bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway
Authors: Uematsu Satoshi , Matsumoto Makoto , Takeda Kiyoshi , Akira Shizuo 
Published: April 2014

AbstractMacrophages produce a large amount of PGE2 during inflammation. This lipid mediator modulates various immune responses. PGE2 acts on macrophages and inhibits production of cytokines such as TNF-α and IL-12. Membrane-bound glutathione-dependent PGE2 synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE2 biosynthesis. Here we identified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE2 in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The mice showed no augmentation of the PGE2 production in response to LPS. However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock. Thus, mPGES is critically involved in the biosynthesis of PGE2 induced by LPS, but is dispensable for the modulation of inflammatory responses.
Acute Renal Failure in Endotoxemia Is Caused by TNF Acting Directly on TNF Receptor-1 in Kidney
Authors: Cunningham Patrick N. , Dyanov Hristem M. , Park Pierce , Wang Jun , Newell Kenneth A. , Quigg Richard J. 
Published: April 2014

AbstractBacterial endotoxin (LPS) is responsible for much of the widespread inflammatory response seen in sepsis, a condition often accompanied by acute renal failure (ARF). In this work we report that mice deficient in TNFR1 (TNFR1−/−) were resistant to LPS-induced renal failure. Compared with TNFR1+/+ controls, TNFR1−/− mice had less apoptosis in renal cells and fewer neutrophils infiltrating the kidney following LPS administration, supporting these as mediators of ARF. TNFR1+/+ kidneys transplanted into TNFR1−/− mice sustained severe ARF after LPS injection, which was not the case with TNFR1−/− kidneys transplanted into TNFR1+/+ mice. Therefore, TNF is a key mediator of LPS-induced ARF, acting through its receptor TNFR1 in the kidney.
Signal-Regulatory Protein α-CD47 Interactions Are Required for the Transmigration of Monocytes Across Cerebral Endothelium
Authors: de Vries Helga E. , Hendriks Jerome J. A. , Honing Henk , de Lavalette Chantal Renardel , van der Pol Susanne M. A. , Hooijberg Erik , Dijkstra Christine D. , van den Berg Timo K. 
Published: April 2014

AbstractMonocyte infiltration into inflamed tissue requires their initial arrest onto the endothelial cells (ECs), followed by firm adhesion and subsequent transmigration. Although several pairs of adhesion molecules have been shown to play a role in the initial adhesion of monocytes to ECs, the mechanism of transendothelial migration is poorly defined. In this study, we have investigated the role of signal-regulatory protein (SIRP)α-CD47 interactions in monocyte transmigration across brain ECs. CD47 expression was observed in vivo on cerebral endothelium of both control animals and animals suffering from experimental allergic encephalomyelitis. To investigate whether SIRPα-CD47 interactions are instrumental in the trafficking of monocytes across cerebral EC monolayers, in vitro assays were conducted in which the migration of monocytes, but not adhesion, was found to be effectively diminished by blocking SIRPα and CD47 on monocytes and ECs, respectively. In this process, SIRPα was found to interact solely with its counterligand CD47 on ECs. Overexpression of the CD47 molecule on brain ECs significantly enhanced monocytic transmigration, but did not affect adhesion. SIRPα-CD47-mediated transendothelial migration involved Gi protein activity, a known signaling component of CD47. Finally, cross-linking of CD47 on brain ECs induced cytoskeletal reorganization of the endothelium, a process that was Gi protein independent. These data provide the first evidence that the interaction of CD47 with its monocytic counterligand SIRPα is of importance in the final step of monocyte trafficking into the brain, a critical event in the development of neuroinflammatory diseases.
Exposure to a Dysfunctional Glucocorticoid Receptor from Early Embryonic Life Programs the Resistance to Experimental Autoimmune Encephalomyelitis Via Nitric Oxide-Induced Immunosuppression
Authors: Marchetti Bianca , Morale Maria C. , Brouwer Jantien , Tirolo Cataldo , Testa Nuccio , Caniglia Salvo , Barden Nicholas , Amor Sandra , Smith Paul A. , Dijkstra Christine D. 
Published: April 2014

Abstract
Glucocorticoid (GC) hormones play a central role in the bidirectional communication between the neuroendocrine and the immune systems and exert, via GC receptors (GR), potent immunosuppressive and anti-inflammatory effects. In this study, we report that GR deficiency of transgenic mice expressing GR antisense RNA from early embryonic life has a dramatic impact in programming the susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. GR deficiency renders mice resistant to myelin oligodendrocyte glycoprotein-induced EAE, and such mice do not develop clinical or histological signs of disease compared with EAE-susceptible wild-type mice. Resistance to EAE in GR-deficient mice is associated not with endogenous GC levels, but with a significant reduction in spleen and lymph node cell proliferation. The use of NO inhibitors in vitro indicates that NO is the candidate immunosuppressor molecule. GR-deficient mice develop 3- to 6-fold higher nitrite levels in the periphery and are resistant to NO inhibition by GCs. Specific inhibition of NO production in vivo by treatment with the inducible NO synthase inhibitor, l-N6-(1-iminoethyl)-lysine, suppressed circulating nitrites, increased myelin oligodendrocyte glycoprotein-specific cell proliferation, and rendered GR-deficient mice susceptible to EAE. Thus, life-long GR deficiency triggers inducible NO synthase induction and NO generation with consequent down-regulation of effector cell proliferation. These findings identify a novel link among GR, NO, and EAE susceptibility and highlight NO as critical signaling molecule in bidirectional communication between the hypothalamic-pituitary-adrenocortical axis and the immune system.
Lipopolysaccharide-Induced Apoptosis of Endothelial Cells and Its Inhibition by Vascular Endothelial Growth Factor
Authors: Munshi Neru , Fernandis Aaron Z. , Cherla Rama P. , Park In-Woo , Ganju Ramesh K. 
Published: April 2014

Abstract
Endothelial injury is a major manifestation of septic shock induced by LPS. Recently, LPS was shown to induce apoptosis in different types of endothelial cells. In this study, we observed that pretreatment with vascular endothelial growth factor (VEGF), a known cell survival factor, blocked LPS-induced apoptosis in endothelial cells. We then further defined this LPS-induced apoptotic pathway and its inhibition by VEGF. We found that LPS treatment increased caspase-3 and caspase-1 activities and induced the cleavage of focal adhesion kinase. LPS also augmented expression of the pro-apoptotic protein Bax and the tumor suppressor gene p53. The pro-apoptotic Bax was found to translocate to the mitochondria from the cytosol following stimulation with LPS. Pretreatment of endothelial cells with VEGF inhibited the induction of both Bax and p53 as well as the activation of caspase-3. These data suggest that VEGF inhibits LPS-induced endothelial apoptosis by blocking pathways that lead to caspase activation.
CD4 and CD8 T Cells in Susceptibility/Protection to Collagen-Induced Arthritis in HLA-DQ8-Transgenic Mice: Implications for Rheumatoid Arthritis
Authors: Taneja Veena , Taneja Neelam , Paisansinsup Tawatchai , Behrens Marshall , Griffiths Marie , Luthra Harvinder , David Chella S. 
Published: April 2014

Abstract
To investigate the role of CD4 and CD8 T cells in arthritis, we generated transgenic mice deficient in CD4 and CD8 molecules expressing RA-susceptible gene HLA-DQ8. DQ8·CD4−/− mice were resistant to developing collagen-induced arthritis (CIA). However, DQ8·CD8−/− mice developed CIA with increased incidence and more severity than DQ8 mice. Both DQ8·CD8−/− and DQ8 mice produced rheumatoid factor. In addition, DQ8·CD8−/− mice produced antinuclear Abs. The B cell compartment and expression of DQ8 were normal in all the strains, although frequency of cells expressing DQ8 was less in CD4−/− mice. An increased frequency of CD3+ double-negative (DN) T cells was found in DQ8·CD8−/− compared with DQ8·CD4−/− and DQ8 mice. These CD3+ DN T cells produced high amounts of IL-10 in CD8-deficient mice. Analysis of cell division using a cell cycle tracking dye showed a higher rate of division of CD3+ and CD3+ DN T cells in DQ8·CD8−/− mice compared with DQ8·CD4−/− and DQ8 mice. Decreased apoptosis was seen in CIA-susceptible DQ8 and CD8-deficient mice, indicating a defect in activation-induced cell death. These observations suggest that CD4 cells are necessary for initiation of CIA in DQ8 mice. We hypothesize that CD8+ T cells are not capable of initiating CIA in DQ8-transgenic mice but may have a regulatory/protective effect.
HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules
Authors: Paisansinsup Tawatchai , Deshmukh Umesh S. , Chowdhary Vaidehi R. , Luthra Harvinder S. , Fu Shu Man , David Chella S. 
Published: April 2014

AbstractAbs to Ro/SSA Ags in the sera of patients with systemic lupus erythematosus and Sjögren’s syndrome are influenced by the HLA class II genes. To investigate the role of individual HLA class II genes in immune responses to human Ro60 (hRo60), mice lacking murine class II molecules and carrying either HLA genes DR2(DRB1*1502), DR3(DRB1*0301), DQ6(DQA1*0103/DQB1*0601), or DQ8(DQA1*0301/DQB1*0302), were immunized with rhRo60. The results show that hRo60 induces strong T and B cell responses in DR2, DR3, and DQ8 mice in comparison to weaker responses in DQ6 mice. In all mice, the majority of the dominant T cell epitopes were located in the amino portion (aa 61–185) and the carboxy portion (aa 381–525) of the hRo60 molecules. In contrast, the early dominant B cell epitopes were located in the middle and carboxy portion of the hRo60 molecule (aa 281–315 and 401–538). In DR2, DR3, and DQ8 mice, the B cell epitopes subsequently spread to the amino and carboxy portion of the hRo60 molecule but were limited to the middle and carboxy portion in DQ6 mice. The DR2 and DR3 mice produced the highest titers of immunoprecipitating Abs against hRo60 and native mouse Ro60. In addition, only DR2 mice exclusively produced immunoprecipitating Abs to native mouse Ro52 and Abs to mouse La by slot blot analysis, whereas in other strains of mice Abs to mouse La were cross-reactive with the immunogen. The results of the present study demonstrate the importance of HLA class II in controlling the immune responses to the Ro-ribonucleoprotein.
Lack of Antibody Production Following Immunization in Old Age: Association with CD8+CD28− T Cell Clonal Expansions and an Imbalance in the Production of Th1 and Th2 Cytokines
Authors: Saurwein-Teissl Maria , Lung Thomas L. , Marx Florentine , Gschösser Claudio , Asch Esther , Blasko Imrich , Parson Walther , Böck Günther , Schönitzer Diether , Trannoy Emanuelle , Grubeck-Loebenstein Beatrix 
Published: April 2014

AbstractAlthough it is generally recognized that the function of the immune system declines with age, the nature of the underlying defects is still poorly understood. We now demonstrate the predominance of CD8+CD28− T cell clonal expansions in elderly persons who fail to produce specific Abs following influenza vaccination. These clones express effector cell markers and are mostly CD45RA+. When isolated and put into culture, they are unable to proliferate, but produce IFN-γ (but no IL-5) upon stimulation with anti-CD3 or autoantigen. These autoreactive CD8+ type 1 effector cells seem to trigger a Th1 polarization, as CD4+ T cells from elderly persons without in vivo Ab production produce Th1, but only low amounts of Th2 cytokines upon in vitro stimulation with PHA. Therefore, the increased occurrence of CD8+CD28− clonal expansions may be decisive for the development of immune deficiency in the elderly.
The Human T Cell Response to Myelin Oligodendrocyte Glycoprotein: A Multiple Sclerosis Family-Based Study
Authors: Koehler Niklas K. U. , Genain Claude P. , Giesser Barbara , Hauser Stephen L. 
Published: April 2014

AbstractMyelin oligodendrocyte glycoprotein (MOG) is an encephalitogenic myelin protein and a likely autoantigen in human multiple sclerosis (MS). In this work, we describe the fine specificity and cytokine profile of T cell clones (TCC) directed against MOG in three nuclear families, comprised of four individuals affected with MS and their HLA-identical siblings. TCC were generated from PBMC by limiting dilution against a mixture of eleven 20-mer overlapping peptides corresponding to the encephalitogenic extracellular domain of human MOG (aa 1–120). The frequency of MOG peptide-reactive T cells was surprisingly high (range, 1:400 to 1:3,000) and, unexpectedly, cloning efficiencies were highest at low seeding densities of 102 or 103 PBMC per well. A total of 235 MOG peptide-reactive TCC were produced, all of which were CD4+CD8−TCRαβ+TCRγδ−. All 11 MOG peptides were recognized by the TCC, and different epitopes of MOG appeared to be immunodominant in the HLA-identical siblings. The patterns of cytokine secretion by TCC from single individuals were generally similar. The healthy individuals exhibited Th2-, Th0-, and T regulatory cell 1-like cytokine profiles, whereas TCC from one sibling with MS had a striking Th1-like phenotype, producing high levels of IFN-γ and TNF-α, and low IL-4 levels. Thus, MOG-reactive T cells appear to constitute an important part of the natural T cell repertoire, a finding that could contribute to the development of autoimmunity to this protein.
Deletion of p21 (WAF-1/Cip1) Does Not Induce Systemic Autoimmunity in Female BXSB Mice
Authors: Lawson Brian R. , Kono Dwight H. , Theofilopoulos Argyrios N. 
Published: April 2014

AbstractCell cycle, apoptosis, and replicative senescence are all influenced by the cyclin-dependent kinase inhibitor, p21. It was previously reported that deletion of p21 in 129/Sv × C57BL/6 mixed genetic background mice induced a severe lupus-like disease, almost exclusively in females. However, we did not confirm this finding in an independently derived stock of 129/Sv × C57BL/6 p21−/− mice. To further address this discrepancy, we examined the effects of p21 deletion in BXSB female mice that develop late-life, mild lupus-like disease. Survival, polyclonal Igs, anti-chromatin Abs, and kidney histopathology in these mice were unremarkable and identical to wild-type littermates for up to 14 mo of age. We conclude that p21 deficiency does not promote autoimmunity even in females of a predisposed strain. The findings indicate that the use of mixed background 129/Sv × C57BL/6 mice to study effects of gene deletions in systemic autoimmunity may be confounded by the genetic heterogeneity of this cross. We suggest that studies addressing gene deletion effects in systemic autoimmunity should use sufficiently backcrossed mice to attain genetic homogeneity, include wild-type littermate controls, and preferentially use congenic inbred strains with late-life lupus predisposition to emulate the polygenic nature of this disease.
Characterization of CD4+ CTLs Ex Vivo
Authors: Appay Victor , Zaunders John J. , Papagno Laura , Sutton Julian , Jaramillo Angel , Waters Anele , Easterbrook Philippa , Grey Pat , Smith Don , McMichael Andrew J. , Cooper David A. , Rowland-Jones Sarah L. , Kelleher Anthony D. 
Published: April 2014

AbstractThe cytotoxic potential of CD8+ T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4+ T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4+ T cells have been the subject of debate. Here we show that a population of CD4+ perforin+ T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4+ T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4+ T cells. The existence of CD4+ cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.
T Cell Responses to an HLA-B*07-Restricted Epitope on the Dengue NS3 Protein Correlate with Disease Severity
Authors: Zivna Iva , Green Sharone , Vaughn David W. , Kalayanarooj Siripen , Stephens Henry A. F. , Chandanayingyong Dasnayanee , Nisalak Ananda , Ennis Francis A. , Rothman Alan L. 
Published: April 2014

Abstract
Dengue hemorrhagic fever (DHF), the severe manifestation of dengue virus (DV) infection characterized by plasma leakage, is more common in secondary DV infections in previously infected individuals and is associated with high levels of immune activation. To determine the Ag specificity of this immune response, we studied the response to an HLA-B*07-restricted T cell epitope, residues 221–232 of the DV NS3 protein, in 10 HLA-B*07+ Thai children who were studied during and after acute DV infections. Peptide-specific T cells were detected in 9 of 10 subjects. The frequency of peptide-specific T cells was higher in subjects who had experienced DHF than in those who had experienced DF. We also detected peptide-specific T cells in PBMC obtained at the time of the acute DV infection in 2 of 5 subjects. These data suggest that the NS3 (221–232) epitope is an important target of CD8+ T cells in secondary DV infection and that the activation and expansion of DV-specific T cells is greater in subjects with DHF than in those with dengue fever. These findings support the hypothesis that activation of DV-specific CD8+ T cells plays an important role in the pathogenesis of DHF.
Cutting Edge: Internalization of Transduced E-Selectin by Cultured Human Endothelial Cells: Comparison of Dermal Microvascular and Umbilical Vein Cells and Identification of a Phosphoserine-Type Di-leucine Motif
Authors: Kluger Martin S. , Shiao Stephen L. , Bothwell Alfred L. M. , Pober Jordan S. 
Published: April 2014

Abstract
Persistent E-selectin expression on human dermal microvascular endothelial cells (HDMEC), believed to mediate skin-specific T cell homing, results from a slow rate of surface protein internalization after cytokine induction. Following transduction of unactivated HDMEC with E-selectin cDNA, the rate of internalization was largely independent of increasing levels of surface protein expression, leading to prolonged t1/2 values of over 4 h, comparable to that observed following cytokine induction. In HUVEC, the rate of internalization increased with surface expression level, leading to an essentially constant t1/2 of under 2 h. Thus, the internalization process rather than cytokine responsiveness or E-selectin structure underlies the difference in endothelial cell behavior. Mutational analysis of the cytoplasmic region demonstrated a role for a di-leucine-type motif involving I588 and L589 but not for a putative tyrosine-type motif. Control of E-selectin surface expression appears to be phosphoserine dependent, since alanine but not aspartic acid substitution for S581 slows E-selectin internalization.
Cutting Edge: Attenuated Experimental Autoimmune Encephalomyelitis in Eta-1/Osteopontin-Deficient Mice
Authors: Jansson Marianne , Panoutsakopoulou Vily , Baker Jessica , Klein Ludger , Cantor Harvey 
Published: April 2014

AbstractRecent studies indicate that early T lymphocyte activation 1 (Eta-1), also known as osteopontin, is a cytokine contributing to the development of Th1 immunity. In the present report, the role of Eta-1 in experimental autoimmune encephalomyelitis (EAE), a disease associated with Th1 immunity, was examined by analysis of disease progression in Eta-1-deficient (Eta-1−/−) mice. Although incidence and onset of peptide-induced EAE were found to be similar in Eta-1−/− and Eta-1+/+ mice, Eta-1−/− mice displayed significantly lower mean maximal clinical score and faster recovery without spontaneous relapses. Accordingly, decreased inflammatory infiltration and demyelination were observed in the spinal cords of Eta-1−/− mice. Furthermore, in comparison to Eta-1+/+, Eta-1−/− CD4+ T cells had reduced expression of IFN-γ and TNF-α upon ex vivo restimulation. Taken together, these results suggest that Eta-1 may sustain autoimmune responses by assisting in maintenance of Th1 immunity during EAE.
Transitional B Lymphocyte Subsets Operate as Distinct Checkpoints in Murine Splenic B Cell Development
Authors: Su Thomas T. , Rawlings David J. 
Published: April 2014

AbstractSignaling through the Ag receptor is required for peripheral B lymphocyte maturation and maintenance. Defects in components of the B cell receptor (BCR) signalosome result in developmental blocks at the transition from immature (heat-stable Ag (HSA)high) to mature (HSAlow) B cells. Recent studies have subdivided the immature, or transitional, splenic B cells into two subsets, transitional 1 (T1) and transitional 2 (T2) cells. T1 and T2 cells express distinct surface markers and are located in distinct anatomic locations. In this report, we evaluated the BCR signaling capacity of T1 and T2 B cell subsets. In response to BCR engagement, T2 cells rapidly entered cell cycle and resisted cell death. In contrast, T1 cells did not proliferate and instead died after BCR stimulation. Correlating with these results, T2 cells robustly induced expression of the cell cycle regulator cyclin D2 and the antiapoptotic factors A1/Bfl-1 and Bcl-xL and exhibited activation of Akt. In contrast, T1 cells failed to up-regulate these markers. BCR stimulation of T2 cells also led to down-regulation of CD21 and CD24 (HSA) expression, resulting in a mature B cell phenotype. In addition, T2 cells from Bruton’s tyrosine kinase-deficient Xid mice failed to generate these proliferative and survival responses, suggesting a requirement for the BCR signalosome specifically at the T2 stage. Taken together, these data clearly demonstrate that T2 immature B cells comprise a discrete developmental subset that mediates BCR-dependent proliferative, prosurvival, and differentiation signals. Their distinct BCR-dependent responses suggest unique roles for T1 vs T2 cells in peripheral B cell selection.