bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples
Authors: Tang Jianming , Shao Wenshuo , Yoo Yun Joo , Brill Ilene , Mulenga Joseph , Allen Susan , Hunter Eric , Kaslow Richard A. 
Published: April 2014

Abstract
Differences in immune control of HIV-1 infection are often attributable to the highly variable HLA class I molecules that present viral epitopes to CTL. In our immunogenetic analyses of 429 HIV-1 discordant Zambian couples (infected index partners paired with cohabiting seronegative partners), several HLA class I variants in index partners were associated with contrasting rates and incidence of HIV-1 transmission within a 12-year study period. In particular, A*3601 on the A*36-Cw*04-B*53 haplotype was the most unfavorable marker of HIV-1 transmission by index partners, while Cw*1801 (primarily on the A*30-Cw*18-B*57 haplotype) was the most favorable, irrespective of the direction of transmission (male to female or female to male) and other commonly recognized cofactors of infection, including age and GUI. The same HLA markers were further associated with contrasting viral load levels in index partners, but they had no clear impact on HIV-1 acquisition by the seronegative partners. Thus, HLA class I gene products not only mediate HIV-1 pathogenesis and evolution but also influence heterosexual HIV-1 transmission.
Attenuated Inflammatory Responses in Hemochromatosis Reveal a Role for Iron in the Regulation of Macrophage Cytokine Translation
Authors: Wang Lijian , Johnson Erin E. , Shi Hai Ning , Walker W. Allan , Wessling-Resnick Marianne , Cherayil Bobby J. 
Published: April 2014

Abstract
Disturbances of iron homeostasis are associated with altered susceptibility to infectious disease, but the underlying molecular mechanisms are poorly understood. To study this phenomenon, we examined innate immunity to oral Salmonella infection in Hfe knockout (Hfe−/−) mice, a model of the human inherited disorder of iron metabolism type I hemochromatosis. Salmonella- and LPS-induced inflammatory responses were attenuated in the mutant animals, with less severe enterocolitis observed in vivo and reduced macrophage TNF-α and IL-6 secretion measured in vitro. The macrophage iron exporter ferroportin (FPN) was up-regulated in the Hfe−/− mice, and correspondingly, intramacrophage iron levels were lowered. Consistent with the functional importance of these changes, the abnormal cytokine production of the mutant macrophages could be reproduced in wild-type cells by iron chelation, and in a macrophage cell line by overexpression of FPN. The results of analyzing specific steps in the biosynthesis of TNF-α and IL-6, including intracellular concentrations, posttranslational stability and transcript levels, were consistent with reduced translation of cytokine mRNAs in Hfe−/− macrophages. Polyribosome profile analysis confirmed that elevated macrophage FPN expression and low intracellular iron impaired the translation of specific inflammatory cytokine transcripts. Our results provide molecular insight into immune function in type I hemochromatosis and other disorders of iron homeostasis, and reveal a novel role for iron in the regulation of the inflammatory response.
Expression and Cellular Provenance of Thymic Stromal Lymphopoietin and Chemokines in Patients with Severe Asthma and Chronic Obstructive Pulmonary Disease
Authors: Ying Sun , O'Connor Brian , Ratoff Jonathan , Meng Qiu , Fang Cailong , Cousins David , Zhang Guizhen , Gu Shuyan , Gao Zhongli , Shamji Betty , Edwards Matthew J. , Lee Tak H. , Corrigan Chris J. 
Published: April 2014

Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are associated with Th2 and Th1 differentiated T cells. The cytokine thymic stromal lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of chemokines which preferentially attract them. We hypothesized that there is distinct airways expression of TSLP and chemokines which preferentially attract Th1- and Th2-type T cells, and influx of T cells bearing their receptors in asthma and COPD. In situ hybridization, immunohistochemistry, and ELISA were used to examine the expression and cellular provenance of TSLP, Th2-attracting (TARC/CCL17, MDC/CCL22, I-309/CCL1), and Th1-attracting (IP-10/CXCL10, I-TAC/CXCL11) chemokines in the bronchial mucosa and bronchoalveolar lavage fluid of subjects with moderate/severe asthma, COPD, and controls. Cells expressing mRNA encoding TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in severe asthma and COPD as compared with non-smoker controls (p &lt; 0.02). This pattern was reflected in bronchoalveolar lavage fluid protein concentrations. Expression of the same chemokines was also increased in ex- and current smokers. The cellular sources of TSLP and chemokines were strikingly similar in severe asthma and COPD. The numbers of total bronchial mucosal T cells expressing the chemokine receptors CCR4, CCR8, and CXCR3 did not significantly differ in asthma, COPD, and controls. Both asthma and COPD are associated with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-attracting chemokines. Increased expression of these chemokines is not, however, associated with selective accumulation of T cells bearing their receptors.
Airway House Dust Extract Exposures Modify Allergen-Induced Airway Hypersensitivity Responses by TLR4-Dependent and Independent Pathways
Authors: Lam Diane , Ng Nicholas , Lee Steve , Batzer Glenda , Horner Anthony A. 
Published: April 2014

Abstract
TLR ligands and other allergen-nonspecific immunostimulatory molecules are ubiquitous in ambient air and have profound modulatory activities in animal models of allergic asthma. However, several of these molecules have been shown to promote exaggerated Th2-biased airway hypersensitivity responses (AHRs), whereas others attenuate the asthmatic phenotype. Therefore, it has proven difficult to extrapolate experimental results with purified molecules toward a more general understanding of the allergen-nonspecific immunomodulatory influence of living environments on the natural history of allergic asthma. These investigations determined how regular and intermittent airway exposures to an unpurified, but sterile house dust extract standard (HDEst) affected the OVA-specific AHR and immune status of previously Th2-sensitized mice. Low-dose daily and high-dose intermittent HDEst exposures modulated ongoing AHRs considerably, reducing eosinophil recruitment and methacholine responsiveness, while increasing neutrophilic inflammation. However, only daily airway delivery of low-dose HDEst attenuated OVA-specific Th2 cytokine production and Th2-biased AHRs to allergen challenge 1 mo later. Finally, whereas LPS mimicked many of the immunomodulatory characteristics of HDEst in this murine asthma model, daily airway HDEst delivery was highly effective in attenuating the AHR of OVA/alum-sensitized TLR4-deficient mice. Taken together, these investigations provide direct evidence that living environments contain allergen-nonspecific immunostimulatory molecules that influence the airway hypersensitivity status of allergen-sensitized mice by TLR4-dependent and independent mechanisms.
Antigen Persistence Is Required for Dendritic Cell Licensing and CD8+ T Cell Cross-Priming
Authors: Jusforgues-Saklani Hélène , Uhl Martin , Blachère Nathalie , Lemaître Fabrice , Lantz Olivier , Bousso Philippe , Braun Deborah , Moon James J. , Albert Matthew L. 
Published: April 2014

Abstract
It has been demonstrated that CD4+ T cells require Ag persistence to achieve effective priming, whereas CD8+ T cells are on “autopilot” after only a brief exposure. This finding presents a disturbing conundrum as it does not account for situations in which CD8+ T cells require CD4+ T cell help. We used a physiologic in vivo model to study the requirement of Ag persistence for the cross-priming of minor histocompatibility Ag-specific CD8+ T cells. We report inefficient cross-priming in situations in which male cells are rapidly cleared. Strikingly, the failure to achieve robust CD8+ T cell activation is not due to a problem with cross-presentation. In fact, by providing “extra help” in the form of dendritic cells (DCs) loaded with MHC class II peptide, it was possible to achieve robust activation of CD8+ T cells. Our data suggest that the “licensing” of cross-presenting DCs does not occur during their initial encounter with CD4+ T cells, thus accounting for the requirement for Ag persistence and suggesting that DCs make multiple interactions with CD8+ T cells during the priming phase. These findings imply that long-lived Ag is critical for efficient vaccination protocols in which the CD8+ T cell response is helper-dependent.
Apoptotic Cells Induce Immunosuppression through Dendritic Cells: Critical Roles of IFN-γ and Nitric Oxide
Authors: Ren Guangwen , Su Juanjuan , Zhao Xin , Zhang Liying , Zhang Jimin , Roberts Arthur I. , Zhang Huatang , Das Gobardhan , Shi Yufang 
Published: April 2014

AbstractApoptotic cells induce immunosuppression through unknown mechanisms. To identify the underlying molecular mediators, we examined how apoptotic cells induce immunoregulation by dendritic cells (DC). We found that administration of DC exposed to apoptotic cells (DCap) strongly inhibited the expansion of lymphocytes in draining lymph nodes in vivo and the subsequent Ag-specific activation of these lymphocytes ex vivo. Unexpectedly, DCap supported T cell activation to a similar extent as normal DC in vitro, leading to proliferation and IL-2 production, except that DCap did not support T cell production of IFN-γ. Surprisingly, when DCap were cocultured with normal DC, they completely lost their ability to support T cell activation, an effect reversed by anti-IFN-γ or inhibitors of inducible NO synthase (iNOS). As expected, exposure to apoptotic cells rendered DCap capable of producing much more NO in response to exogenous IFN-γ than normal DC. Furthermore, DCap from iNOS−/− or IFN-γR1−/− mice were not inhibitory in vitro or in vivo. Therefore, the IFN-γ-induced production of NO by apoptotic cell-sensitized DC plays a key role in apoptotic cell-mediated immunosuppression.
Tumor-Induced CD11b+Gr-1+ Myeloid Cells Suppress T Cell Sensitization in Tumor-Draining Lymph Nodes
Authors: Watanabe Satoshi , Deguchi Katsuya , Zheng Rongxiu , Tamai Hidemasa , Wang Li-xin , Cohen Peter A. , Shu Suyu 
Published: April 2014

Abstract
Suppression of tumor-specific T cell sensitization is a predominant mechanism of tumor escape. To identify tumor-induced suppressor cells, we transferred spleen cells from mice bearing progressive MCA205 sarcoma into sublethally irradiated mice. These mice were then inoculated subdermally with tumor cells to stimulate T cell response in the tumor-draining lymph-node (TDLN). Tumor progression induced splenomegaly with a dramatic increase (22.1%) in CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) compared with 2.6% of that in normal mice. Analyses of therapeutic effects by the adoptive immunotherapy revealed that the transfer of spleen cells from tumor-bearing mice severely inhibited the generation of tumor-immune T cells in the TDLN. We further identified MDSC to be the dominant suppressor cells. However, cells of identical phenotype from normal spleens lacked the suppressive effects. The suppression was independent of CD4+CD25+ regulatory T cells. Intracellular IFN-γ staining revealed that the transfer of MDSC resulted in a decrease in numbers of tumor-specific CD4+ and CD8+ T cells. Transfer of MDSC from MCA207 tumor-bearing mice also suppressed the MCA205 immune response indicating a lack of immunologic specificity. Further analyses demonstrated that MDSC inhibited T cell activation that was triggered either by anti-CD3 mAb or by tumor cells. However, MDSC did not suppress the function of immune T cells in vivo at the effector phase. Our data provide the first evidence that the systemic transfer of MDSC inhibited and interfered with the sensitization of tumor-specific T cell responses in the TDLN.
Transcription Factor-Dependent Chromatin Remodeling of Il18r1 during Th1 and Th2 Differentiation
Authors: Yu Qing , Chang Hua-Chen , Ahyi Ayele-Nati N. , Kaplan Mark H. 
Published: April 2014

Abstract
The IL-18Rα-chain is expressed on Th1 but not Th2 cells. We have recently shown that Stat4 is an important component of programming the Il18r1 locus (encoding IL-18Rα) for maximal expression in Th1 cells. Il18r1 is reciprocally repressed during Th2 development. In this report, we demonstrate the establishment of DH patterns that are distinct among undifferentiated CD4 T, Th1, and Th2 cells. Stat6 is required for the repression of Il18r1 expression and in Stat6-deficient Th2 cultures, mRNA levels, histone acetylation, and H3K4 methylation levels are intermediate between levels observed in Th1 and Th2 cells. Despite the repressive effects of IL-4 during Th2 differentiation, we observed only modest binding of Stat6 to the Il18r1 locus. In contrast, we observed robust GATA-3 binding to a central region of the locus where DNase hypersensitivity sites overlapped with conserved non-coding sequences in Il18r1 introns. Ectopic expression of GATA-3 in differentiated Th1 cells repressed Il18r1 mRNA and surface expression of IL-18Rα. These data provide further mechanistic insight into transcription factor-dependent establishment of Th subset-specific patterns of gene expression.
Statins Induce Regulatory T Cell Recruitment via a CCL1 Dependent Pathway
Authors: Mira Emilia , León Beatriz , Barber Domingo F. , Jiménez-Baranda Sonia , Goya Iñigo , Almonacid Luis , Márquez Gabriel , Zaballos Angel , Martínez-A. Carlos , Stein Jens V. , Ardavín Carlos , Mañes Santos 
Published: April 2014

Abstract
The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.
Splenectomy Protects against Sepsis Lethality and Reduces Serum HMGB1 Levels
Authors: Huston Jared M. , Wang Haichao , Ochani Mahendar , Ochani Kanta , Rosas-Ballina Mauricio , Gallowitsch-Puerta Margot , Ashok Mala , Yang Lihong , Tracey Kevin J. , Yang Huan 
Published: April 2014

Abstract
High mobility group box 1 (HMGB1) is a critical mediator of lethal sepsis. Previously, we showed that apoptotic cells can activate macrophages to release HMGB1. During sepsis, apoptosis occurs primarily in lymphoid organs, including the spleen and thymus. Currently, it is unclear whether this accelerated lymphoid organ apoptosis contributes to systemic release of HMGB1 in sepsis. In this study, we report that splenectomy significantly reduces systemic HMGB1 release and improves survival in mice with polymicrobial sepsis. Treatment with a broad-spectrum caspase inhibitor reduces systemic lymphocyte apoptosis, suppresses circulating HMGB1 concentrations, and improves survival during polymicrobial sepsis, but fails to protect septic mice following splenectomy. These findings indicate that apoptosis in the spleen is essential to the pathogenesis of HMGB1-mediated sepsis lethality.
The Induction of Inflammation by Dectin-1 In Vivo Is Dependent on Myeloid Cell Programming and the Progression of Phagocytosis
Authors: Rosas Marcela , Liddiard Kate , Kimberg Matti , Faro-Trindade Inês , McDonald Jacqueline U. , Williams David L. , Brown Gordon D. , Taylor Philip R. 
Published: April 2014

AbstractDectin-1 is the archetypal signaling, non-Toll-like pattern recognition receptor that plays a protective role in immune defense to Candida albicans as the major leukocyte receptor for β-glucans. Dectin-1-deficiency is associated with impaired recruitment of inflammatory leukocytes and inflammatory mediator production at the site of infection. In this study, we have used mice to define the mechanisms that regulate the dectin-1-mediated inflammatory responses. Myeloid cell activation by dectin-1 is controlled by inherent cellular programming, with distinct macrophage and dendritic cell populations responding differentially to the engagement of this receptor. The inflammatory response is further modulated by the progression of the phagocytosis, with “frustrated phagocytosis” resulting in dramatically augmented inflammatory responses. These studies demonstrate that dectin-1 in isolation is sufficient to drive a potent inflammatory response in a context-dependent manner. This has implications for the mechanism by which myeloid cells are activated during fungal infections and the processes involved in the therapeutic manipulation of the immune system via exogenous dectin-1 stimulation or blockade.
Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis
Authors: Uozumi Naonori , Kita Yoshihiro , Shimizu Takao 
Published: April 2014

Abstract
Cytosolic phospholipase A2α (cPLA2α) is one of the key enzymes in lipid mediator generation. It preferentially hydrolyzes arachidonoyl-phospholipid in response to cellular stimuli, liberating arachidonic acid, the shared precursor of PGs and leukotrienes. Mice with disruption of the cPLA2α gene exhibit a more than 80% decrease in the generation of these lipid mediators, leading to dramatic phenotypes in various models of inflammatory and allergic disease. In this study, we use the cecal ligation and puncture model of sepsis along with multiplex quantitation systems to explore interactions between eicosanoids and protein mediators. cPLA2α-deficient mice exhibited significantly less weight loss accompanied by decreased generation of PGs, leukotriene B4, IL-6, and CCL2. Despite these differences, genetic ablation of cPLA2α did not provide any survival advantage. Unexpectedly, abundant production of 12-hydroxy-eicosatetraenoic acid, another arachidonic acid-derived lipid mediator, was found to be unaffected by disruption of the cPLA2α gene. Eicosanoid production preceded the production of cytokines. Eicosanoid modulation of IL-6 and CCL2 expression was suggested by scattergram analyses. These results provide in vivo evidence for the rapid generation of eicosanoids, regulatory role(s) for cPLA2α-derived lipid mediators on protein mediator production, and the existence of a robust cPLA2α-independent pathway(s) of eicosanoid generation.
Protection of Murine Systemic Lupus by theEaTransgene without Expression of I-E Heterodimers
Authors: Martínez-Soria Eduardo , Santiago-Raber Marie-Laure , Ho Liza , Moll Thomas , Izui Shozo 
Published: April 2014

AbstractA high-level expression of the Ea transgene encoding the MHC class II I-E α-chain is very effective in the protection from systemic lupus erythematosus (SLE) in mice. However, it has not been elucidated whether this protection results from the induction or increased expression of I-E heterodimers or from the generation of I-E α-chain-derived peptides displaying high affinity for I-A molecules, because previous studies were conducted in lupus-prone mice expressing I-E β-chains. To address this question, we assessed the protective effect of the Ea transgene in lupus-prone BXSB mice bearing the H2q haplotype (i.e., unable to express I-E heterodimers because of a deficiency in I-E β-chains). We observed that the Ea transgene expression resulted in a marked suppression of the development of SLE in H2q BXSB mice despite the absence of I-E expression. The observed protection was not associated with any detectable levels of T cell depletion and regulatory T cell expansion. Significantly, transgenic I-E α-chains were substantially expressed on the surface of B lymphocytes and dendritic cells, but not of macrophages, without apparent formation of mixed-isotype heterodimers with I-A β-chains. Our results demonstrate for the first time that the Ea transgene is able to prevent the development of SLE without induction of I-E heterodimer expression, indicating a critical role of I-E α-chains, but not I-E heterodimers, in the Ea transgene-mediated protection from SLE. Taken together, our data favor a model of autoimmunity prevention based on competition for Ag presentation between I-E α-chain-derived peptides and autoantigens.
PP2A Dephosphorylates Elf-1 and Determines the Expression of CD3ζ and FcRγ in Human Systemic Lupus Erythematosus T Cells
Authors: Juang Yuang-Taung , Wang Ying , Jiang Guisen , Peng Hai-Bin , Ergin Sukran , Finnell Michelle , Magilavy Abigail , Kyttaris Vasileios C. , Tsokos George C. 
Published: April 2014

AbstractT cells from patients with systemic lupus erythematosus are characterized by decreased expression of CD3ζ-chain and increased expression of FcRγ-chain, which becomes part of the CD3 complex and contributes to aberrant signaling. Elf-1 enhances the expression of CD3ζ, whereas it suppresses the expression of FcRγ gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3ζ and FcRγ promoters. Suppression of the expression of the PP2A leads to increased expression of CD3ζ and decreased expression of FcRγ genes and correction of the early signaling response. Therefore, PP2A serves as a central determinant of abnormal T cell function in human lupus and may represent an appropriate treatment target.
Cutting Edge: Th1 Cells Facilitate the Entry of Th17 Cells to the Central Nervous System during Experimental Autoimmune Encephalomyelitis
Authors: O'Connor Richard A. , Prendergast Catriona T. , Sabatos Catherine A. , Lau Clement W. Z. , Leech Melanie D. , Wraith David C. , Anderton Stephen M. 
Published: April 2014

Abstract
It has recently been proposed that experimental autoimmune encephalomyelitis, once considered the classical Th1 disease, is predominantly Th17 driven. In this study we show that myelin-reactive Th1 preparations devoid of contaminating IL-17+ cells are highly pathogenic. In contrast, Th17 preparations lacking IFN-γ+ cells do not cause disease. Our key observation is that only Th1 cells can access the noninflamed CNS. Once Th1 cells establish the experimental autoimmune encephalomyelitis lesion, Th17 cells appear in the CNS. These data shed important new light on the ability of Th1 vs Th17 cells to access inflamed vs normal tissue. Because the IL-17-triggered release of chemokines by stromal cells could attract many other immune cells, allowing Th17 cells to access the tissues only under conditions of inflammation may be a key process limiting (auto)immune pathology. This has major implications for the design of therapeutic interventions, many of which are now aiming at Th17 rather than Th1 cells.