bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Innate Immune Defense Mechanisms by Signaling through RIG-I/IPS-1 in Intestinal Epithelial Cells
Authors: Hirata Yoshihiro , Broquet Alexis H. , Menchén Luis , Kagnoff Martin F. 
Published: April 2014

Abstract
Intestinal epithelial cells (IECs) are a first line of defense against microbial pathogens that enter the host through the intestinal tract. Moreover, viral pathogens that infect the host via the intestinal epithelium are an important cause of morbidity and mortality. However, the mechanisms by which viral pathogens activate antiviral defense mechanisms in IECs are largely unknown. The synthetic dsRNA analog polyinosinic-polycytidylic acid and infection with live virus were used to probe the molecules that are activated and the mechanisms of signaling in virus-infected human IECs. Polyinosinic-polycytidylic acid activated IFN regulatory factor 3 dimerization and phosphorylation, increased activity of the IFN-stimulated response element, induced a significant increase in IFN-β mRNA transcripts and IFN-β secretion, and up-regulated the expression of IFN-regulated genes in IECs. Those responses were dependent upon activation of the dsRNA binding protein retinoic acid inducible gene I (RIG-I) and the RIG-I interacting protein IFN promoter stimulator-1, but not on dsRNA-activated protein kinase or TLR3, which also were expressed by IECs. Virus replication and virus-induced cell death increased in IECs in which RIG-I was silenced, consistent with the importance of the RIG-I signaling pathway in IEC antiviral innate immune defense mechanisms.
Helicobacter pylori Vacuolating Cytotoxin Inhibits Activation-Induced Proliferation of Human T and B Lymphocyte Subsets
Authors: Torres Victor J. , VanCompernolle Scott E. , Sundrud Mark S. , Unutmaz Derya , Cover Timothy L. 
Published: April 2014

Abstract
Helicobacter pylori are Gram-negative bacteria that persistently colonize the human gastric mucosa despite the recruitment of immune cells. The H. pylori vacuolating cytotoxin (VacA) recently has been shown to inhibit stimulation-induced proliferation of primary human CD4+ T cells. In this study, we investigated effects of VacA on the proliferation of various other types of primary human immune cells. Intoxication of PBMC with VacA inhibited the stimulation-induced proliferation of CD4+ T cells, CD8+ T cells, and B cells. VacA also inhibited the proliferation of purified primary human CD4+ T cells that were stimulated by dendritic cells. VacA inhibited both T cell-induced and PMA/anti-IgM-induced proliferation of purified B cells. Intoxication with VacA did not alter the magnitude of calcium flux that occurred upon stimulation of CD4+ T cells or B cells, indicating that VacA does not alter early signaling events required for activation and proliferation. VacA reduced the mitochondrial membrane potential of CD4+ T cells, but did not reduce the mitochondrial membrane potential of B cells. We propose that the immunomodulatory actions of VacA on T and B lymphocytes, the major effectors of the adaptive immune response, may contribute to the ability of H. pylori to establish a persistent infection in the human gastric mucosa.
Specific Leukotriene Receptors Couple to Distinct G Proteins to Effect Stimulation of Alveolar Macrophage Host Defense Functions
Authors: Peres Camila M. , Aronoff David M. , Serezani Carlos H. , Flamand Nicolas , Faccioli Lucia H. , Peters-Golden Marc 
Published: April 2014

Abstract
Leukotrienes (LTs) are lipid mediators implicated in asthma and other inflammatory diseases. LTB4 and LTD4 also participate in antimicrobial defense by stimulating phagocyte functions via ligation of B leukotriene type 1 (BLT1) receptor and cysteinyl LT type 1 (cysLT1) receptor, respectively. Although both Gαi and Gαq proteins have been shown to be coupled to both BLT1 and cysLT1 receptors in transfected cell systems, there is little known about specific G protein subunit coupling to LT receptors, or to other G protein-coupled receptors, in primary cells. In this study we sought to define the role of specific G proteins in pulmonary alveolar macrophage (AM) innate immune responses to LTB4 and LTD4. LTB4 but not LTD4 reduced cAMP levels in rat AM by a pertussis toxin (PTX)-sensitive mechanism. Enhancement of FcγR-mediated phagocytosis and bacterial killing by LTB4 was also PTX-sensitive, whereas that induced by LTD4 was not. LTD4 and LTB4 induced Ca2+ and intracellular inositol monophosphate accumulation, respectively, highlighting the role of Gαq protein in mediating PTX-insensitive LTD4 enhancement of phagocytosis and microbicidal activity. Studies with liposome-delivered G protein blocking Abs indicated a dependency on specific Gαq/11 and Gαi3 subunits, but not Gαi2 or Gβγ, in LTB4-enhanced phagocytosis. The selective importance of Gαq/11 protein was also demonstrated in LTD4-enhanced phagocytosis. The present investigation identifies differences in specific G protein subunit coupling to LT receptors in antimicrobial responses and highlights the importance of defining the specific G proteins coupled to heptahelical receptors in primary cells, rather than simply using heterologous expression systems.
Identification of the IL-17 Receptor Related Molecule IL-17RC as the Receptor for IL-17F
Authors: Kuestner Rolf E. , Taft David W. , Haran Aaron , Brandt Cameron S. , Brender Ty , Lum Karen , Harder Brandon , Okada Shannon , Ostrander Craig D. , Kreindler James L. , Aujla Shean J. , Reardon Brian , Moore Margaret , Shea Pamela , Schreckhise Randall , Bukowski Thomas R. , Presnell Scott , Guerra-Lewis Patricia , Parrish-Novak Julia , Ellsworth Jeff L. , Jaspers Stephen , Lewis Katherine E. , Appleby Mark , Kolls Jay K. , Rixon Mark , West James W. , Gao Zeren , Levin Steven D. 
Published: April 2014

Abstract
The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
The Chemokine CCL6 Promotes Innate Immunity via Immune Cell Activation and Recruitment
Authors: Coelho Ana L. , Schaller Matthew A. , Benjamim Claudia F. , Orlofsky Amos Z. , Hogaboam Cory M. , Kunkel Steven L. 
Published: April 2014

Abstract
Septic syndrome is a consequence of innate immune failure. Recent studies showed that the CC chemokine CCL6 enhanced antimicrobial immunity during experimental sepsis through an unknown mechanism. The present study demonstrates that transgenic CCL6 expression abolishes mortality in a septic peritonitis model via the modulation of resident peritoneal cell activation and, more importantly, through the recruitment of IFN-producing NK cells and killer dendritic cells into the peritoneum. Thus, CCL6 attenuates the immune failure during sepsis, in part, through a protective type 1-cytokine mediated mechanism.
Proteinase-Activated Receptor-2 Exerts Protective and Pathogenic Cell Type-Specific Effects in Alzheimer’s Disease
Authors: Afkhami-Goli Amir , Noorbakhsh Farshid , Keller Avril J. , Vergnolle Nathalie , Westaway David , Jhamandas Jack H. , Andrade-Gordon Patricia , Hollenberg Morley D. , Arab Hosseinali , Dyck Richard H. , Power Christopher 
Published: April 2014

Abstract
The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and their effects in neurodegenerative diseases remain uncertain. Alzheimer’s disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p &lt; 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p &lt; 0.01), a cognate receptor for a fibrillar 42-aa form of β-amyloid (Aβ1–42), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p &lt; 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of Aβ1–42 (p &lt; 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p &lt; 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal Aβ1–42 implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p &lt; 0.05), together with improved neurobehavioral outcomes (p &lt; 0.05). Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to Aβ1–42-mediated neurodegeneration.
Hepatocyte Growth Factor Significantly Suppresses Collagen-Induced Arthritis in Mice
Authors: Okunishi Katsuhide , Dohi Makoto , Fujio Keishi , Nakagome Kazuyuki , Tabata Yasuhiko , Okasora Takahiro , Seki Makoto , Shibuya Mihoko , Imamura Mitsuru , Harada Hiroaki , Tanaka Ryoichi , Yamamoto Kazuhiko 
Published: April 2014

Abstract
Hepatocyte growth factor (HGF) plays an important role in angiogenesis, cell proliferation, antifibrosis, and antiapoptosis. Moreover, recent studies have highlighted the immunosuppressive effect of HGF in animal models of allogenic heart transplantation and autoimmune myocarditis and in studies in vitro as well. We also reported that HGF significantly suppresses dendritic cell function, thus down-regulating Ag-induced Th1-type and Th2-type immune responses in allergic airway inflammation. However, the immunosuppressive effect of HGF in many other situations has not been fully clarified. In the present study, using a mouse model of collagen-induced arthritis (CIA) and experiments in vitro, we examined the effect of HGF on autoimmune arthritis and then elucidated the mechanisms of action of HGF. To achieve sufficient delivery of HGF, we used biodegradable gelatin hydrogels as a carrier. HGF suppressed Ag-induced T cell priming by regulating the functions of dendritic cells in the Ag-sensitization phase with down-regulation of IL-10. In contrast, under continuous Ag stimulation HGF induced IL-10-producing immunocytes both in vivo and in vitro. Moreover, HGF potently inhibited the development of CIA with enhancing the Th2-type immune response. We also confirmed that HGF significantly suppressed the production of IL-17 by immunocytes. These results indicate that HGF suppresses the development of CIA through different ways at different phases. They also suggest that HGF could be an attractive tool for treating patients with rheumatoid arthritis.
The Heat Shock Protein HSP70 Promotes Mouse NK Cell Activity against Tumors That Express Inducible NKG2D Ligands
Authors: Elsner Leslie , Muppala Vijayakumar , Gehrmann Mathias , Lozano Jingky , Malzahn Dörthe , Bickeböller Heike , Brunner Edgar , Zientkowska Marta , Herrmann Thomas , Walter Lutz , Alves Frauke , Multhoff Gabriele , Dressel Ralf 
Published: April 2014

Abstract
The stress-inducible heat shock protein (HSP) 70 is known to function as an endogenous danger signal that can increase the immunogenicity of tumors and induce CTL responses. We show in this study that HSP70 also activates mouse NK cells that recognize stress-inducible NKG2D ligands on tumor cells. Tumor size and the rate of metastases derived from HSP70-overexpressing human melanoma cells were found to be reduced in T and B cell-deficient SCID mice, but not in SCID/beige mice that lack additionally functional NK cells. In the SCID mice with HSP70-overexpressing tumors, NK cells were activated so that they killed ex vivo tumor cells that expressed NKG2D ligands. In the tumors, the MHC class I chain-related (MIC) A and B molecules were found to be expressed. Interestingly, a counter selection was observed against the expression of MICA/B in HSP70-overexpressing tumors compared with control tumors in SCID, but not in SCID/beige mice, suggesting a functional relevance of MICA/B expression. The melanoma cells were found to release exosomes. HSP70-positive exosomes from the HSP70-overexpressing cells, in contrast to HSP70-negative exosomes from the control cells, were able to activate mouse NK cells in vitro to kill YAC-1 cells, which express NKG2D ligands constitutively, or the human melanoma cells, in which MICA/B expression was induced. Thus, HSP70 and inducible NKG2D ligands synergistically promote the activation of mouse NK cells resulting in a reduced tumor growth and suppression of metastatic disease.
Intravenous Immunoglobulin Therapy Affects T Regulatory Cells by Increasing Their Suppressive Function
Authors: Kessel Aharon , Ammuri Hana , Peri Regina , Pavlotzky Elsa R. , Blank Miri , Shoenfeld Yehuda , Toubi Elias 
Published: April 2014

Abstract
Intravenous Ig therapy (IVIg) is reported to be a useful regimen in treating autoimmune diseases. In this study, we asked whether IVIg (in vitro) could increase the expression of TGF-β, IL-10, and the transcription factor FoxP3 in T regulatory (Treg) cells, and the idea that IVIg could enhance suppressive properties of these cells. CD4+ T cells from 12 healthy individuals were cultured in the presence or absence of IVIg vs human control IgG during 16, 24, and 36 h. Using FACS analysis and gating on CD4+CD25high Treg cells, we assessed the expression of intracellular TGF-β, IL-10, and FoxP3. In addition, the production of TNF-α by stimulated CD4+ T cells alone or in culture with CD25+ by itself or together with IVIg was also assessed. The presence of IVIg with Treg cells in culture significantly increased the intracellular expression of TGF-β (17.7 ± 8.5% vs 29.8 ± 13%; p = 0.02), IL-10 (20.7 ± 4.7% vs 34.2 ± 5.2%; p = 0.008) and FoxP3 (20.8 ± 5.2% vs 33.7 ± 5.9%; p = 0.0006) when compared with cells cultured alone or with control human IgG. The suppressive effect of CD4+CD25+ T cells presented as the decrease of TNF-α production by stimulated CD4+CD25− (effector T cells) was further increased by adding IVIg to cell culture. We hereby demonstrate an additional mechanism by which IVIg could maintain self-tolerance and decrease immune-mediated inflammation.
Exacerbation of Collagen-Induced Arthritis by Oligoclonal, IL-17-Producing γδ T Cells
Authors: Roark Christina L. , French Jena D. , Taylor Molly A. , Bendele Alison M. , Born Willi K. , O’Brien Rebecca L. 
Published: April 2014

Abstract
Murine γδ T cell subsets, defined by their Vγ chain usage, have been shown in various disease models to have distinct functional roles. In this study, we examined the responses of the two main peripheral γδ T cell subsets, Vγ1+ and Vγ4+ cells, during collagen-induced arthritis (CIA), a mouse model that shares many hallmarks with human rheumatoid arthritis. We found that whereas both subsets increased in number, only the Vγ4+ cells became activated. Surprisingly, these Vγ4+ cells appeared to be Ag selected, based on preferential Vγ4/Vδ4 pairing and very limited TCR junctions. Furthermore, in both the draining lymph node and the joints, the vast majority of the Vγ4/Vδ4+ cells produced IL-17, a cytokine that appears to be key in the development of CIA. In fact, the number of IL-17-producing Vγ4+ γδ T cells in the draining lymph nodes was found to be equivalent to the number of CD4+αβ+ Th-17 cells. When mice were depleted of Vγ4+ cells, clinical disease scores were significantly reduced and the incidence of disease was lowered. A decrease in total IgG and IgG2a anti-collagen Abs was also seen. These results suggest that Vγ4/Vδ4+ γδ T cells exacerbate CIA through their production of IL-17.
IL-10- and TGF-β-Mediated Susceptibility in Kala-azar and Post-kala-azar Dermal Leishmaniasis: The Significance of Amphotericin B in the Control of Leishmania donovani Infection in India
Authors: Saha Samiran , Mondal Smriti , Ravindran Rajesh , Bhowmick Swati , Modak Dolanchampa , Mallick Sudeshna , Rahman Mehboobar , Kar Sourjya , Goswami Ramaprasad , Guha Subhasis Kamal , Pramanik Netai , Saha Bibhuti , Ali Nahid 
Published: April 2014

Abstract
Visceral leishmaniasis (VL) or kala-azar is known to be associated with a mixed Th1-Th2 response, and effective host defense requires the induction of IFN-γ and IL-12. We address the role of the differential decline of IL-10 and TGF-β in response to sodium antimony gluconate (SAG) and amphotericin B (AmB), the therapeutic success of SAG and AmB in Indian VL, and the significance of IL-10 and TGF-β in the development and progression of post-kazla-azar dermal leishmaniasis (PKDL). In the active disease, PBMC from VL patients showed suppressed Ag-specific lymphoproliferation, IFN-γ and IL-12 production, and elevation of IL-10 and TGF-β. Cure corresponded with an elevation in IFN-γ and IL-12 production and down-regulation of IL-10 and TGF-β. Both CD4+ and CD8+ T cells were involved in IFN-γ and IL-10 production. Interestingly, the retention and maintenance of residual IL-10 and TGF-β in some SAG-treated individuals and the elevation of IL-10 and TGF-β in PKDL, a sequel to kala-azar, probably reflects the role of these cytokines in reactivation of the disease in the form of PKDL. Contrastingly, AmB treatment of VL resulted in negligible TGF-β levels and absolute elimination of IL-10, reflecting the better therapeutic activity of AmB and its probable role in the recent decline in PKDL occurrences in India. Moreover, elucidation of immune responses in Indian PKDL patients revealed a spectral pattern of disease progression where disease severity could be correlated inversely with lymphoproliferation and directly with TGF-β, IL-10, and Ab production. In addition, the enhancement of CD4+CD25+ T cells in active VL, their decline at cure, and reactivation in PKDL suggest their probable immunosuppressive role in these disease forms.
Perspectives on Mucosal Vaccines: Is Mucosal Tolerance a Barrier?
Authors: Mestecky Jiri , Russell Michael W. , Elson Charles O. 
Published: April 2014

AbstractMucosal administration of Ags induces specific Abs in external secretions and systemic unresponsiveness termed oral or mucosal tolerance. The dominant response depends on the species studied, the nature, dose, frequency, route of Ag application, and the use of adjuvants. The temporal sequence of Ag exposure determines the quality of the ensuing immune response; although initial mucosal Ag exposure results in systemic T cell hyporesponsiveness, pre-existing systemic responses are refractory to the tolerizing effects of mucosal Ag encounter. Mucosal and systemic humoral responses may be induced concomitantly with diminished systemic T cell responses, thereby permitting Ab-mediated containment of mucosal Ags without stimulation of the systemic immune compartment. B cell Ig isotype switching and differentiation toward IgA production share common regulatory mechanisms with the suppression of T cells. Optimization of mucosal vaccination strategies has the potential for enhancing protective immune responses and suppressing systemic responses to autoantigens desirable for the treatment of autoimmune diseases.
Cutting Edge: TCR Revision Affects Predominantly Foxp3− Cells and Skews Them toward the Th17 Lineage
Authors: Zehn Dietmar , Bevan Michael J. , Fink Pamela J. 
Published: April 2014

AbstractCD4+ T cells respond to peripheral endogenous superantigen stimulation by undergoing deletion or TCR revision. The latter involves RAG re-expression, TCR gene rearrangement, and expression of a novel TCR. TCR-revised T cells are functional and express a diverse TCR repertoire. Because TCR revision harbors the potential to create self-reactivity, it is important to explore whether T cells known to be self-reactive (regulatory T cells) or those involved in autoimmunity (Th17 cells) arise from TCR revision. Interestingly, we observed that Foxp3+ cells are excluded from revising their TCR and that only a small fraction of postrevision cells expresses Foxp3. In contrast, Th17 cells are 20 times more frequent among revised than among C57BL/6 CD4+ T cells, indicating that postrevision cells are biased toward the Th17 lineage. The link between Th17 differentiation and TCR revision might be highly relevant to the role of Th17 cells in promoting autoimmunity.
Targeting the Gut Vascular Endothelium Induces Gut Effector CD8 T Cell Responses Via Cross-Presentation by Dendritic Cells
Authors: Bourges Dorothee , Zhan Yifan , Brady Jamie L. , Braley Hal , Caminschi Irina , Prato Sandro , Villadangos José A. , Lew Andrew M. 
Published: April 2014

Abstract
Systemic delivery of Ag usually induces poor mucosal immunity. To improve the CD8 T cell response at mucosal sites, we targeted the Ag to MAdCAM-1, a mucosal addressin cell adhesion molecule expressed mainly by high endothelial venules (HEV) in mesenteric lymph nodes (MLN) and Peyer’s patches of gut-associated lymphoid tissue. When chemical conjugates of anti-MAdCAM-1 Ab and model Ag OVA were injected i.v., a greatly enhanced proliferative response of Ag-specific OT-I CD8 T cells was detected in MLN. This was preceded by prolonged accumulation, up to 2 wk, of the anti-MAdCAM OVA conjugate on HEV of Peyer’s patches and MLN. In contrast, nontargeted OVA conjugate was very inefficient in inducing OT-I CD8 T cell proliferation in MLN and required at least 20-fold more Ag to induce a comparable response. In addition, MAdCAM targeting elicits an endogenous OVA-specific CD8 T cell response, evident by IFN-γ production and target killing. Induced response offers protection against an OVA-expressing B cell lymphoma. We propose that the augmentation of gut CD8 T cell responses by MAdCAM targeting is due to both accumulation of Ag in the HEV and conversion of a soluble Ag to a cell-associated one, allowing cross-presentation by DCs.