bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Proliferation Arrest within Intrathymic Lymphocyte Progenitor Cells Causes Thymic Atrophy Mediated by the Aryl Hydrocarbon Receptor
Authors: Laiosa Michael D. , Wyman Amber , Murante Francis G. , Fiore Nancy C. , Staples J. Erin , Gasiewicz Thomas A. , Silverstone Allen E. 
Published: April 2014

Abstract
Activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix transcription factor, in lymphocytes by the immunosuppressive environmental contaminant 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to cause thymic atrophy in every species studied. We set out to identify the specific hemopoietic cellular populations in which the AHR was activated to lead to thymic atrophy and to determine the effect of AHR activation in those cellular populations. Initially, we examined whether AHR activation in intrathymic dendritic cells could mediate TCDD-induced thymic atrophy. It was found that thymic atrophy occurred only when the AHR could be activated in the thymocytes but not hemopoietic-derived dendritic cells or other APCs. We next analyzed the effect of TCDD on the proliferation of thymocytes in vivo. There was a significant increase in the percentage of thymocytes in the G1 phase of the cell cycle and a significant decrease in the percentage of S plus G2/M thymocytes, especially in the CD4−CD8−CD3− triple-negative intrathymic progenitor cell population 24 h after exposure to 30 μg/kg TCDD. Furthermore, by 12 h after exposure to TCDD, we observed ∼60% reduction of 5-bromo-2′-deoxyuridine incorporation in specific intrathymic progenitor cell populations. This reduction persisted for at least 6 days. These data indicate that intrathymic progenitor cells are direct targets of TCDD in the thymus and suggest that TCDD causes thymic atrophy by reducing entrance into cell cycle in these populations.
A Murine Locus on Chromosome 18 Controls NKT Cell Homeostasis and Th Cell Differentiation
Authors: Zhang Feng , Liang Zhiyan , Matsuki Naoto , Van Kaer Luc , Joyce Sebastian , Wakeland Edward K. , Aune Thomas M. 
Published: April 2014

Abstract
Th cell differentiation is a critical event in the adaptive immune response. C57BL strains develop predominant Th1 responses while BALB/c develops a predominant Th2 response. To identify quantitative trait loci controlling this variation, we performed Th1/Th2 differentiation assays of F1 × BALB/c progeny. A single strong quantitative trait locus was identified on chromosome 18, with weaker effects detectable on chromosomes 5, 12, and 14. By preparing a congenic BALB.B10.D2c18 strain, we were able to demonstrate that this single locus was sufficient to “repolarize” spleen cell cultures. This difference was not due to intrinsic differences in CD4+ T cells. Rather, introgression of the chromosome 18 locus into BALB/c disrupted Va14Ja18 NKT cell homeostasis resulting in the almost complete absence of this T cell subset. Taken together, these data indicate that genes within chromosome 18 control strain-dependent development of Va14Ja18 NKT cells.
Genomic Organization and Expression Analysis of B7-H4, an Immune Inhibitory Molecule of the B7 Family
Authors: Choi In-Hak , Zhu Gefeng , Sica Gabriel L. , Strome Scott E. , Cheville John C. , Lau Julie S. , Zhu Yuwen , Flies Dallas B. , Tamada Koji , Chen Lieping 
Published: April 2014

Abstract
B7-H4 is a recently identified B7 family member that negatively regulates T cell immunity by the inhibition of T cell proliferation, cytokine production, and cell cycle progression. In this study, we report that the genomic DNA of human B7-H4 is mapped on chromosome 1 comprised of six exons and five introns spanning 66 kb, of which exon 6 is used for alternative splicing to generate two different transcripts. Similar B7-H4 structure is also found in mouse genomic DNA in chromosome 3. A human B7-H4 pseudogene is identified in chromosome 20p11.1 with a single exon and two stop codons in the coding region. Immunohistochemistry analysis using B7-H4-specific mAb demonstrates that B7-H4 is not expressed on the majority of normal human tissues. In contrast, up to 85% (22 of 26) of ovarian cancer and 31% (5 of 16) of lung cancer tissues constitutively express B7-H4. Our results indicate a tight regulation of B7-H4 expression in the translational level in normal peripheral tissues and a potential role of B7-H4 in the evasion of tumor immunity.
Infant and Adult Human B Cell Responses to Rotavirus Share Common Immunodominant Variable Gene Repertoires
Authors: Weitkamp Jörn-Hendrik , Kallewaard Nicole , Kusuhara Koichi , Bures Elizabeth , Williams John V. , LaFleur Bonnie , Greenberg Harry B. , Crowe James E. 
Published: April 2014

Abstract
Ab repertoires exhibit marked restrictions during fetal life characterized by biases of variable gene usage and lack of junctional diversity. We tested the hypothesis that Ab repertoire restriction contributes to the observed poor quality of specific Ab responses made by infants to viral infections. We analyzed the molecular determinants of B cell responses in humans to two Ags of rotavirus (RV), a common and clinically important infection of human infants. We sequenced Ab H and L chain V region genes (VH and VL) of clones expanded from single B cells responding to RV virus protein 6 or virus protein 7. We found that adults exhibited a distinct bias in use of gene segments in the VH1 and VH4 families, for example, VH1–46, VH4–31, and VH4–61. This gene segment bias differed markedly from the VH3 dominant bias seen in randomly selected adult B cells. Recombinant Abs incorporating any of those three immunodominant VH segments bound to RV-infected cells and also to purified RV particles. The RV-specific B cell repertoires of infants aged 2–11 mo and those of adults were highly related when compared by VH, D, JH, VL, and JL segment selection, extent of junctional diversity, and mean H chain complementarity determining region 3 length. These data suggest that residual fetal bias of the B cell repertoire is not a limiting determinant of the quality of Ab responses to viruses of infants beyond the neonatal period.
Th1 Cell-Mediated Resistance to Cutaneous Infection with Leishmania major Is Independent of P- and E-Selectins
Authors: Zaph Colby , Scott Phillip 
Published: April 2014

Abstract
Studies in several models of inflammation have underscored the importance of P- and E-selectins in the migration of T cells to inflamed tissues. However, the role of the endothelial selectins in infection-induced cutaneous inflammation and host-protective immunity has not been investigated. In this study, we demonstrate that CD4+ T cells recruited to the cutaneous compartment during infection with Leishmania major express P- and E-selectin ligands. Furthermore, expression of P- and E-selectin ligands correlates with activated Leishmania-specific Th1 cells and is dependent upon IL-12. To investigate the functional role of the endothelial selectins during leishmaniasis, we infected mice either singly or doubly deficient in the expression of P- and E- selectins. Mice lacking both P- and E-selectins developed significantly less inflammation at the site of a primary and secondary infection, and exhibited an impaired delayed-type hypersensitivity response. Surprisingly, the absence of the endothelial selectins had no effect on the control of parasite replication or immunity to reinfection. Thus, these data demonstrate that although the endothelial selectins contribute to the inflammatory response, they are not required for protective immunity to L. major. Moreover, these data suggest that by blocking P- and E-selectins, the immune pathology associated with cutaneous leishmaniasis might be ameliorated without compromising immunity to infection.
Deficient CD4+ T Cell Priming and Regression of CD8+ T Cell Functionality in Virus-Infected Mice Lacking a Normal B Cell Compartment
Authors: Christensen Jan Pravsgaard , Kauffmann Susanne Ørding , Thomsen Allan Randrup 
Published: April 2014

Abstract
In this study, we investigate the state of T cell-mediated immunity in B cell-deficient (B−/−) mice infected with two strains of lymphocytic choriomeningitis virus known to differ markedly in their capacity to persist. In B−/− C57BL mice infected with the more persisting virus, virus-specific CD8+ T cells are initially generated that are qualitatively similar to those in wild-type mice. However, although cell numbers are well sustained over time, the capacity to produce cytokines is rapidly impaired. In similarly infected B−/− BALB/c mice, virus-specific CD8+ T cells are completely deleted, indicating that host genotype influences the severity of the T cell defect. In B−/− C57BL mice infected with the less persisting virus, CD8+ T cell dysfunction was not as pronounced, although it was clearly present. Most importantly, the appearance of dysfunctional CD8+ T cells clearly precedes recrudescence of detectable virus, indicating that the T cell defect is not simply a secondary event due to virus buildup resulting from the failure of B−/− mice to produce neutralizing Abs. In contrast with CD8+ T cells, which initially respond almost as in wild-type mice, the priming of virus-specific CD4+ T cells was markedly impaired in B−/− mice infected with either virus strain. Thus, our results indicate that B cells play an important role in antiviral immunity not only as Ab producers, but also in promoting an optimal and sustained T cell response. The T cell defects are likely to contribute to the chronic course of viral infection in B−/− mice.
An Inclusion Membrane Protein from Chlamydia trachomatis Enters the MHC Class I Pathway and Stimulates a CD8+ T Cell Response
Authors: Starnbach Michael N. , Loomis Wendy P. , Ovendale Pam , Regan David , Hess Bruce , Alderson Mark R. , Fling Steven P. 
Published: April 2014

Abstract
During its developmental cycle, the intracellular bacterial pathogen Chlamydia trachomatis remains confined within a protective vacuole known as an inclusion. Nevertheless, CD8+ T cells that recognize Chlamydia Ags in the context of MHC class I molecules are primed during infection. MHC class I-restricted presentation of these Ags suggests that these proteins or domains from them have access to the host cell cytoplasm. Chlamydia products with access to the host cell cytoplasm define a subset of molecules uniquely positioned to interface with the intracellular environment during the pathogen’s developmental cycle. In addition to their use as candidate Ags for stimulating CD8+ T cells, these proteins represent novel candidates for therapeutic intervention of infection. In this study, we use C. trachomatis-specific murine T cells and an expression-cloning strategy to show that CT442 from Chlamydia is targeted by CD8+ T cells. CT442, also known as CrpA, is a 15-kDa protein of undefined function that has previously been shown to be associated with the Chlamydia inclusion membrane. We show that: 1) CD8+ T cells specific for an H-2Db-restricted epitope from CrpA are elicited at a significant level (∼4% of splenic CD8+ T cells) in mice in response to infection; 2) the response to this epitope correlates with clearance of the organism from infected mice; and 3) immunization with recombinant vaccinia virus expressing CrpA elicits partial protective immunity to subsequent i.v. challenge with C. trachomatis.
Inhibition of Neutrophil Leukotriene B4 Production by a Novel Synthetic N-3 Polyunsaturated Fatty Acid Analogue, β-Oxa 21:3n-3
Authors: Robinson Brenton S. , Rathjen Deborah A. , Trout Neil A. , Easton Christopher J. , Ferrante Antonio 
Published: April 2014

Abstract
We recently reported the synthesis and anti-inflammatory properties of a novel long chain polyunsaturated fatty acid (PUFA) with an oxygen atom in the β-position, β-oxa-21:3 n-3 (Z,Z,Z)-(octadeca-9,12,15-trienyloxy) acetic acid). Our data, from studies aimed at elucidating the mechanism of its action, show that pretreatment of human neutrophils with the β-oxa-PUFA substantially depresses the production of leukotriene B4 (LTB4) in response to calcium ionophore, A23187, comparable to standard leukotriene inhibitors such as zileuton and nordihydroguaiaretic acid. Interestingly, the n-6 equivalent, β-oxa 21:3 n-6, is also a strong inhibitor of LTB4 production. In contrast, naturally occurring PUFA only slightly reduce, for eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids, or increase, for arachidonic acid (20:4n-6), the formation of LTB4. The parent β-oxa-21:3n-3 molecule, rather than its derivatives (methyl ester, saturated, monohydroperoxy, or monohydroxy forms), is exclusively responsible for attenuation of LTB4 formation. β-Oxa-21:3n-3 inhibits the conversion of [3H]20:4n-6 to [3H]5-hydroxyeicosatetraenoic acid and [3H]LTB4 by neutrophils in the presence of calcium ionophore and also suppresses the activity of purified 5-lipoxygenase, but not cyclooxygenase 1 and 2. β-Oxa-21:3n-3 is taken up by neutrophils and incorporated into phospholipids and neutral lipids. In the presence of calcium ionophore, the leukocytes convert a marginal amount of β-oxa-21:3n-3 to a 16-monohydroxy-β-oxa-21:3n-3 derivative. After administration to rodents by gavage or i.p. injection, β-oxa-21:3n-3 is found to be incorporated into the lipids of various tissues. Thus, β-oxa-21:3n-3 has the potential to be used in the treatment of inflammatory diseases, which are mediated by products of the lipoxygenase pathway.
CpG-Containing Oligodeoxynucleotide 1826 Converts the Weak Uveitogenic Rat Interphotoreceptor Retinoid-Binding Protein Peptide 1181–1191 into a Strong Uveitogen
Authors: Shao Hui , Lei Song , Sun Sheher L. , Xiang Jim , Kaplan Henry J. , Sun Deming 
Published: April 2014

Abstract
Aberrant activation of autoreactive T cells is one of the major causes of autoimmune disease. Autoantigens are sequestered and in many cases weak immunogens. For example, in experimental autoimmune uveitis, immunization of naive rats with autologous interphotoreceptor retinoid-binding protein (IRBP) fails to induce intraocular inflammation or a strong T cell response, whereas bovine IRBP is a strong inducer of experimental autoimmune uveitis. Such observations challenge the view that the autoantigen alone is responsible for the development of autoimmunity. Here, we demonstrate that autologous rat IRBP is converted to a strong immunogen in the presence of a small dose of CpG-containing oligodeoxynucleotides. Our results indicate that specific CpG-containing oligodeoxynucleotides may play an important role in the activation and expansion of autoreactive T cells in vivo, leading to autoimmune disease.
In Vivo Impairment of Neutrophil Recruitment during Lentivirus Infection
Authors: Kubes Paul , Heit Bryan , van Marle Guido , Johnston James B. , Knight Derrice , Khan Adil , Power Christopher 
Published: April 2014

Abstract
Evidence indicates that the lentivirus, HIV, infection affects neutrophil response to bacteria and bacterial products in vitro. We used a novel model of rapid onset immunosuppression following infection with a similar lentivirus, feline immunodeficiency virus (FIV), in cats to examine neutrophil function within the microvasculature in vivo and to determine the steps that are impaired in the neutrophil recruitment cascade. In uninfected cats and cats infected neonatally with FIV, the mesentery was exteriorized, but remained autoperfused during intravital microscopy for 4 h. When the tissue was superfused with 10 μg/ml of LPS for 4 h, intravital microscopy displayed a profound increase in neutrophil rolling at both 8 and 12 wk of age in uninfected cats. At 12 wk of age, FIV-infected animals showed a profound decrease in the number of rolling neutrophils. In vitro studies revealed that neutrophils from infected and uninfected animals rolled equally well on surrogate selectin substrata. In addition, in vivo neutrophil adhesion and emigration out of the vasculature were severely reduced, and in vitro neutrophil chemotaxis from FIV-infected animals was significantly impaired in response to fMLP or IL-8. However, FIV infection of neutrophils could not be detected. In summary, in vivo lentivirus infection with immunosuppression leads to a severe impairment in neutrophil rolling, adhesion, and emigration in response to bacterial stimulants potentially involving both endothelial and neutrophil dysfunction. These in vivo studies also indicate that neutrophil dysfunction should be taken into account when treating infections and tissue injury.
Short-Time Infusion of Fish Oil-Based Lipid Emulsions, Approved for Parenteral Nutrition, Reduces Monocyte Proinflammatory Cytokine Generation and Adhesive Interaction with Endothelium in Humans
Authors: Mayer Konstantin , Meyer Sandra , Reinholz-Muhly Marion , Maus Ulrich , Merfels Martina , Lohmeyer Jürgen , Grimminger Friedrich , Seeger Werner 
Published: April 2014

AbstractPotential impact of ω-3 fatty acids, as contained in fish oil, on immunological function has been suggested because observations of reduced inflammatory diseases in Greenland Inuit were published. A fish oil-based lipid emulsion has recently been approved for parenteral nutrition in many countries. We investigated the influence of a short infusion course of fish oil-based (ω-3) vs conventional (ω-6) lipid emulsion on monocyte function. In a randomized design, twelve healthy volunteers received ω-3 or ω-6 lipid infusion for 48 h, with cross-over repetition of the infusion course after 3 mo. Fatty acid profiles, monocyte cytokine release and adhesive monocyte-endothelium interaction were investigated. Resultant ω-6 lipid emulsion increased plasma-free fatty acids including arachidonic acid, whereas the ω-3/ω-6 fatty acid ratio in monocyte membranes remained largely unchanged. It also caused a tendency toward enhanced monocyte proinflammatory cytokine release and adhesive monocyte-endothelium interaction. In contrast, ω-3 lipid emulsion significantly increased the ω-3/ω-6 fatty acid ratio in the plasma-free fatty acid fraction and in monocyte membrane lipid pool, markedly suppressing monocyte generation of TNF-α, IL-1, IL-6, and IL-8 in response to endotoxin. In addition, it also significantly inhibited both monocyte-endothelium adhesion and transendothelial monocyte migration, although monocyte surface expression of relevant adhesive molecules (CD11b, CD18, CD49 days, CCR2) was unchanged. Although isocaloric, ω-3 and ω-6 lipid emulsions exert differential impact on immunological processes in humans. In addition to its nutritional value, fish oil-based ω-3 lipid emulsion significantly suppresses monocyte proinflammatory cytokine generation and features of monocyte recruitment.
Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection
Authors: Belperio John A. , Keane Michael P. , Burdick Marie D. , Lynch Joseph P. , Zisman David A. , Xue Ying Ying , Li Kewang , Ardehali Abbas , Ross David J. , Strieter Robert M. 
Published: April 2014

Abstract
Acute allograft rejection is a major complication postlung transplantation and is the main risk factor for the development of bronchiolitis obliterans syndrome. Acute rejection is characterized by intragraft infiltration of activated mononuclear cells. The ELR-negative CXC chemokines CXCL9, CXCL10, and CXCL11) are potent chemoattractants for mononuclear cells and act through their shared receptor, CXCR3. Elevated levels of these chemokines in bronchoalveolar lavage fluid have been associated with human acute lung allograft rejection. This led to the hypothesis that the expression of these chemokines during an allogeneic response promotes the recruitment of mononuclear cells, leading to acute lung allograft rejection. We performed studies in a rat orthotopic lung transplantation model of acute rejection, and demonstrated increased expression of CXCL9 and CXCL10 paralleling the recruitment of mononuclear cells and cells expressing CXCR3 to the allograft. However, CXCL9 levels were 15-fold greater than CXCL10 during maximal rejection. Inhibition of CXCL9 decreased intragraft recruitment of mononuclear cells and cellular expression of CXCR3, resulting in lower acute lung allograft rejection scores. Furthermore, the combination of low dose cyclosporin A with anti-CXCL9 therapy had more profound effects on intragraft leukocyte infiltration and in reducing acute allograft rejection scores. This supports the notion that CXCL9 interaction with cells expressing CXCR3 has an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of acute lung allograft rejection.
Accumulation of Peribronchial Mast Cells in a Mouse Model of Ovalbumin Allergen Induced Chronic Airway Inflammation: Modulation by Immunostimulatory DNA Sequences
Authors: Ikeda Reid K. , Miller Marina , Nayar Jyothi , Walker Linda , Cho Jae Youn , McElwain Kirsti , McElwain Shauna , Raz Eyal , Broide David H. 
Published: April 2014

Abstract
Few peribronchial mast cells are noted either in the lungs of naive mice or in the lungs of OVA-sensitized mice challenged acutely with OVA by inhalation. In this study, we demonstrate that OVA-sensitized mice exposed to repetitive OVA inhalation for 1–6 mo have a significant accumulation of peribronchial mast cells. This accumulation of peribronchial mast cells is associated with increased expression of the Th2 cell-derived mast cell growth factors, including IL-4 and IL-9, but not with the non-Th2 cell-derived mast cell growth factor, stem cell factor. Pretreating mice with immunostimulatory sequences (ISS) of DNA containing a CpG motif significantly inhibited the accumulation of peribronchial mast cells and the expression of IL-4 and IL-9. To determine whether mast cells express Toll-like receptor-9 (TLR-9; the receptor for ISS), TLR-9 expression by mouse bone marrow-derived mast cells (MBMMCs) was assessed by RT-PCR. MBMMCs strongly expressed TLR-9 and bound rhodamine-labeled ISS. However, incubation of MBMMCs with ISS in vitro neither inhibited MBMMC proliferation nor inhibited Ag/IgE-mediated MBMMC degranulation, but they did induce IL-6. Overall these studies demonstrate that mice exposed to repetitive OVA challenge, but not acute OVA challenge, have an accumulation of peribronchial mast cells and express increased levels of mast cell growth factors in the lung. Although mast cells express TLR-9, ISS does not directly inhibit mast cell proliferation in vitro, suggesting that ISS inhibits accumulation of peribronchial mast cells in vivo by indirect mechanism(s), which include inhibiting the lung expression of Th2 cell-derived mast cell growth factors.