bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disseminated and Rapidly Fatal Tuberculosis in Mice Bearing a Defective Allele at IFN Regulatory Factor 8
Authors: Marquis Jean-François , LaCourse Ronald , Ryan Lynn , North Robert J. , Gros Philippe 
Published: February 2009

Abstract
The interferon regulatory factor (IRF) family member IRF-8 participates in IFN-γ-dependent transcriptional activation of genes containing in their promoter regions IFN-stimulated response element or IFN-γ activation site elements. To test the role of IRF-8 in host defenses against tuberculosis, BXH-2 mice, which bear a defective IRF-8R294C allele, were challenged with low doses of virulent Mycobacterium tuberculosis via the i.v. and aerosol routes. BXH-2 mice were found to be extremely susceptible to M. tuberculosis, as demonstrated by rapid and uncontrolled microbial replication in spleen, liver, and lungs leading to very early death. The BXH-2 defect was expressed very early (10 days postinfection) as uncontrolled intracellular pathogen replication in NOS2-expressing lung macrophages, impaired granuloma formation, rapid dissemination of the infection to distant sites, and rapid necrosis of infected tissues. There was complete absence of IL-12p40 induction, severely reduced IFN-γ production, and impaired T cell priming in the lungs of infected BXH-2, highlighting the critical role of IRF-8 in this process. Collectively, these results identify IRF-8 as a critical regulator of host defenses against tuberculosis.
Gap Junction Communication between Autologous Endothelial and Tumor Cells Induce Cross-Recognition and Elimination by Specific CTL
Authors: Benlalam Houssem , Jalil Abdelali , Hasmim Meriem , Pang Baoxu , Tamouza Ryad , Mitterrand Michèle , Godet Yann , Lamerant Nathalie , Robert Caroline , Avril Marie-Françoise , Neefjes Jacques , Tursz Thomas , Mami-Chouaib Fathia , Kieda Claudine , Chouaib Salem 
Published: February 2009

Abstract
Cellular interactions in the tumor stroma play a major role in cancer progression but can also induce tumor rejection. To explore the role of endothelial cells in these interactions, we used an in vitro three-dimensional collagen matrix model containing a cytotoxic T lymphocyte CTL clone (M4.48), autologous tumor cells (M4T), and an endothelial cell (M4E) line that are all derived from the same tumor. We demonstrate in this study that specific killing of the endothelial cells by the CTL clone required the autologous tumor cells and involved Ag cross-presentation. The formation of gap junctions between endothelial and tumor cells is required for antigenic peptide transfer to endothelial cells that are then recognized and eliminated by CTL. Our results indicate that gap junctions facilitate an effective CTL-mediated destruction of endothelial cells from the tumor microenvironment that may contribute to the control of tumor progression.
Suppression of Autoimmune Diabetes by Soluble Galectin-1
Authors: Perone Marcelo J. , Bertera Suzanne , Shufesky William J. , Divito Sherrie J. , Montecalvo Angela , Mathers Alicia R. , Larregina Adriana T. , Pang Mabel , Seth Nilufer , Wucherpfennig Kai W. , Trucco Massimo , Baum Linda G. , Morelli Adrian E. 
Published: February 2009

AbstractType 1 diabetes (T1D) is a T cell-mediated autoimmune disease that targets the β-cells of the pancreas. We investigated the ability of soluble galectin-1 (gal-1), an endogenous lectin that promotes T cell apoptosis, to down-regulate the T cell response that destroys the pancreatic β-cells. We demonstrated that in nonobese diabetic (NOD) mice, gal-1 therapy reduces significantly the amount of Th1 cells, augments the number of T cells secreting IL-4 or IL-10 specific for islet cell Ag, and causes peripheral deletion of β-cell-reactive T cells. Administration of gal-1 prevented the onset of hyperglycemia in NOD mice at early and subclinical stages of T1D. Preventive gal-1 therapy shifted the composition of the insulitis into an infiltrate that did not invade the islets and that contained a significantly reduced number of Th1 cells and a higher percentage of CD4+ T cells with content of IL-4, IL-5, or IL-10. The beneficial effects of gal-1 correlated with the ability of the lectin to trigger apoptosis of the T cell subsets that cause β-cell damage while sparing naive T cells, Th2 lymphocytes, and regulatory T cells in NOD mice. Importantly, gal-1 reversed β-cell autoimmunity and hyperglycemia in NOD mice with ongoing T1D. Because gal-1 therapy did not cause major side effects or β-cell toxicity in NOD mice, the use of gal-1 to control β-cell autoimmunity represents a novel alternative for treatment of subclinical or ongoing T1D.
NK-Dependent Increases in CCL22 Secretion Selectively Recruits Regulatory T Cells to the Tumor Microenvironment
Authors: Mailloux Adam W. , Young M. Rita I. 
Published: February 2009

Abstract
Tumor-induced immune suppression involves the accumulation of immune-suppressive infiltrates in the microenvironment. This study demonstrates increased numbers of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in the lungs of C57BL/6 mice bearing a metastatic Lewis lung carcinoma (LLC) variant. These Tregs suppressed the proliferation of endogenous CD4+CD25− cells and expressed higher levels of the chemokine receptor CCR4 than other types of T cells. LLC-bearing lungs secreted elevated levels of the CCR4-associated chemokine CCL22 compared with normal lungs. However, CCL22 was not secreted by LLC or normal epithelial controls, suggesting that CCL22 is secreted by a nonepithelial component of the microenvironment. Migration assays revealed that medium conditioned by LLC-bearing lungs selectively recruited Tregs at higher frequencies than did medium conditioned by normal lungs. Neutralization of CCL22 significantly reduced this selective recruitment toward both conditioned media. A series of immunomagnetic isolations, FACS, and flow cytometric analyses were used to isolate different cellular fractions from both normal and LLC-bearing lungs. When isolated, only the NK-containing fractions secreted CCL22, and the same fraction isolated from LLC-bearing lungs secreted higher levels. Depletion of NK cells from both normal and LLC-bearing lung tissue significantly reduced CCL22 secretion, suggesting that a large portion of secreted CCL22 is NK cell dependent. Flow cytometric analysis of the lung NK compartments revealed no significant increase in NK cell numbers across LLC-bearing lung tissue as a whole as compared with normal tissue. However, immunofluorescent staining revealed an increased frequency of NK cells at the tumor periphery that were closely associated with the elevated FoxP3+ infiltrate.
NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells
Authors: Scheuplein Felix , Schwarz Nicole , Adriouch Sahil , Krebs Christian , Bannas Peter , Rissiek Björn , Seman Michel , Haag Friedrich , Koch-Nolte Friedrich 
Published: February 2009

AbstractExtracellular NAD+ and ATP trigger the shedding of CD62L and the externalization of phosphatidylserine on murine T cells. These events depend on the P2X7 ion channel. Although ATP acts as a soluble ligand to activate P2X7, gating of P2X7 by NAD+ requires ecto-ADP-ribosyltransferase ART2.2-catalyzed transfer of the ADP-ribose moiety from NAD+ onto Arg125 of P2X7. Steady-state concentrations of NAD+ and ATP in extracellular compartments are highly regulated and usually are well below the threshold required for activating P2X7. The goal of this study was to identify possible endogenous sources of these nucleotides. We show that lysis of erythrocytes releases sufficient levels of NAD+ and ATP to induce activation of P2X7. Dilution of erythrocyte lysates or incubation of lysates at 37°C revealed that signaling by ATP fades more rapidly than that by NAD+. We further show that the routine preparation of primary lymph node and spleen cells induces the release of NAD+ in sufficient concentrations for ART2.2 to ADP-ribosylate P2X7, even at 4°C. Gating of P2X7 occurs when T cells are returned to 37°C, rapidly inducing CD62L-shedding and PS-externalization by a substantial fraction of the cells. The “spontaneous” activation of P2X7 during preparation of primary T cells could be prevented by i.v. injection of either the surrogate ART substrate etheno-NAD or ART2.2-inhibitory single domain Abs 10 min before sacrificing mice.
Influenza Virus and Poly(I:C) Inhibit MHC Class I-Restricted Presentation of Cell-Associated Antigens Derived from Infected Dead Cells Captured by Human Dendritic Cells
Authors: Frleta Davor , Yu Chun I. , Klechevsky Eynav , Flamar Anne-Laure , Zurawski Gerard , Banchereau Jacques , Palucka A. Karolina 
Published: February 2009

Abstract
During viral infection, dendritic cells (DCs) capture infected cells and present viral Ags to CD8+ T cells. However, activated DCs might potentially present cell-associated Ags derived from captured dead cells. In this study, we find that human DCs that captured dead cells containing the TLR3 agonist poly(I:C) produced cytokines and underwent maturation, but failed to elicit autologous CD8+ T cell responses against Ags of dead cells. Accordingly, DCs that captured dead cells containing poly(I:C), or influenza virus, are unable to activate CD8+ T cell clones specific to cell-associated Ags of captured dead cells. CD4+ T cells are expanded with DCs that have captured poly(I:C)-containing dead cells, indicating the inhibition is specific for MHC class I-restricted cross-presentation. Furthermore, these DCs can expand naive allogeneic CD8+ T cells. Finally, soluble or targeted Ag is presented when coloaded onto DCs that have captured poly(I:C)-containing dead cells, indicating the inhibition is specific for dead cell cargo that is accompanied by viral or poly(I:C) stimulus. Thus, DCs have a mechanism that prevents MHC class I-restricted cross-presentation of cell-associated Ag when they have captured dead infected cells.
Nonresolving Inflammation in gp91phox−/− Mice, a Model of Human Chronic Granulomatous Disease, Has Lower Adenosine and Cyclic Adenosine 5′-Monophosphate
Authors: Rajakariar Ravindra , Newson Justine , Jackson Edwin K. , Sawmynaden Precilla , Smith Andrew , Rahman Farooq , Yaqoob Muhammad M. , Gilroy Derek W. 
Published: February 2009

AbstractIn chronic granulomatous disease (CGD), there is failure to generate reactive oxygen metabolites, resulting in recurrent infections and persistent inflammatory events. Because responses to sterile stimuli in murine models of CGD also result in nonresolving inflammation, we investigated whether defects in endogenous counterregulatory mechanisms and/or proresolution pathways contribute to the etiology of CGD. To this end, we conducted a series of experiments finding, in the first instance that adenosine and cAMP, which dampen innate immune-mediated responses, show a biphasic profile in resolving peritonitis; peaking at onset, waning as inflammation progresses, and rising again at resolution. We also found elevations in adenosine and cAMP in resolving human peritonitis. In gp91phox−/− mice, an experimental model of CGD, levels of adenosine and cAMP were significantly lower at onset and again at resolution. Corroborating the finding of others, we show that adenosine, signaling through its A2A receptor and therefore elevating cAMP, is not only anti-inflammatory, but, importantly, it does not impair proresolution pathways, properties typical of nonsteroidal anti-inflammatory drugs. Conversely, antagonizing the A2A receptor worsens acute inflammation and prolongs resolution. Taking this further, activating the A2A receptor in gp91phox−/− mice was dramatically anti-inflammatory regardless of the phase the inflammatory response A2A agonists were administered, i.e., onset or resolution, demonstrating wide and robust pharmacological flexibility that is unlikely to subvert proresolution pathways. Therefore, we describe the biphasic profile of adenosine and cAMP throughout the time course of acute inflammation that is dysregulated in CGD.
Chemotaxis and Phagocytosis in Neutrophils Is Independent of Coronin 1
Authors: Combaluzier Benoit , Pieters Jean 
Published: February 2009

Abstract
The WD repeat protein family member coronin 1 is exclusively expressed in leukocytes, where it colocalizes with the cortical cytoskeleton. Although initially coronin 1 was believed to regulate F-actin dynamics such as leukocyte motility, phagocytosis, and membrane ruffling, recent work showed that in macrophages, T cells, and B cells, coronin 1 is dispensable for these F-actin dependent processes, instead being involved in the regulation of calcium dependent signaling reactions. In this study, we show that in mice lacking coronin 1 neutrophil populations developed normally, and that coronin 1-deficient neutrophils are fully functional with respect to adherence, membrane dynamics, migration, phagocytosis and the oxidative burst. Therefore, these data argue against a role for coronin 1 in the modulation of F-actin and suggest that coronin 1 is dispensable for neutrophil functioning.
Genome-Wide Comparison between IL-17A- and IL-17F-Induced Effects in Human Rheumatoid Arthritis Synoviocytes
Authors: Zrioual Saloua , Ecochard René , Tournadre Anne , Lenief Vanina , Cazalis Marie-Angélique , Miossec Pierre 
Published: February 2009

AbstractIL-17A is implicated in rheumatoid arthritis (RA) pathogenesis; however, the contribution of IL-17F remains to be clarified. Using microarrays and gene-specific expression assays, we compared the regulatory effects of IL-17A and IL-17F alone or in combination with TNF-α on RA synoviocytes. IL-17A and IL-17F expression was studied in osteoarthritis and RA synovium by immunohistochemistry. The comparison between the IL-17A and IL-17F stimulatory effect on RA synoviocytes was assessed at the protein level by ELISA and at the mRNA level by microarrays and real-time RT-PCR. TNFRII expression was studied by real-time RT-PCR and immunofluorescence, and neutralizing Ab was used to analyze its contribution to CCL20 secretion. IL-17A and IL-17F were detected in plasma cell-like cells from RA but not osteoarthritis synovium. In microarrays, IL-17A and IL-17F alone had similar regulatory effects, IL-17F being quantitatively less active. Both cytokines induced a similar expression pattern in the presence of TNF-α. Based on a cooperation index, 130 and 203 genes were synergistically induced by IL-17A or IL-17F plus TNF-α, respectively. Among these, the new target genes CXCR4, LPL, and IL-32 were validated by real-time RT-PCR. IL-17A and IL-17F up-regulated TNFRII expression, but had no effects on TNFRI, IL-17RA or IL-17RC. TNFRII blockade inhibited the synergistic induction of CCL20 by IL-17A or IL-17F and TNF-α. IL-17A and IL-17F are both expressed in RA synovium. In the presence of TNF-α, they induced a similar expression pattern in RA synoviocytes. Accordingly, IL-17F appears as a target in Th17-mediated diseases such as RA.
Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity
Authors: Thiel Steffen , Kolev Martin , Degn Søren , Steffensen Rudi , Hansen Annette G. , Ruseva Marieta , Jensenius Jens C. 
Published: February 2009

Abstract
Mannan-binding lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune system. MASP-2 forms complexes with the pattern recognition molecules mannan-binding lectin (MBL), H-ficolin, L-ficolin, or M-ficolin, and is activated when one of these proteins recognizes microorganisms and subsequently cleaves complement factors C4 and C2, thus initiating the activation of the complement system. Missense polymorphisms of MASP-2 exist in different ethnic populations. To further characterize the nature of these, we have produced and characterized rMASP-2s representing the following naturally occurring polymorphisms: R99Q, D120G, P126L, H155R, 156_159dupCHNH (CHNHdup), V377A, and R439H. Only very low levels of CHNHdup were secreted from the cells, whereas quantities similar to wild-type MASP-2 were found intracellularly, indicating that this mutation results in a misfolded protein. We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL. Accordingly, when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed, whereas R99Q, P126L, and V377A cleaved C4 with an activity comparable to wild-type MASP-2 and H155R slightly better. In contrast, the R439H variant was deficient in this process despite its normal binding to MBL. This variant was also not able to autoactivate in the presence of MBL and mannan. We find the R439H variant is common in Sub-Saharan Africans with a gene frequency of 10%. Our results indicate that individuals with different types of MASP-2 defects may be identified through genotyping.
IL-17 Signaling-Independent Central Nervous System Autoimmunity Is Negatively Regulated by TGF-β
Authors: Gonzalez-García Ines , Zhao Yani , Ju Songguang , Gu Qin , Liu Lin , Kolls Jay K. , Lu Binfeng 
Published: February 2009

Abstract
Recent studies have established an important role of Th17 in induction of autoimmune diseases. We have found that although IL-17 receptor A (IL-17RA)−/− mice were resistant to experimental autoimmune encephalomyelitis, a small number of them developed milder clinical signs of this autoimmune disease. In addition, blockade of TGF-β in IL-17RA−/− mice resulted in much more severe clinical signs of experimental autoimmune encephalomyelitis and significantly increased parenchymal lymphocyte infiltration in the CNS. Furthermore, the number of autoreactive Th1 cells was greatly increased in the inflamed spinal cord of IL-17RA−/− mice. These data support a role of IL-17RA-independent mechanisms in causing autoimmunity and its regulation by TGF-β.
Subversion of Pulmonary Dendritic Cell Function by Paramyxovirus Infections
Authors: Guerrero-Plata Antonieta , Kolli Deepthi , Hong Chao , Casola Antonella , Garofalo Roberto P. 
Published: February 2009

Abstract
Lower respiratory tract infections caused by the paramyxoviruses human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are characterized by short-lasting virus-specific immunity and often long-term airway morbidity, both of which may be the result of alterations in the Ag-presenting function of the lung which follow these infections. In this study, we investigated whether hMPV and RSV experimental infections alter the phenotype and function of dendritic cell (DC) subsets that are recruited to the lung. Characterization of lung DC trafficking demonstrated a differential recruitment of plasmacytoid DC (pDC), conventional DC (cDC), and IFN-producing killer DC to the lung and draining lymph nodes after hMPV and RSV infection. In vitro infection of lung DC indicated that in pDC, production of IFN-α, TNF-α, and CCL5 was induced only by hMPV, whereas CCL3 and CCL4 were induced by both viruses. In cDC, a similar repertoire of cytokines was induced by hMPV and RSV, except for IFN-β, which was not induced by RSV. The function of lung pDC was altered following hMPV or RSV infection in vivo, as we demonstrated a reduced capacity of lung pDC to produce IFN-α as well as other cytokines including IL-6, TNF-α, CCL2, CCL3, and CCL4 in response to TLR9 stimulation. Moreover, we observed an impaired capacity of cDC from infected mice to present Ag to CD4+ T cells, an effect that lasted beyond the acute phase of infection. Our findings suggest that acute paramyxovirus infections can alter the long-term immune function of pulmonary DC.
Activation of Inflammasomes Requires Intracellular Redistribution of the Apoptotic Speck-Like Protein Containing a Caspase Recruitment Domain
Authors: Bryan Nicole B. , Dorfleutner Andrea , Rojanasakul Yon , Stehlik Christian 
Published: February 2009

Abstract
Activation of caspase 1 is essential for the maturation and release of IL-1β and IL-18 and occurs in multiprotein complexes, referred to as inflammasomes. The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is the essential adaptor protein for recruiting pro-caspase 1 into inflammasomes, and consistently gene ablation of ASC abolishes caspase 1 activation and secretion of IL-1β and IL-18. However, distribution of endogenous ASC has not yet been examined in detail. In the present study, we demonstrated that ASC localized primarily to the nucleus in resting human monocytes/macrophages. Upon pathogen infection, ASC rapidly redistributed to the cytosol, followed by assembly of perinuclear aggregates, containing several inflammasome components, including caspase 1 and Nod-like receptors. Prevention of ASC cytosolic redistribution completely abolished pathogen-induced inflammasome activity, which affirmed that cytosolic localization of ASC is essential for inflammasome function. Thus, our study characterized a novel mechanism of inflammasome regulation in host defense.
Transitional B Cells Exhibit a B Cell Receptor-Specific Nuclear Defect in Gene Transcription
Authors: Andrews Sarah F. , Rawlings David J. 
Published: February 2009

Abstract
The signaling programs that enforce negative selection in early transitional (T1) B cells in response to BCR engagement remain poorly defined. We conducted a comprehensive comparison of BCR signaling in T1 vs follicular mature splenic B cells. T1, in contrast to follicular mature B cells, failed to express key NF-κB target genes in response to BCR engagement and exhibited a striking defect in assembly of an active transcriptional complex at the promoter of the survival and proliferative genes A1 and c-Myc. Surprisingly, and contrary to previous models, classical protein kinase C and IκB kinase activation, NF-κB nuclear translocation and DNA binding were intact in T1 B cells. Furthermore, despite a marked reduction in NFAT1 expression, differential NFAT or AP-1 activation cannot explain this transcriptional defect. Our combined findings demonstrate that T1 B cells are programmed for signal- and stage-specific “nuclear nonresponsiveness” upon encounter with self-Ags.
Bone Marrow Monocyte PECAM-1 Deficiency Elicits Increased Osteoclastogenesis Resulting in Trabecular Bone Loss
Authors: Wu Yue , Tworkoski Kathryn , Michaud Michael , Madri Joseph A. 
Published: February 2009

Abstract
In our investigations of the bone marrow (BM) of PECAM-1 null (knockout, KO) mice, we observed that the trabecular bone volume and number of trabeculae were significantly reduced in femural and tibial long bones. Further studies in vitro revealed increased numbers and size of osteoclasts, enhanced bone resorption on dentin substrates, and hypersensitivity to macrophage CSF and receptor activator of NF-κB ligand in BM-derived osteoclast precursor cultures from KO mice. Associations among PECAM-1, Syk, and SHP-1 were found in wild-type BM monocyte derived osteoclast-like cells. The absence of PECAM-1 and SHP-1 interactions in the KO cells leads to the dysregulation of Syk kinases and/or phosphatases, possibly SHP-1. Indeed, KO derived osteoclast-like cells exhibited increased Syk tyrosine phosphorylation levels compared with WT cells. Lastly, WT mice engrafted with marrow from KO kindred showed loss of trabecular bone analogous to KO mice, consistent with increased osteoclastogenesis.