bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neonatally Primed Lymph Node, but Not Splenic T Cells, Display a Gly-Gly Motif within the TCR β-Chain Complementarity-Determining Region 3 That Controls Affinity and May Affect Lymphoid Organ Retention
Authors: Caprio-Young Jacque C. , Bell J. Jeremiah , Lee Hyun-Hee , Ellis Jason , Nast Danielle , Sayler Gary , Min Booki , Zaghouani Habib 
Published: April 2014

Abstract
Ig-proteolipid protein 1 (Ig-PLP1) is an Ig chimera expressing the encephalitogenic PLP1 peptide corresponding to amino acid residues 139–151 of PLP. Newborn mice given Ig-PLP1 in saline on the day of birth and challenged 7 wk later with PLP1 peptide in CFA develop an organ-specific neonatal immunity that confers resistance against experimental allergic encephalomyelitis. The T cell responses in these animals are comprised of Th2 cells in the lymph node and anergic Th1 lymphocytes in the spleen. Intriguingly, the anergic splenic T cells, although nonproliferative and unable to produce IFN-γ or IL-4, secrete significant amounts of IL-2. Studies were performed to determine whether the two populations display any structural differences in the TCR H chain variable region that could contribute to the differential affinity and retention in different organs. Responsive Th2 lymph node T cells and anergic splenic lymphocytes were immortalized, and the structures of their TCR Vβ were determined. The results show that Vβ and Jβ usage was random, but the CDR3 regions of the lymph node cells had a conserved Gly-Gly motif. Analysis of TCR affinity/avidity correlated the Gly-Gly motif with lower affinity and retention of the Th2 cells in the lymph node. Also, it is suggested that a higher TCR affinity may be a contributing factor for the development of the neonatal Th1 response in the spleen.
Novel Insights into the Mechanism of Action of FTY720 in a Transgenic Model of Allograft Rejection: Implications for Therapy of Chronic Rejection
Authors: Habicht Antje , Clarkson Michael R. , Yang Jun , Henderson Joel , Brinkmann Volker , Fernandes Stacey , Jurewicz Mollie , Yuan Xueli , Sayegh Mohamed H. 
Published: April 2014

Abstract
FTY720 is a high-affinity agonist at the sphingosine 1-phosphate receptor 1 that prevents lymphocyte egress from lymphoid tissue and prolongs allograft survival in several animal models of solid organ transplantation. In this study we used a recently developed adoptive transfer model of TCR transgenic T cells to track allospecific CD4+ T cell expansion and trafficking characteristics, cytokine secretion profiles, and surface phenotype in vivo in the setting of FTY720 administration. We report that FTY720 administration had no effect on alloantigen-driven T cell activation, proliferation, acquisition of effector-memory function, or T cell apoptosis. However, FTY720 caused a reversible sequestration of alloantigen-specific effector-memory T cells in regional lymphoid tissue associated with a decrease in T cell infiltration within the allograft and a subsequent prolongation in allograft survival. Furthermore, delayed administration of FTY720 in a cardiac model of chronic allograft rejection attenuated the progression of vasculopathy and tissue fibrosis consistent with the hypothesis that FTY720 interrupts the trafficking of activated effector-memory T cells. These data have important implications for targeting the sphingosine 1-phosphate receptor 1 in solid organ transplantation.
Altered Self-Erythrocyte Recognition and Destruction in an Inbred Line of Tilapia (Oreochromis aureus)
Authors: Shirak Andrey , Bendersky Anna , Hulata Gideon , Ron Micha , Avtalion Ramy R. 
Published: April 2014

Abstract
Carboxyfluorescein diacetate (cFDA)-stained autologous and syngeneic tilapia (Oreochromis aureus) erythrocytes are recognized by effector peripheral blood leukocytes and lysed after a short culture period of 4 h. The hemolysis level was evaluated by measuring the fluorescence of the released cFDA. The degree of lysis of stained target erythrocytes of 60 individuals revealed a trimodal distribution statistically stratified into three groups of low (LR), intermediate (IR), and high (HR) responders. Depletion of the majority of phagocytes from leukocytes lowered the lysis level of HR to that of LR. A highly significant increase of LR cytotoxicity was obtained after the addition of conditioned medium from HR but only in the presence of phagocytes. Genetic analysis of offspring from four crosses (IR × HR, IR × LR, HR × LR, and LR × LR) revealed a quantitative trait locus (QTL) segregating for the level of response linked to markers UNH207 and UNH231 on linkage group 6 of tilapia. Based on segregation analysis of 58 gynogenetic BIU-1 offspring, the distances from the centromere were estimated as 21.5, 11.5, and 9.0 cM for UNH207, UNH231, and the QTL, respectively. It is suggested that 1) self-target recognition and destruction requires both cFDA-altered self-erythrocyte membrane and membrane structures normally present in autologous, syngeneic, and xenogeneic targets; 2) natural cytotoxic cells and/or macrophages are involved in erythrocyte lysis; and 3) the lysis level is codominantly inherited by a QTL segregating on tilapia linkage group 6.
A Signal Adaptor SLAM-Associated Protein Regulates Spontaneous Autoimmunity and Fas-Dependent Lymphoproliferation in MRL-Fas
lpr Lupus Mice
Authors: Komori Hiroaki , Furukawa Hiroshi , Mori Shiro , Ito Mitsuko R. , Terada Miho , Zhang Ming-Cai , Ishii Naoto , Sakuma Nobuhiro , Nose Masato , Ono Masao 
Published: April 2014

Abstract
Autoantibody production and lymphadenopathy are common features of systemic autoimmune disease. Targeted or spontaneous mutations in the mouse germline have generated many autoimmune models with these features. Importantly, the models have provided evidence for the gene function in prevention of autoimmunity, suggesting an indispensable role for the gene in normal immune response and homeostasis. We describe here pathological and genetic characterizations of a new mutant strain of mice, the mutation of which spontaneously occurred in the Fas-deficient strain, MRL/Mp.Faslpr (MRL/lpr). MRL/lpr is known to stably exhibit systemic lupus erythematosus-like diseases. However, the mutant mice barely displayed autoimmune phenotypes, though the original defect in Fas expression was unchanged. Linkage analysis using (mutant MRL/lpr × C3H/lpr)F2 mice demonstrated a nucleotide insertion that caused loss of expression of small adaptor protein, signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). SAP is known to be a downstream molecule of SLAM family receptors and to mediate the activation signal for tyrosine kinase Fyn. Recent studies have shown pleiotropic roles of SAP in T, B, and NK cell activations and NKT cell development. The present study will provide evidence for an essential role for SAP in the development of autoimmune diseases, autoantibodies, and lymphadenopathy in MRL/lpr lupus mice.
Defining the Origins and Evolution of the Chemokine/Chemokine Receptor System
Authors: DeVries Mark E. , Kelvin Alyson A. , Xu Luoling , Ran Longsi , Robinson John , Kelvin David J. 
Published: April 2014

Abstract
The chemokine system has a critical role in mammalian immunity, but the evolutionary history of chemokines and chemokine receptors are ill-defined. We used comparative whole genome analysis of fruit fly, sea urchin, sea squirt, pufferfish, zebrafish, frog, and chicken to identify chemokines and chemokine receptors in each species. We report 127 chemokine and 70 chemokine receptor genes in the 7 species, with zebrafish having the most chemokines, 63, and chemokine receptors, 24. Fruit fly, sea urchin, and sea squirt have no identifiable chemokines or chemokine receptors. This study represents the most comprehensive analysis of the chemokine system to date and the only complete characterization of chemokine systems outside of mouse and human. We establish a clear evolutionary model of the chemokine system and trace the origin of the chemokine system to ∼650 million years ago, identifying critical steps in their evolution and demonstrating a more extensive chemokine system in fish than previously thought.
The Viral Protein A238L Inhibits TNF-α Expression through a CBP/p300 Transcriptional Coactivators Pathway
Authors: Granja Aitor G. , Nogal Maria L. , Hurtado Carolina , del Aguila Carmen , Carrascosa Angel L. , Salas María L. , Fresno Manuel , Revilla Yolanda 
Published: April 2014

Abstract
African swine fever virus (ASFV) is able to inhibit TNF-α-induced gene expression through the synthesis of A238L protein. This was shown by the use of deletion mutants lacking the A238L gene from the Vero cell-adapted Ba71V ASFV strain and from the virulent isolate E70. To further analyze the molecular mechanism by which the viral gene controls TNF-α, we have used Jurkat cells stably transfected with the viral gene to identify the TNF-α regulatory elements involved in the induction of the gene after stimulation with PMA and calcium ionophore. We have thus identified the cAMP-responsive element and κ3 sites on the TNF-α promoter as the responsible of the gene activation, and demonstrate that A238L inhibits TNF-α expression through these DNA binding sites. This inhibition was partially reverted by overexpression of the transcriptional factors NF-AT, NF-κB, and c-Jun. Furthermore, we present evidence that A238L inhibits the activation of TNF-α by modulating NF-κB, NF-AT, and c-Jun trans activation through a mechanism that involves CREB binding protein/p300 function, because overexpression of these transcriptional coactivators recovers TNF-α promoter activity. In addition, we show that A238L is a nuclear protein that binds to the cyclic AMP-responsive element/κ3 complex, thus displacing the CREB binding protein/p300 coactivators. Taken together, these results establish a novel mechanism in the control of TNF-α gene expression by a viral protein that could represent an efficient strategy used by ASFV to evade the innate immune response.
Helminth-Primed Dendritic Cells Alter the Host Response to Enteric Bacterial Infection
Authors: Chen Chien-Chang , Louie Steve , McCormick Beth A. , Walker W. Allan , Shi Hai Ning 
Published: April 2014

Abstract
To examine whether intestinal helminth infection may be a risk factor for enteric bacterial infection, a murine model was established using the intestinal helminth Heligomosomoides polygyrus and a murine pathogen Citrobacter rodentium, which causes infectious colitis. Using this model we recently have shown that coinfection with the Th2-inducing H. polygyrus and C. rodentium promotes bacterial-associated disease and colitis. In this study, we expand our previous observations and examine the hypothesis that dendritic cells (DC) stimulated by helminth infection may play an important role in the regulation of the intestinal immune response to concurrent C. rodentium infection as well as in the modulation of the bacterial pathogenesis. We show that H. polygyrus infection induces DC activation and IL-10 expression, and that adoptive transfer of parasite-primed DC significantly impairs host protection to C. rodentium infection, resulting in an enhanced bacterial infection and in the development of a more severe colonic injury. Furthermore, we demonstrate that adoptive transfer of parasite-primed IL-10-deficient DCs fails to result in the development of a significantly enhanced C. rodentium-mediated colitis. Similarly, when the DC IL-10 response was neutralized by anti-IL-10 mAb treatment in mice that received parasite-primed DC, no deleterious effect of the parasite-primed DC on the host intestinal response to C. rodentium was detected. Thus, our results provide evidence to indicate that the H. polygyrus-dependent modulation of the host response to concurrent C. rodentium infection involves IL-10-producing DCs.
Listeria monocytogenes Activated p38 MAPK and Induced IL-8 Secretion in a Nucleotide-Binding Oligomerization Domain 1-Dependent Manner in Endothelial Cells
Authors: Opitz Bastian , Püschel Anja , Beermann Wiebke , Hocke Andreas C. , Förster Stefanie , Schmeck Bernd , van Laak Vincent , Chakraborty Trinad , Suttorp Norbert , Hippenstiel Stefan 
Published: April 2014

Abstract
Nucleotide-binding oligomerization domain (Nod) proteins serve as intracellular pattern recognition molecules recognizing peptidoglycans. To further examine intracellular immune recognition, we used Listeria monocytogenes as an organism particularly amenable for studying innate immunity to intracellular pathogens. In contrast to wild-type L. monocytogenes, the nonpathogenic Listeria innocua, or L. monocytogenes mutants lacking internalin B or listeriolysin O, poorly invaded host cells and escaped into host cell cytoplasm, respectively, and were therefore used as controls. In this study, we show that only the invasive wild-type L. monocytogenes, but not the listeriolysin O- or internalin B-negative L. monocytogenes mutants or L. innocua, substantially induced IL-8 production in HUVEC. RNA interference and Nod1-overexpression experiments demonstrated that Nod1 is critically involved in chemokine secretion and NF-κB activation initiated by L. monocytogenes in human endothelial cells. Moreover, we show for the first time that Nod1 mediated activation of p38 MAPK signaling induced by L. monocytogenes. Finally, L. monocytogenes- and Nod1-induced IL-8 production was blocked by a specific p38 inhibitor. In conclusion, L. monocytogenes induced a Nod1-dependent activation of p38 MAPK signaling and NF-κB which resulted in IL-8 production in endothelial cells. Thus, Nod1 is an important component of a cytoplasmic surveillance pathway.
Functional Importance of Regional Differences in Localized Gene Expression of Receptors for IL-13 in Murine Gut
Authors: Morimoto Motoko , Morimoto Masahiro , Zhao Aiping , Madden Kathleen B. , Dawson Harry , Finkelman Fred D. , Mentink-Kane Margaret , Urban Joseph F. , Wynn Thomas A. , Shea-Donohue Terez 
Published: April 2014

Abstract
IL-13 induces a STAT6-dependent hypercontractility of intestinal smooth muscle that is mediated by binding to the IL-13Rα1 component of the type 2 IL-4R that is linked to STAT6. IL-13 also binds to the IL-13Rα2 that is not linked to STAT6 and functions to limit the effects of IL-13 in vivo. In this study we assessed the contributions of regional and cellular differences in the distribution of the IL-13R components to the physiological regulation of smooth muscle function in wild-type mice and mice deficient in STAT6 or IL-13Rα2. The expression of IL-13 and IL-13Rα2 was higher in colon than in small intestine. Laser capture microdissection of specific cell types revealed that the expression of IL-13Rα2 was higher in the smooth muscle layer compared with levels in the epithelial cells of the mucosa. In contrast, there was a uniform distribution of IL-13α1 in smooth muscle, epithelia, and myenteric neurons. The significant hypercontractility of smooth muscle in mice deficient in IL-13Rα2, but not in STAT6, shows the physiological importance of IL-13 binding to IL-13Rα2. The pronounced differences in the expression of IL-13Rα2 suggest that the gut has developed sophisticated mechanisms for controlling the physiological and pathophysiological activities of IL-13.
Integrin αIIbβ3 Induces the Adhesion and Activation of Mast Cells through Interaction with Fibrinogen
Authors: Oki Toshihiko , Kitaura Jiro , Eto Koji , Lu Yang , Maeda-Yamamoto Mari , Inagaki Naoki , Nagai Hiroichi , Yamanishi Yoshinori , Nakajina Hideaki , Kumagai Hidetoshi , Kitamura Toshio 
Published: April 2014

Abstract
Integrin αIIb, a well-known marker of megakaryocyte-platelet lineage, has been recently recognized on hemopoietic progenitors. We now demonstrate that integrin αIIbβ3 is highly expressed on mouse and human mast cells including mouse bone marrow-derived mast cells, peritoneal mast cells, and human cord blood-derived mast cells, and that its binding to extracellular matrix proteins leads to enhancement of biological functions of mast cells in concert with various stimuli. With exposure to various stimuli, including cross-linking of FcεRI and stem cell factor, mast cells adhered to extracellular matrix proteins such as fibrinogen and von Willebrand factor in an integrin αIIbβ3-dependent manner. In addition, the binding of mast cells to fibrinogen enhanced proliferation, cytokine production, and migration and induced uptake of soluble fibrinogen in response to stem cell factor stimulation, implicating integrin αIIbβ3 in a variety of mast cell functions. In conclusion, mouse and human mast cells express functional integrin αIIbβ3.
Endotoxin-Induced Expression of Murine Bactericidal Permeability/Increasing Protein Is Mediated Exclusively by Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β-Dependent Pathways
Authors: Eckert Melanie , Wittmann Irene , Röllinghoff Martin , Gessner André , Schnare Markus 
Published: April 2014

Abstract
Antimicrobial effector proteins are a key mechanism for the innate immune system to combat pathogens once they infect the host. We report the identification and cloning of the mouse homologue of human bactericidal permeability/increasing protein (BPI). Mouse BPI is constitutively expressed in lymphatic organs and tissues as well as in mouse testis. Upon stimulation with different TLR ligands, mouse BPI is strongly expressed in granulocytes and, surprisingly, in bone marrow-derived dendritic cells. Mouse BPI is most strongly induced by bacterial LPS through a signaling pathway that is completely dependent on TLR4-Toll/IL-1R domain-containing adaptor inducing IFN-β. Functional studies revealed that mouse BPI does have the potential to neutralize LPS and inhibits bacterial growth. Mouse BPI is expressed in granulocytes and bone marrow-derived dendritic cells, and the transcriptional activation is controlled by TLRs.
CD4+ T Lymphocytes Expressing CD40 Ligand Help the IgM Antibody Response to Soluble Pneumococcal Polysaccharides via an Intermediate Cell Type
Authors: Jeurissen Axel , Billiau An D. , Moens Leen , Shengqiao Li , Landuyt Willy , Wuyts Greet , Boon Louis , Waer Mark , Ceuppens Jan L. , Bossuyt Xavier 
Published: April 2014

Abstract
Streptococcus pneumoniae causes serious infections in children, the elderly, and immunocompromised patients. Protection against infections with S. pneumoniae is mediated through Abs against the capsular polysaccharides (caps-PS). We previously showed that the murine Ab response to caps-PS is dependent on CD40-CD40L interaction. In the present paper, we addressed the question of whether the CD40-CD40L-mediated modulation of the anti-caps-PS immune reaction is the result of a direct interaction between B lymphocytes and T lymphocytes or of an indirect interaction. SCID/SCID mice reconstituted with B lymphocytes from wild-type mice did not mount anti-caps-PS Abs. SCID/SCID mice reconstituted with B lymphocytes from wild-type mice and CD4+ T lymphocytes from wild-type mice but not CD4+ T lymphocytes from CD40L knockout mice stimulated the anti-caps-PS Ab response. This indicated that CD4+ T lymphocytes stimulated the anti-caps-PS Ab response in a CD40L-dependent manner. SCID/SCID mice reconstituted with B lymphocytes from CD40 knockout mice and CD4+ T lymphocytes from wild-type mice generated an anti-caps-PS Ab response that could be inhibited by MR1, a blocking anti-CD40L Ab. These data indicated that CD4+ T lymphocytes stimulated the anti-caps-PS Ab response in an indirect way. Finally, lethally irradiated CD40 knockout mice reconstituted with bone marrow from wild-type mice mounted an anti-caps-PS Ab response that was comparable to the Ab response in wild-type mice, revealing that the required CD40 was on hemopoietic cells. In conclusion, we provide evidence that CD4+ T lymphocytes expressing CD40L stimulate the Ab response to soluble caps-PS by interacting with CD40-expressing non-B cells.
Memory T Cell Populations in the Lung Airways Are Maintained by Continual Recruitment
Authors: Ely Kenneth H. , Cookenham Tres , Roberts Alan D. , Woodland David L. 
Published: April 2014

Abstract
Effector memory T cell populations in the periphery play a key role in cellular immune responses to secondary infections. However, it is unclear how these populations are maintained under steady-state conditions in nonlymphoid peripheral sites, such as the lung airways. In this study, we show that LFA-1 expression is selectively down-regulated following entry of memory T cells into the lung airways. Using Sendai virus as a mouse model of respiratory virus infection, we use LFA-1 expression levels to demonstrate that effector memory T cell populations in the lung airways are maintained by continual recruitment of new cells from the circulation. The rate of memory cell recruitment is surprisingly rapid, resulting in replacement of 90% of the population every 10 days, and is maintained for well over 1 year following viral clearance. These data indicate that peripheral T cell memory is dynamic and depends on a systemic source of T cells.
Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells
Authors: Hoyt Jeffrey C. , Ballering Janelle , Numanami Hiroki , Hayden John M. , Robbins Richard A. 
Published: April 2014

Abstract
Many effective therapeutic agents exhibit effects that are different from their intended primary mode of action. Antibiotics such as doxycycline and erythromycin A are no exception. They also display anti-inflammatory activity. Using LA4 murine lung alveolar epithelial cells, effects of doxycycline and erythromycin A on inducible NO synthase (iNOS) NO production as well as iNOS protein and mRNA production were investigated. Induction of iNOS was accomplished by treatment with cytomix (TNF-α, IL-1β, and IFN-γ each at 5 ng/ml). Production of NO or iNOS was not detected in controls with or without erythromycin A. In the presence of cytomix, erythromycin A did not decrease NO, nitrite, iNOS protein, or mRNA production. In contrast, doxycycline caused a dose-dependent decrease in NO, nitrite, iNOS protein, and mRNA production in cytomix-treated cells. Doxycycline at 30 μg/ml produced a 90% decrease in nitrite and NO production and a 52% decrease in iNOS mRNA transcription compared with cytomix treatment alone. Actinomycin D treatment suggests that doxycycline decreases stability of iNOS mRNA in cytomix-treated cells. To determine a mechanism for the decrease in iNOS expression, NF-κB and AP-1 transcription regulatory systems and p38 MAPK were examined. Doxycycline treatment gave no statistically significant change in NF-κB activation but did decrease p38 MAPK protein in cytomix-treated cells by 50%, suggesting that p38 MAPK may be responsible for stabilization of iNOS mRNA. These results demonstrate that doxycycline decreases NO production from iNOS by destabilization of iNOS mRNA via decreased expression of p38 MAPK.