bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role of Apoptotic Speck Protein Containing a Caspase Recruitment Domain (ASC) and NLRP3 in Causing Necrosis and ASC Speck Formation Induced by Porphyromonas gingivalis in Human Cells
Authors: Huang Max Tze-Han , Taxman Debra J. , Holley-Guthrie Elizabeth A. , Moore Chris B. , Willingham Stephen B. , Madden Victoria , Parsons Rebecca Keyser , Featherstone Gerald L. , Arnold Roland R. , O'Connor Brian P. , Ting Jenny Pan-Yun 
Published: February 2009

Abstract
Periodontal disease is a chronic inflammatory disorder that leads to the destruction of tooth-supporting tissue and affects 10–20 million people in the U.S. alone. The oral pathogen Porphyromonas gingivalis causes inflammatory host response leading to periodontal and other secondary inflammatory diseases. To identify molecular components that control host response to P. gingivalis in humans, roles for the NLR (NBD-LRR) protein, NLRP3 (cryopyrin, NALP3), and its adaptor apoptotic speck protein containing a C-terminal caspase recruitment domain (ASC) were studied. P. gingivalis strain A7436 induces cell death in THP1 monocytic cells and in human primary peripheral blood macrophages. This process is ASC and NLRP3 dependent and can be replicated by P. gingivalis LPS and Escherichia coli. P. gingivalis-induced cell death is caspase and IL-1 independent and exhibits morphological features consistent with necrosis including loss of membrane integrity and release of cellular content. Intriguingly, P. gingivalis-induced cell death is accompanied by the formation of ASC aggregation specks, a process not previously described during microbial infection. ASC specks are observed in P. gingivalis-infected primary human mononuclear cells and are dependent on NLRP3. This work shows that P. gingivalis causes ASC- and NLRP3-dependent necrosis, accompanied by ASC speck formation.
Cutting Edge: Phenotypic Characterization and Differentiation of Human CD8+ T Cells Producing IL-17
Authors: Kondo Takaaki , Takata Hiroshi , Matsuki Fumichika , Takiguchi Masafumi 
Published: February 2009

Abstract
Although IL-17-producing CD8+ T cells (Tc17 cells) have recently been identified, the detailed information about these cells still remains unclear. In this article we describe a study investigating the phenotype and differentiation of human Tc17 cells. Human Tc17 cells were detected in a minor population of CD8+ T cells and were predominantly found in CD27−/+CD28+CD45RA− memory subsets. They also expressed CCR6 and a high level of CCR5. Though most Tc17 cells produced IFN-γ, a small part of the Tc17 cell population was IFN-γ negative in some individuals. Analysis of the in vitro induction of Tc17 cells showed that these cells were induced from the CD27+CD28+CD45RA+ naive subset and that they expressed the CD27−CD28+CD45RA− and CCR6+ phenotype. These results together indicate that Tc17 cells have a unique phenotype and suggest that they differentiate from the same precursors that differentiate into IFN-γ-producing CD8+ T cells.
Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway
Authors: Kim Ju-Hyun , Kim Seon-Ju , Lee Im-Soon , Lee Myung-Shik , Uematsu Satoshi , Akira Shizuo , Oh Kwon Ik 
Published: February 2009

Abstract
Sepsis is a devastating condition characterized by a systemic inflammatory response. Recently, high mobility group box 1 (HMGB1) was identified as a necessary and sufficient mediator of the lethal systemic inflammation caused by sepsis. However, despite its clinical importance, the mechanism of HMGB1 release has remained to be elusive. In this study, we demonstrate that the IFN-β-mediated JAK/STAT pathway is essential for LPS or Escherichia coli-induced HMGB1 release, which is dependent on Toll/IL-1R domain-containing adapter-inducing IFN-β adaptor. Additionally, we show that NO acts as a downstream molecule of the IFN-β signaling. Furthermore, the JAK inhibitor treatment as well as the STAT-1 or IFN-β receptor deficiency reduced HMGB1 release in a murine model of endotoxemia. Our results suggest that HMGB1 release in sepsis is dependent on the IFN-β signaling axis; thus, therapeutic agents that selectively inhibit IFN-β signaling could be beneficial in the treatment of sepsis.
The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils
Authors: Marois Louis , Vaillancourt Myriam , Marois Sébastien , Proulx Sophie , Paré Guillaume , Rollet-Labelle Emmanuelle , Naccache Paul H. 
Published: February 2009

Abstract
Little is known about the mechanisms that arrest FcγRIIa signaling in human neutrophils once engaged by immune complexes or opsonized pathogens. In our previous studies, we observed a loss of immunoreactivity of Abs directed against FcγRIIa following its cross-linking. In this study, we report on the mechanisms involved in this event. A stimulated internalization of FcγRIIa leading to the down-regulation of its surface expression was observed by flow cytometry and confocal microscopy. Immunoprecipitation of the receptor showed that FcγRIIa is ubiquitinated after stimulation. MG132 and clasto-lactacystin β-lactone inhibited the loss of immunoreactivity of FcγRIIa, suggesting that this receptor was down-regulated via the proteasomal pathway. The E3 ubiquitin ligase c-Cbl was found to translocate from the cytosol to the plasma membrane following receptor cross-linking. Furthermore, c-Cbl was recruited to the same subset of high-density, detergent-resistant membrane fractions as stimulated FcγRIIa itself. Silencing the expression of c-Cbl by small interfering RNA decreased FcγRIIa ubiquitination and prevented its degradation without affecting the internalisation process. It also prolonged the stimulation of the tyrosine phosphorylation response to the cross-linking of the receptor. We conclude that c-Cbl mediates the ubiquitination of stimulated FcγRIIa and thereby contributes to the termination of FcγRIIa signaling via its proteasomal degradation, thus leading to the down-regulation of neutrophil signalisation and function (phagocytosis) through this receptor.
CD8+ T Cell Responses to a Viral Escape Mutant Epitope: Active Suppression via Altered SHP-1 Activity
Authors: Schnell Frederick J. , Alberts-Grill Noah , Evavold Brian D. 
Published: February 2009

Abstract
One mechanism viruses use to subvert immune surveillance is through mutation of MHC contact residues of antigenic epitopes that weaken T cell recognition to the point that the immune system is ignorant of the infection. However, in contrast to ignorance, results presented herein demonstrate that intracellular signaling does occur upon stimulation with a lymphocytic choriomeningitis virus-derived escape mutant as demonstrated by the sustained activation of Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1). In addition to the increased SHP-1 activity, we found that the mutated epitope failed to induce oxidation of SHP-1, further enhancing enzymatic activity. Sustained activation of SHP-1 in a reduced form correlated with ERK and early growth response gene 1 activation and failure of T cells to commit to the effector lineage. Thus, instead of immune ignorance, these studies demonstrate the activation of a negative signaling pathway that actively suppresses T cell responses and limits recognition of viral escape mutants.
Coronin 1 Is Essential for IgM-Mediated Ca2+ Mobilization in B Cells but Dispensable for the Generation of Immune Responses In Vivo
Authors: Combaluzier Benoit , Mueller Philipp , Massner Jan , Finke Daniela , Pieters Jean 
Published: February 2009

Abstract
Coronin 1 is a leukocyte specific regulator of Ca2+-dependent signaling and is essential for the survival of peripheral T lymphocytes, but its role in B cells is unknown. In this study, we show that coronin 1 is essential for intracellular Ca2+ mobilization and proliferation upon triggering of the BCR. However, the presence of costimulatory signals rendered coronin 1 dispensable for B cell signaling, consistent with the generation of normal immune responses against a variety of Ags in coronin 1-deficient mice. We conclude that coronin 1, while being essential for T cell function and survival, is dispensable for B cell function in vivo.
Human IgA-Inducing Protein from Dendritic Cells Induces IgA Production by Naive IgD+ B Cells
Authors: Endsley Mark A. , Njongmeta Leo M. , Shell Elisabeth , Ryan Matthew W. , Indrikovs Alexander J. , Ulualp Seckin , Goldblum Randall M. , Mwangi Waithaka , Estes D. Mark 
Published: February 2009

Abstract
Over the last several years, there has been a great deal of progress in characterizing the role of dendritic cells (DCs) in the activation and modulation of B cells. DC-secreted chemokines can induce B cell trafficking to the lymph nodes. DC-produced survival factors such as B cell-activating factor of the TNF family and a proliferation-inducing ligand have been shown to be essential for B cell maturation, but have also been implicated in class-switch recombination and B cell lymphoma survival. Recently added to this list of DC-derived factors effecting B cells is IgA-inducing protein (IGIP). In this study, we characterize production of IGIP by human DCs, and examine its capacity to induce IgA class switching and differentiation of naive B cells in vitro. Monocyte-derived DCs were cultured in vitro with TLR agonists (TLR3, 4, 5, and 9) and other factors, including CD40 ligand, GM-CSF, and IL-4 as well as the neuropeptide vasoactive intestinal peptide. Under in vitro stimulation with vasoactive intestinal peptide and CD40L, IGIP mRNA expression could be up-regulated as much as 35-fold above nonstimulated samples within 12–48 h. Naive B cells cultured with exogenous recombinant human IGIP produced IgA in greater quantities than nonstimulated controls. Finally, we demonstrate that IGIP stimulation drives the production of μ-α switch circles from IgM+IgD+ naive human B cells, indicating its role as an IgA switch factor.
Lactate Boosts TLR4 Signaling and NF-κB Pathway-Mediated Gene Transcription in Macrophages via Monocarboxylate Transporters and MD-2 Up-Regulation
Authors: Samuvel Devadoss J. , Sundararaj Kamala P. , Nareika Alena , Lopes-Virella Maria F. , Huang Yan 
Published: February 2009

Abstract
It has been shown that lactate induces insulin resistance. However, the underlying mechanisms have not been well understood. Based on our observation that lactate augments LPS-stimulated inflammatory gene expression, we proposed that lactate may enhance TLR4 signaling in macrophages, which has been shown to play an important role in insulin resistance in adipocytes. In this study, we demonstrated that lactate stimulated MD-2, a coreceptor for TLR4 signaling activation, NF-κB transcriptional activity, and the expression of inflammatory genes in human U937 histiocytes (resident macrophages). Similar enhancement of the inflammatory gene expression by lactate was also observed in human monocyte-derived macrophages. The essential role of MD-2 in lactate-augmented TLR4 signaling was confirmed by observation that the suppression of MD-2 expression by small interfering RNA led to significant inhibition of inflammatory gene expression. To further elucidate how lactate treatment enhances TLR4 activation, we showed that the augmentation of inflammatory gene expression by lactate was abrogated by antioxidant treatment, suggesting a critical role of reactive oxygen species in the enhancement of TLR4 activation by lactate. Finally, we showed that α-cyano-4-hydroxycinnamic acid, a classic inhibitor for monocarboxylate transporters, blocked lactate-augmented inflammatory gene expression and nuclear NF-κB activity, indicating that lactate transport through monocarboxylate transporters is required for lactate-enhanced TLR4 activation. Collectively, this study documents that lactate boosts TLR4 activation and NF-κB-dependent inflammatory gene expression via monocarboxylate transporters and MD-2 up-regulation.
Regulatory T Cells: A Role in the Control of Helminth-Driven Intestinal Pathology and Worm Survival
Authors: D'Elia Riccardo , Behnke Jerzy M. , Bradley Janette E. , Else Kathryn J. 
Published: February 2009

Abstract
The chronic nature of intestinal nematode infections suggests that these parasites have evolved sophisticated immunomodulatory strategies. The induction of regulatory responses during chronic helminth infections could be advantageous to the host by minimizing damage incurred by these organisms. Regulation of the host immune response to infection could however be exploited by parasites as a survival strategy. We have explored both these aspects using the murine model of whipworm infection, Trichuris muris. Of the three laboratory isolates of T. muris in use, two (the E (Edinburgh) and J (Japan, subcultured from E)) are readily expelled by C57BL/6 mice, whereas the third, the S isolate (Sobreda, isolated from wild mice in Portugal) survives for much longer. The existence of the T. muris isolates thus presents a powerful tool to explore the mechanisms underlying chronic infection in a single strain of mouse. In this study, we show that S isolate-infected mice have increased numbers of Foxp3+ T cells in the gut compared with mice infected with the E isolate. Treatment of mice infected with the S isolate with either anti-CD25 or anti-glucocorticoid-induced TNFR exacerbated intestinal pathology, and, in addition, mice treated with anti-glucocorticoid-induced TNFR were able to expel worms more rapidly, implying the release of local effector mechanisms from a regulatory influence. Thus, our data show for the first time that T regulatory cells protect the host from worm-driven intestinal pathology. In addition, our data reveal a subversion of this damage-limiting response by the S isolate to facilitate its own survival.
Dendritic Cells and Monocyte/Macrophages That Create the IL-6/APRIL-Rich Lymph Node Microenvironments Where Plasmablasts Mature
Authors: Mohr Elodie , Serre Karine , Manz Rudolf A. , Cunningham Adam F. , Khan Mahmood , Hardie Deborah L. , Bird Roger , MacLennan Ian C. M. 
Published: February 2009

Abstract
IL-6 and APRIL influence the growth, differentiation, and survival of normal and neoplastic Ab-forming cells (AFC). In this study, we identify two subsets of myeloid cells that associate with the AFC and are the main producers of these factors during a T-dependent Ab response to alum-precipitated protein in mouse lymph nodes. First CD11c+CD8α− dendritic cells located in the perivascular area of the T zone provide about half of the IL-6 mRNA produced in the node together with significant amounts of APRIL mRNA. The number of these cells increases during the response, at least in part due to local proliferation. The second subset comprises Gr1+CD11b+F4/80+ monocyte/macrophages. These colonize the medullary cords during the response and are the other main IL-6 mRNA producers and the greatest source of APRIL mRNA. This medullary cord monocyte/macrophage subset results in local increase of APRIL mRNA that mirrors the polarity of CXCL12 expression in the node. The distribution of these myeloid cell subsets correlates with a gradient of AFC maturation assessed by progressive loss of Ki67 as AFC pass from the B cell follicle along the perivascular areas to the medullary cords.
IL-21: An Executor of B Cell Fate
Authors: Konforte Danijela , Simard Nathalie , Paige Christopher J. 
Published: February 2009

Abstract
IL-21 is a type I cytokine that shares the common receptor γ-chain with IL-2, IL-4, IL-7, IL-9, and IL-15. B cells are one of the lymphoid cell types whose development and function are regulated by IL-21. Depending on the interplay with costimulatory signals and on the developmental stage of a B cell, IL-21 can induce proliferation, differentiation into Ig-producing plasma cells, or apoptosis in both mice and humans. Alone and in combination with Th cell-derived cytokines IL-21 can regulate class switch recombination to IgG, IgA, or IgE isotypes, indicating its important role in shaping the effector function of B cells. This review highlights the role of IL-21 in B cell development, function, and disease and provides some perspectives on the future studies in this area.
γδ T Lymphocyte Homeostasis Is Negatively Regulated by β2-Microglobulin
Authors: French Jena D. , Roark Christina L. , Born Willi K. , O'Brien Rebecca L. 
Published: February 2009

AbstractSuccessful application of γδ T cells in adoptive cell therapies depends upon our ability to maintain these cells in vivo. Using an adoptive transfer model to study lymphopenia-induced homeostatic expansion, we show that CD8+ and NK1.1+ γδ T cell subsets are differentially regulated. While CD8+ γδ T cells have an early and sustained advantage following transfer into TCRβ−/−/δ−/− mice, NK1.1+ γδ T cells proliferate slowly and are maintained at low numbers. The advantage of the CD8+ subset could not be explained by increased bcl-2 or cytokine receptor expression but did correlate with Vγ4+ and Vδ5+ expression. Despite the role of CD8 in MHC class I recognition by αβ T cells, β2-microglobulin (β2m)-associated MHC class I molecules were not required for CD8+ γδ T cell homeostatic expansion. Surprisingly, all γδ T cells, including the CD8+ subset, exhibited enhanced proliferation following adoptive transfer into Rag1−/−/β2m−/− compared with Rag1−/− recipients. This effect was most notable for the NK1.1+ subset, which expresses high levels of NKG2A/CD94 and Ly49. Although expression of these inhibitory receptors correlated with poor homeostatic expansion in the presence of β2m, γδ T cell homeostatic proliferation in TCRβ−/−/δ−/− mice was not altered in the presence of Ly49C/I- and NKG2-blocking Abs. While the mechanism by which β2m negatively regulates γδ T cell homeostasis remains to be determined, this observation is unique to γδ T cells and confirms that multiple mechanisms are in place to maintain strict regulation of both the size and the composition of the γδ T cell pool.
Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice
Authors: Spach Karen M. , Blake Melissa , Bunn Janice Y. , McElvany Ben , Noubade Rajkumar , Blankenhorn Elizabeth P. , Teuscher Cory 
Published: February 2009

Abstract
Multiple sclerosis is a sexually dimorphic, demyelinating disease of the CNS, and experimental allergic encephalomyelitis (EAE) is its principal autoimmune model. Young male SJL/J mice are relatively resistant to EAE whereas older males and SJL/J females of any age are susceptible. By comparing a wide age range of proteolipid protein peptide 139–151 immunized mice, we found that female disease severity remains constant with age. In contrast, EAE disease severity increases with age in SJL/J males, with young males having significantly less severe disease and older males having significantly more disease than equivalently aged females. To determine whether the Y chromosome contributes to this sexual dimorphism, EAE was induced in consomic SJL/J mice carrying a B10.S Y chromosome (SJL.YB10.S). EAE was significantly more severe in young male SJL.YB10.S mice compared with young male SJL/J mice. These studies show that a Y chromosome-linked polymorphism controls the age-dependent EAE sexual dimorphism observed in SJL/J mice.
Specific Targeting of the EBV Lytic Phase Protein BNLF2a to the Transporter Associated with Antigen Processing Results in Impairment of HLA Class I-Restricted Antigen Presentation
Authors: Horst Daniëlle , van Leeuwen Daphne , Croft Nathan P. , Garstka Malgorzata A. , Hislop Andrew D. , Kremmer Elisabeth , Rickinson Alan B. , Wiertz Emmanuel J. H. J. , Ressing Maaike E. 
Published: February 2009

Abstract
EBV persists for life in the human host while facing vigorous antiviral responses that are induced upon primary infection. This persistence supports the idea that herpesviruses have acquired dedicated functions to avoid immune elimination. The recently identified EBV gene product BNLF2a blocks TAP. As a result, reduced amounts of peptides are transported by TAP from the cytoplasm into the endoplasmic reticulum (ER) lumen for binding to newly synthesized HLA class I molecules. Thus, BNLF2a perturbs detection by cytotoxic T cells. The 60-aa-long BNLF2a protein prevents the binding of both peptides and ATP to TAP, yet further mechanistic insight is, to date, lacking. In this study, we report that EBV BNLF2a represents a membrane-associated protein that colocalizes with its target TAP in subcellular compartments, primarily the ER. In cells devoid of TAP, expression levels of BNLF2a protein are greatly diminished, while ER localization of the remaining BNLF2a is retained. For interactions of BNLF2a with the HLA class I peptide-loading complex, the presence of TAP2 is essential, whereas tapasin is dispensible. Importantly, we now show that in B cells supporting EBV lytic replication, the BNLF2a protein is expressed early in infection, colocalizing and associating with the peptide-loading complex. These results imply that, during productive EBV infection, BNLF2a contributes to TAP inhibition and surface HLA class I down-regulation. In this way, EBV BNLF2a-mediated evasion from HLA class I-restricted T cell immunity contributes to creating a window for undetected virus production.
Human Liver Dendritic Cells Promote T Cell Hyporesponsiveness
Authors: Bamboat Zubin M. , Stableford Jennifer A. , Plitas George , Burt Bryan M. , Nguyen Hoang M. , Welles Alexander P. , Gonen Mithat , Young James W. , DeMatteo Ronald P. 
Published: February 2009

Abstract
The liver is believed to promote tolerance, which may be beneficial due to its constant exposure to foreign Ags from the portal circulation. Although dendritic cells (DCs) are critical mediators of immune responses, little is known about human liver DCs. We compared freshly purified liver DCs from surgical specimens with autologous blood DCs. Liver and blood DCs were equally immature, but had distinct subset compositions. BDCA-1+ DCs represented the most prevalent liver DC subset, whereas the majority of peripheral blood DCs were CD16+. Upon TLR4 ligation, blood DCs secreted multiple proinflammatory cytokines, whereas liver DCs produced substantial amounts of IL-10. Liver DCs induced less proliferation of allogeneic T cells both in a primary MLR and after restimulation. Similarly, Ag-specific CD4+ T cells were less responsive to restimulation when initially stimulated by autologous liver DCs rather than blood DCs. In addition, liver DCs generated more suppressive CD4+CD25+FoxP3+ T regulatory cells and IL-4-producing Th2 cells via an IL-10-dependent mechanism. Our findings are critical to understanding hepatic immunity and demonstrate that human liver DCs promote immunologic hyporesponsiveness that may contribute to hepatic tolerance.