Vincent , Rossato Marzia , Donini Marta , McCartney Stephen , Calzetti Federica , Colonna Marco , Bazzoni Flavia , Cassatella Marco A. 
Published: April 2014

Abstract
Neutrophils, historically known for their involvement in acute inflammation, are also targets for infection by many different DNA and RNA viruses. However, the mechanisms by which they recognize and respond to viral components are poorly understood. Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic mimetic of viral dsRNA that is known to interact either with endosomal TLR3 (not expressed by human neutrophils) or with cytoplasmic RNA helicases such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). In this study, we report that intracellularly administered poly(I:C) stimulates human neutrophils to specifically express elevated mRNA levels encoding type I IFNs, immunoregulatory cytokines, and chemokines, such as TNF-α, IL-12p40, CXCL10, CXCL8, CCL4, and CCL20, as well as classical IFN-responsive genes (IRG), including IFIT1 (IFN-induced protein with tetratricopeptide repeats 1)/IFN-stimulated gene (ISG)56, G1P2/ISG15, PKR (dsRNA-dependent protein kinase), and IFN-regulatory factor (IRF)7. Investigations into the mechanisms whereby transfected poly(I:C) promotes gene expression in neutrophils uncovered a crucial involvement of the MAPK-, PKR-, NF-κB-, and TANK (TNF receptor-associated NF-κB kinase)-binding kinase (TBK1)/IRF3-signaling transduction pathways, as illustrated by the use of specific pharmacological inhibitors. Consistent with the requirement of the cytoplasmic dsRNA pathway for antiviral signaling, human neutrophils were found to constitutively express significant levels of both MDA5 and RIG-I, but not TLR3. Accordingly, neutrophils isolated from MDA5-deficient mice had a partial impairment in the production of IFN-β and TNF-α upon infection with encephalomyocarditis virus. Taken together, our data demonstrate that neutrophils are able to activate antiviral responses via helicase recognition, thus acting at the frontline of immunity against viruses.
Up-Regulation of Vascular Endothelial Growth Factor-D Expression in Clear Cell Renal Cell Carcinoma by CD74: A Critical Role in Cancer Cell Tumorigenesis
Authors: Liu Yu-Huei , Lin Chang-Yueh , Lin Wei-Chou , Tang Sai-Wen , Lai Ming-Kuen , Lin Jung-Yaw 
Published: April 2014

Abstract
Elevation of CD74 is associated with a number of human cancers, including clear cell renal cell carcinoma (ccRCC). To understand the role of CD74 in the oncogenic process of ccRCC, we ectopically expressed CD74 in human embryonic kidney 293 cells (HEK/CD74) and evaluated its oncogenic potential. Through overexpression of CD74 in HEK293 and Caki-2 cells and down-regulation of CD74 in Caki-1 cells, we show that vascular endothelial growth factor-D (VEGF-D) expression is modified accordingly. A significant, positive correlation between CD74 and VEGF-D is found in human ccRCC tissues (Pearson’s correlation, r = 0.65, p &lt; 0.001). In HEK/CD74 xenograft mice, CD74 significantly induced the formation of tumor masses, increased tumor-induced angiogenesis, and promoted cancer cell metastasis. Blockage of VEGF-D expression by small interference RNA resulted in a decrease in cell proliferation, invasion, and cancer cell-induced HUVEC migration enhanced by CD74. Furthermore, we provide evidence that the intracellular signaling cascade responsible for VEGF-D up-regulation by CD74 is both PI3K/AKT- and MEK/ERK-dependent, both of which are associated with NF-κB nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis.
Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients
Authors: Tassi Elena , Gavazzi Francesca , Albarello Luca , Senyukov Vladimir , Longhi Renato , Dellabona Paolo , Doglioni Claudio , Braga Marco , Di Carlo Valerio , Protti Maria Pia 
Published: April 2014

Abstract
Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients’ sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80–90% of pancreatic carcinomas and contains epitopes recognized by CD4+ T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the anti-CEA and antiviral CD4+ T cell immunity. CD4+ T cells from 23 normal donors and 44 patients undergoing surgical resection were tested for recognition of peptides corresponding to CEA and viral naturally processed promiscuous epitopes by proliferation and cytokine release assays. Anti-CEA CD4+ T cell immunity was present in a significantly higher number of normal donors than pancreatic cancer patients. Importantly, whereas CD4+ T cells from normal donors produced mainly GM-CSF and IFN-γ, CD4+ T cells from the patients produced mainly IL-5, demonstrating a skew toward a Th2 type. On the contrary, the extent of antiviral CD4+ T cell immunity was comparable between the two groups and showed a Th1 type. The immunohistochemical analysis of tumor-infiltrating lymphocytes showed a significantly higher number of GATA-3+ compared with T-bet+ lymphoid cells, supporting a Th2 skew also at the tumor site. Collectively, these results demonstrate that Th2-immune deviation in pancreatic cancer is not generalized but tumor related and suggests that the skew might be possibly due to factor(s) present at the tumor site.
Immunodominant Epitopes in Herpes Simplex Virus Type 2 Glycoprotein D Are Recognized by CD4 Lymphocytes from Both HSV-1 and HSV-2 Seropositive Subjects
Authors: Kim Min , Taylor Janette , Sidney John , Mikloska Zorka , Bodsworth Neil , Lagios Katerina , Dunckley Heather , Byth-Wilson Karen , Denis Martine , Finlayson Robert , Khanna Rajiv , Sette Alessandro , Cunningham Anthony L. 
Published: April 2014

Abstract
In human recurrent cutaneous herpes simplex, there is a sequential infiltrate of CD4 and then CD8 lymphocytes into lesions. CD4 lymphocytes are the major producers of the key cytokine IFN-γ in lesions. They recognize mainly structural proteins and especially glycoproteins D and B (gD and gB) when restimulated in vitro. Recent human vaccine trials using recombinant gD showed partial protection of HSV seronegative women against genital herpes disease and also, in placebo recipients, showed protection by prior HSV1 infection. In this study, we have defined immunodominant peptide epitopes recognized by 8 HSV1+ and/or 16 HSV2+ patients using 51Cr-release cytotoxicity and IFN-γ ELISPOT assays. Using a set of 39 overlapping 20-mer peptides, more than six immunodominant epitopes were defined in gD2 (two to six peptide epitopes were recognized for each subject). Further fine mapping of these responses for 4 of the 20-mers, using a panel of 9 internal 12-mers for each 20-mers, combined with MHC II typing and also direct in vitro binding assay of these peptides to individual DR molecules, showed more than one epitope per 20-mers and promiscuous binding of individual 20-mers and 12-mers to multiple DR types. All four 20-mer peptides were cross-recognized by both HSV1+/HSV2− and HSV1−/HSV2+ subjects, but the sites of recognition differed within the 20-mers where their sequences were divergent. This work provides a basis for CD4 lymphocyte cross-recognition of gD2 and possibly cross-protection observed in previous clinical studies and in vaccine trials.
Strategic Nonmyeloablative Conditioning: CD154:CD40 Costimulatory Blockade at Primary Bone Marrow Transplantation Promotes Engraftment for Secondary Bone Marrow Transplantation after Engraftment Failure
Authors: Xu Hong , Huang Yiming , Chilton Paula M. , Hussain Lala-Rukh , Tanner Michael K. , Yan Jun , Ildstad Suzanne T. 
Published: April 2014

Abstract
There is an increased risk of failure of engraftment following nonmyeloablative conditioning. Sensitization resulting from failed bone marrow transplantation (BMT) remains a major challenge for secondary BMT. Approaches to allow successful retransplantation would have significant benefits for BMT candidates living with chronic diseases. We used a mouse model to investigate the effect of preparative regimens at primary BMT on outcome for secondary BMT. We found that conditioning with TBI or recipient T cell lymphodepletion at primary BMT did not promote successful secondary BMT. In striking contrast, successful secondary BMT could be achieved in mice conditioned with anti-CD154 costimulatory molecule blockade at first BMT. Blockade of CD154 alone or combined with T cell depletion inhibits generation of the humoral immune response after primary BMT, as evidenced by abrogation of production of anti-donor Abs. The humoral barrier is dominant in sensitization resulting from failed BMT, because almost all CFSE-labeled donor cells were killed at 0.5 and 3 h in sensitized recipients in in vivo cytotoxicity assay, reflecting Ab-mediated cytotoxicity. CD154:CD40 costimulatory blockade used at primary BMT promotes allogeneic engraftment in secondary BMT after engraftment failure at first BMT. The prevention of generation of anti-donor Abs at primary BMT is critical for successful secondary BMT.
Characterization of the Antibody Response against NeuGcGM3 Ganglioside Elicited in Non-Small Cell Lung Cancer Patients Immunized with an Anti-Idiotype Antibody
Authors: Hernández Ana María , Toledo Darién , Martínez Darel , Griñán Tania , Brito Victor , Macías Amparo , Alfonso Sailyn , Rondón Teresa , Suárez Eduardo , Vázquez Ana María , Pérez Rolando 
Published: April 2014

Abstract1E10 mAb is an anti-Id murine mAb (Ab2 mAb) specific for an Ab1 mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In preclinical studies, this Ab2 Ab was able to mimic NeuGc-containing gangliosides only in animals lacking expression of these Ags in normal tissues. In this study, we report on the immune responses elicited in 20 non-small cell lung cancer patients treated with 1 mg of aluminum hydroxide-precipitated 1E10 mAb. In the hyperimmune sera from 16 of 20 patients, a strong specific Ab response of both IgM and IgG isotypes against NeuGcGM3 ganglioside was observed. Patient immune sera were able to induce complement-independent cell death of NeuGcGM3-expressing X63 murine myeloma target cells. Significant immunoreactivity to NeuGcGM3 was still detected after the complete abrogation of the reactivity against 1E10 mAb by the adsorption of patient sera with this Ab. We hypothesize that Id−Ag+ Abs could reflect the activation of an autologous idiotypic cascade into the patients. Both Id+Ag+ and Id−Ag+ fractions were separated by affinity chromatography and characterized. Although IgG isotype Abs were found in both fractions, IgM isotype Abs were found only in the Id−Ag+ fraction. Both Id+Ag+ and Id−Ag+ Abs were able to specifically recognize and induce cell death in NeuGcGM3-expressing X63 myeloma target cells. Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times.