bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lupus Serum IgG Induces Skin Inflammation through the TNFR1 Signaling Pathway
Authors: Deng Guo-Min , Liu Lena , Kyttaris Vasileios C. , Tsokos George C. 
Published: May 2010

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high autoantibody levels and multiorgan tissue damage, including kidney and skin. Cutaneous manifestations are frequent in patients with SLE, yet the etiology and pathogenesis of skin injury in SLE remains unclear. We reasoned that lupus serum containing high levels of autoreactive Ig contributes to skin injury. In this article, we report that serum from SLE patients and lupus-prone mice induces skin inflammation following intradermal injection into normal mice. Lupus serum depleted of IgG failed to cause skin inflammation. Monocytes, but not lymphocytes, were found to be crucial in the development of lupus serum-induced skin inflammation, and lupus serum IgG induced monocyte differentiation into dendritic cells (DCs). TNF-α and TNFR1, but not TNFR2, were required for the development of lupus serum-induced skin inflammation. TNFR1, not TNFR2, represented the main molecule expressed in the skin lesions caused by injected lupus serum. Our studies demonstrated that lupus serum IgG causes skin injury by involving the TNFR1 signaling pathway and monocyte differentiation to DCs. Accordingly, disruption of the TNFR1-mediated signaling pathway and blockade of DC generation may prove to be of therapeutic value in patients with cutaneous lupus erythematosus.
Fusion Proteins for Versatile Antigen Targeting to Cell Surface Receptors Reveal Differential Capacity to Prime Immune Responses
Authors: Kratzer Roland , Mauvais François-Xavier , Burgevin Anne , Barilleau Émilie , van Endert Peter 
Published: May 2010

Abstract
Targeting of proteins to APCs is an attractive strategy for eliciting adaptive immune responses. However, the relationship between the choice of the targeted receptor and the quality and quantity of responses remains poorly understood. We describe a strategy for expression of Ags including hydrophobic proteins as soluble fusion proteins that are optimized for proteasome-dependent MHC class I-restricted cross-presentation and form stable complexes with a wide variety of targeting Abs. Upon s.c. immunization, these complexes were initially taken up by CD169+ lymph node subcapsular sinus macrophages. In the OVA model system, receptor-targeted antigenic complexes primed specific T and B cell responses in vitro and in vivo at least 100-fold more efficiently than Ag alone. Comparison of 10 targeting receptors allowed us to establish a ranking with respect to priming of CD8+ T cell responses and demonstrated striking differences with respect to the relative efficacy of CD8+ and CD4+ T cell subset and B cell priming. The described fusion proteins should help in developing optimized strategies for targeted delivery of protein Ags in the context of tolerization or vaccination.
Increased Hematopoietic Cells in the mertk−/− Mouse Peritoneal Cavity: A Result of Augmented Migration
Authors: Williams Julie C. , Wagner Nikki J. , Earp H. Shelton , Vilen Barbara J. , Matsushima Glenn K. 
Published: May 2010

Abstract
The peritoneal cavity is recognized as an important site for autoreactive B cells prior to their transit to other immune tissues; however, little is known of the genes that may regulate this process. Mice lacking the receptor tyrosine kinase, Mertk, display a lupus-like autoimmune phenotype with splenomegaly and high autoantibodies titers. In this study, we investigate whether Mertk regulates the composition of peritoneal cells that favor an autoimmune phenotype. We found an increase in the number of macrophages, dendritic cells (DCs), plasmacytoid DCs, T cells, and B cells in the peritoneal cavity of mertk−/− mice when compared with wild-type mice. This disparity in cell numbers was not due to changes in cell proliferation or cell death. In adoptive transfer experiments, we showed an increase in migration of labeled donor cells into the mertk−/− peritoneal cavity. In addition, bone marrow chimeric mice showed hematopoietic-derived factors were also critical for T cell migration. Consistent with this migration and the increase in the number of cells, we identified elevated expression of CXCL9, its receptor CXCR3, and IL-7R on peritoneal cells from mertk−/− mice. To corroborate the migratory function of CXCR3 on cells, the depletion of CXCR3 donor cells significantly reduced the number of adoptively transferred cells that entered into the peritoneum of mertk−/− mice. This control of peritoneal cells numbers correlated with autoantibody production and was exclusively attributed to Mertk because mice lacking other family members, Axl or Tyro 3, did not display dysregulation in peritoneal cell numbers or the autoimmune phenotype.
The Differential Evolutionary Dynamics of Avian Cytokine and TLR Gene Classes
Authors: Downing Tim , Lloyd Andrew T. , O’Farrelly Cliona , Bradley Daniel G. 
Published: May 2010

Abstract
The potential for investigating immune gene diversity has been greatly enhanced by recent advances in sequencing power. In this study, variation at two categories of avian immune genes with differing functional roles, pathogen detection and mediation of immune mechanisms, was examined using high-throughput sequencing. TLRs identify and alert the immune system by detecting molecular motifs that are conserved among pathogenic microorganisms, whereas cytokines act as mediators of resulting inflammation and immunity. Nine genes from each class were resequenced in a panel of domestic chickens and wild jungle fowl (JF). Tests on population-wide genetic variation between the gene classes indicated that allele frequency spectra at each group were distinctive. TLRs showed evidence pointing toward directional selection, whereas cytokines had signals more suggestive of frequency-dependent selection. This difference persisted between the distributions considering only coding sites, suggesting functional relevance. The unique patterns of variation at each gene class may be constrained by their different functional roles in the immune response. TLRs identify a relatively limited number of exogeneous pathogenic-related patterns and would be required to adapt quickly in response to evolving novel microbes encountered in new environmental niches. In contrast, cytokines interact with many molecules in mediating the power of immune mechanisms, and accordingly respond to the selective stimuli of many infectious diseases. Analyses also indicated that a general pattern of high variability has been enhanced by widespread genetic exchange between chicken and red JF, and possibly between chicken and gray JF at TLR1LA and TLR2A.
CommensalEscherichia coliReduces Epithelial Apoptosis through IFN-αA–Mediated Induction of Guanylate Binding Protein-1 in Human and Murine Models of Developing Intestine
Authors: Mirpuri Julie , Brazil Jennifer C. , Berardinelli Andrew J. , Nasr Tala R. , Cooper Kiesha , Schnoor Michael , Lin Patricia W. , Parkos Charles A. , Louis Nancy A. 
Published: May 2010

AbstractAppropriate microbial colonization protects the developing intestine by promoting epithelial barrier function and fostering mucosal tolerance to luminal bacteria. Commensal flora mediate their protective effects through TLR9-dependent activation of cytokines, such as type I IFNs (α, β) and IL-10. Although IFN-β promotes apoptosis, IFN-α activates specific antiapoptotic target genes whose actions preserve epithelial barrier integrity. We have recently identified guanylate binding protein-1 (GBP-1) as an antiapoptotic protein, regulated by both type I and type II IFNs, that promotes intestinal epithelial barrier integrity in mature intestine. However, the mechanisms by which commensal bacteria regulate epithelial apoptosis during colonization of immature intestine and the contributions of GBP-1 are unknown. The healthy newborn intestine is initially colonized with bacterial species present in the maternal gastrointestinal tract, including nonpathogenic Escherichia coli. Therefore, we examined the influence of commensal E. coli on cytokine expression and candidate mediators of apoptosis in preweaned mice. Specifically, enteral exposure of 2 wk-old mice to commensal E. coli for 24 h selectively increased both IFN-αA and GBP-1 mRNA expression and prevented staurosporine-induced epithelial apoptosis. Exogenous IFN-αA treatment also induced GBP-1 expression and protected against staurosporine-induced apoptosis in a GBP-1 dependent manner, both in vitro and ex vivo. These findings identify a role for IFN-αA–mediated GBP-1 expression in the prevention of intestinal epithelial apoptosis by commensal bacteria. Thus IFN-αA mediates the beneficial effects of commensal bacteria and may be a promising therapeutic target to promote barrier integrity and prevent the inappropriate inflammatory responses seen in developing intestine as in necrotizing enterocolitis.
Dendritic Cell-Directed CTLA-4 Engagement during Pancreatic β Cell Antigen Presentation Delays Type 1 Diabetes
Authors: Karumuthil-Melethil Subha , Perez Nicolas , Li Ruobing , Prabhakar Bellur S. , Holterman Mark J. , Vasu Chenthamarakshan 
Published: May 2010

Abstract
The levels of expression of alternatively spliced variants of CTLA-4 and insufficient CTLA-4 signaling have been implicated in type 1 diabetes. Hence, we hypothesized that increasing CTLA-4–specific ligand strength on autoantigen-presenting dendritic cells (DCs) can enhance ligation of CTLA-4 on T cells and lead to modulation of autoreactive T cell response. In this study, we show that DC-directed enhanced CTLA-4 engagement upon pancreatic β cell Ag presentation results in the suppression of autoreactive T cell response in NOD mice. The T cells from prediabetic NOD mice treated with an agonistic anti–CTLA-4 Ab-coated DC (anti–CTLA-4-Ab DC) showed significantly less proliferative response and enhanced IL-10 and TGF-β1 production upon exposure to β cell Ags. Furthermore, these mice showed increased frequency of Foxp3+ and IL-10+ T cells, less severe insulitis, and a significant delay in the onset of hyperglycemia compared with mice treated with control Ab-coated DCs. Further analyses showed that diabetogenic T cell function was modulated primarily through the induction of Foxp3 and IL-10 expression upon Ag presentation by anti–CTLA-4-Ab DCs. The induction of Foxp3 and IL-10 expression appeared to be a consequence of increased TGF-β1 production by T cells activated using anti–CTLA-4-Ab DCs, and this effect could be enhanced by the addition of exogenous IL-2 or TGF-β1. Collectively, this study demonstrates the potential of a DC-directed CTLA-4 engagement approach not only in treating autoimmunity in type 1 diabetes, but also in altering diabetogenic T cell function ex vivo for therapy.
High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching
Authors: Turner Marian L. , Corcoran Lynn M. , Brink Robert , Hodgkin Philip D. 
Published: May 2010

Abstract
The selection of an appropriate Ig isotype is critical for an effective immune response against pathogens. Isotype regulation is sensitive to external signals, particularly cytokines secreted by Th cells. For example, IL-4 induces isotype switching to IgG1 via a STAT6-dependent signaling pathway. In this study, we show that BCR ligation also induces IgG1 switching in mouse B cells. The extent of switch induction by Ag is affinity-dependent, and high-affinity Ag binding leads to IgG1 switching levels comparable to those induced by saturating IL-4. However, the Ag-induced IgG1 switch does not require additional cytokine signals and occurs in a STAT6-independent manner. Thus, BCR ligation represents a novel pathway for direct isotype switching leading to IgG1 secretion.
Amphioxus SARM Involved in Neural Development May Function as a Suppressor of TLR Signaling
Authors: Yuan Shaochun , Wu Kui , Yang Manyi , Xu Liqun , Huang Ling , Liu Huiling , Tao Xin , Huang Shengfeng , Xu Anlong 
Published: May 2010

Abstract
Among five Toll/IL-1R resistance adaptors, sterile α and Toll/IL-1R resistance motif containing protein (SARM) is the only one conserved from Caenorhabditis elegans to human. However, its physiologic roles are hardly understood, and its involvement in TLR signaling remains debatable. In this study, we first demonstrated a predominant expression of amphioxus SARM (Branchiostoma belcheri tsingtauense SARM) in neural cells during embryogenesis and its predominant expression in the digestive system from larva to adult, suggesting its primitive role in neural development and a potential physiologic role in immunity. We further found that B. belcheri tsingtauense SARM was localized in mitochondria and could attenuate the TLR signaling via interacting with amphioxus MyD88 and tumor necrosis receptor associated factor 6. Thus, amphioxus SARM appears unique in that it may play dual functions in neural development and innate immunity by targeting amphioxus TLR signaling.
NK Cells Delay Allograft Rejection in Lymphopenic Hosts by Downregulating the Homeostatic Proliferation of CD8+ T Cells
Authors: Zecher Daniel , Li Qi , Oberbarnscheidt Martin H. , Demetris Anthony J. , Shlomchik Warren D. , Rothstein David M. , Lakkis Fadi G. 
Published: May 2010

Abstract
T cells present in lymphopenic environments undergo spontaneous (homeostatic) proliferation resulting in expansion of the memory T cell pool. Homeostatically generated memory T cells protect the host against infection but can cause autoimmunity and allograft rejection. Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is germane to clinical settings in which lymphodepletion is used. In this study, we asked whether NK cells, which regulate immune responses in lymphocyte-replete hosts, also regulate homeostatic T cell proliferation under lymphopenic conditions. We found that T cells transferred into genetically lymphocyte-deficient RAG−/− mice proliferate faster and generate more CD8+ memory T cells if NK cells were absent. CD8+ T cells that underwent homeostatic proliferation in the presence of NK cells generated mostly effector memory (CD44highCD62Llow) lymphocytes, whereas those that divided in the absence of NK cells were skewed toward central memory (CD44highCD62Lhigh). The latter originated predominantly from proliferation of the “natural” central memory CD8+ T cell pool. Regulation of homeostatic proliferation by NK cells occurred independent of perforin but was reversed by excess IL-15. Importantly, NK depletion enhanced CD8+ T cell recovery in T cell-depleted wild-type mice and accelerated rejection of skin allografts, indicating that regulation of homeostatic proliferation by NK cells is not restricted to genetically lymphocyte-deficient animals. These results demonstrate that NK cells downregulate homeostatic CD8+ T cell proliferation in lymphopenic environments by competing for IL-15. Concomitant NK and T cell depletion may be undesirable in transplant recipients because of enhanced expansion of memory CD8+ T cells that increase the risk of rejection.
Structural and Functional Insights of RANKL–RANK Interaction and Signaling
Authors: Liu Changzhen , Walter Thomas S. , Huang Peng , Zhang Shiqian , Zhu Xuekai , Wu Ying , Wedderburn Lucy R. , Tang Peifu , Owens Raymond J. , Stuart David I. , Ren Jingshan , Gao Bin 
Published: May 2010

Abstract
Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-κB ligand (RANKL)/receptor activator of the NF-κB (RANK)/osteoprotegerin molecular triad. RANKL, a member of the TNF superfamily, induces osteoclast differentiation, activation and survival upon interaction with its receptor RANK. The decoy receptor osteoprotegerin inhibits osteoclast formation by binding to RANKL. Imbalance in this molecular triad can result in diseases, including osteoporosis and rheumatoid arthritis. In this study, we report the crystal structures of unliganded RANK and its complex with RANKL and elucidation of critical residues for the function of the receptor pair. RANK represents the longest TNFR with four full cysteine-rich domains (CRDs) in which the CRD4 is stabilized by a sodium ion and a rigid linkage with CRD3. On association, RANK moves via a hinge region between the CRD2 and CRD3 to make close contact with RANKL; a significant structural change previously unseen in the engagement of TNFR superfamily 1A with its ligand. The high-affinity interaction between RANK and RANKL, maintained by continuous contact between the pair rather than the patched interaction commonly observed, is necessary for the function because a slightly reduced affinity induced by mutation produces significant disruption of osteoclast formation. The structures of RANK and RANKL–RANK complex and the biological data presented in the paper are essential for not only our understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design.
Distinct Roles for IL-2 and IL-15 in the Differentiation and Survival of CD8+ Effector and Memory T Cells
Authors: Mitchell Diana M. , Ravkov Eugene V. , Williams Matthew A. 
Published: May 2010

Abstract
IL-2 provides a memory differentiation signal to CD8+ T cells during the primary response that impacts the ability of the subsequent memory pool to mount a successful recall response. In this study, we find that although primary effector CTL development is modestly decreased in the absence of IL-2, the persistence of short-term and long-term effector memory CD8+ T cells on pathogen clearance is greatly diminished. Furthermore, secondary challenge of CD8+ memory T cells lacking the high-avidity IL-2R results in a failure to repopulate the effector pool. The role of IL-2 in promoting effector differentiation is not shared with the highly related cytokine, IL-15. Although IL-15 supports the survival of effector CD8+ T cells after pathogen clearance, its absence does not impair either primary or secondary effector CTL differentiation, nor does it impact the differentiation of long-term effector memory CD8+ T cells. These findings indicate a unique role for IL-2, but not IL-15, in promoting the differentiation not only of primary effector CD8+ T cells, but also of CD8+ memory T cells capable of secondary effector differentiation.
Human Neuronal Cells Possess Functional Cytoplasmic and TLR-Mediated Innate Immune Pathways Influenced by Phosphatidylinositol-3 Kinase Signaling
Authors: Peltier Daniel C. , Simms Allison , Farmer Jocelyn R. , Miller David J. 
Published: May 2010

Abstract
Innate immune pathways are early defense responses important for the immediate control and eventual clearance of many pathogens, where signaling is initiated via pattern recognition receptor (PRR)-mediated events that occur in a ligand- and cell-type specific manner. Within CNS neurons, innate immune pathways are likely crucial to control pathogens that target these essential yet virtually irreplaceable cells. However, relatively little is known about the induction and regulation of neuronal PRR signaling. In this report, we used human neuronal cell lines and primary rat neuronal cultures to examine PRR expression and function. We found that several innate immune receptor ligands, including Sendai virus, the dsRNA mimetic polyinosinic-polycytidylic acid, and LPS all activated differentiation-dependent neuronal innate immune pathways. Functional genetic analyses revealed that IFN regulatory factor 3-mediated pathways that resulted in IFN-β transcriptional upregulation were activated in cultured human neuronal cells by the PRRs TLR3, MDA5, or RIG-I in a ligand-specific manner. Furthermore, genome-wide transcriptional array and targeted genetic and pharmacologic analyses identified PI3K signaling as crucial for the induction of innate immune pathways in neurons. These results indicate that human neuronal cells possess specific and functional PRR pathways essential for the effective induction of innate immune responses, and suggest that neurons can play an active role in defense against neurotropic pathogens.
Impact of TCR Reactivity and HLA Phenotype on Naive CD8 T Cell Frequency in Humans
Authors: Legoux François , Debeaupuis Emilie , Echasserieau Klara , De La Salle Henri , Saulquin Xavier , Bonneville Marc 
Published: May 2010

Abstract
The impact of MHC phenotype on the shaping of the peripheral naive T cell repertoire in humans remains unknown. To address this, we compared the frequency and antigenic avidity of naive T cells specific for immunodominant self-, viral, and tumor Ags presented by a human MHC class I allele (HLA-A*02, referred to as A2) in individuals expressing or not this allele. Naive T cell frequencies varied from one Ag specificity to another but were restrained for a given specificity. Although A2-restricted T cells showed similar repertoire features and antigenic avidities in A2+ and A2− donors, A2 expression had either a positive, neutral, or negative impact on the frequency of A2-restricted naive CD8 T cells, depending on their fine specificity. We also identified in all donors CD4 T cells specific for A2/peptide complexes, whose frequencies were not affected by MHC class I expression, but nevertheless correlated with those of their naive CD8 T cell counterparts. Therefore, both selection by self-MHC and inherent TCR reactivity regulate the frequency of human naive T cell precursors. Moreover this study also suggests that T cell repertoire shaping by a given self-MHC allele is dispensable for generation of immunodominant T cell responses restricted by this particular allele.
Cytokine Requirements for the Differentiation and Expansion of IL-17A– and IL-22–Producing Human Vγ2Vδ2 T Cells
Authors: Ness-Schwickerath Kristin J. , Jin Chenggang , Morita Craig T. 
Published: May 2010

Abstract
Human γδ T cells expressing the Vγ2Vδ2 TCR play important roles in immune responses to microbial pathogens by monitoring prenyl pyrophosphate isoprenoid metabolites. Most adult Vγ2Vδ2 cells are memory cytotoxic cells that produce IFN-γ. Recently, murine γδ T cells were found to be major sources of IL-17A in antimicrobial and autoimmune responses. To determine if primate γδ T cells play similar roles, we characterized IL-17A and IL-22 production by Vγ2Vδ2 cells. IL-17A–producing memory Vγ2Vδ2 cells exist at low but significant frequencies in adult humans (1:2762 T cells) and at even higher frequencies in adult rhesus macaques. Higher levels of Vγ2Vδ2 cells produce IL-22 (1:1864 T cells), although few produce both IL-17A and IL-22. Unlike adult humans, in whom many IL-17A+ Vγ2Vδ2 cells also produce IFN-γ (Tγδ1/17), the majority of adult macaques IL-17A+ Vδ2 cells (Tγδ17) do not produce IFN-γ. To define the cytokine requirements for Tγδ17 cells, we stimulated human neonatal Vγ2Vδ2 cells with the bacterial Ag, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, and various cytokines and mAbs in vitro. We find that IL-6, IL-1β, and TGF-β are required to generate Tγδ17 cells in neonates, whereas Tγδ1/17 cells additionally required IL-23. In adults, memory Tγδ1/17 and Tγδ17 cells required IL-23, IL-1β, and TGF-β, but not IL-6. IL-22–producing cells showed similar requirements. Both neonatal and adult IL-17A+ Vγ2Vδ2 cells expressed elevated levels of retinoid-related orphan receptor γt. Our data suggest that, like Th17 αβ T cells, Vγ2Vδ2 T cells can be polarized into Tγδ17 and Tγδ1/17 populations with distinct cytokine requirements for their initial polarization and later maintenance.
B
achelier,
L
ouis (1870–1946)
Authors: Bru Bernard 
Published: May 2010

Abstract

In his thesis, “theory of speculation”, defended in 1900, Bachelier modeled the prices of stocks in the Paris stock market by a continuous random process, which he constructed and which has been known since then as
Brownian motion
. He could then calculate the prices of the major financial products of the Belle Epoque, and also, by introducing time and continuity to classical probability theory, he reinvigorated the field itself and anticipated the development of the theory of stochastic processes in the 1930s and decades thereafter.