bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chlamydia trachomatis Native Major Outer Membrane Protein Induces Partial Protection in Nonhuman Primates: Implication for a Trachoma Transmission-Blocking Vaccine
Authors: Kari Laszlo , Whitmire William M. , Crane Deborah D. , Reveneau Nathalie , Carlson John H. , Goheen Morgan M. , Peterson Ellena M. , Pal Sukumar , de la Maza Luis M. , Caldwell Harlan D. 
Published: June 2009

Abstract
A vaccine is likely the most effective strategy for controlling human chlamydial infections. Recent studies have shown immunization with Chlamydia muridarum major outer membrane protein (MOMP) can induce significant protection against infection and disease in mice if its native trimeric structure is preserved (nMOMP). The objective of this study was to investigate the immunogenicity and vaccine efficacy of Chlamydia trachomatis nMOMP in a nonhuman primate trachoma model. Cynomolgus monkeys (Macaca fascicularis) were immunized systemically with nMOMP, and monkeys were challenged ocularly. Immunization induced high serum IgG and IgA ELISA Ab titers, with Abs displaying high strain-specific neutralizing activity. The PBMCs of immunized monkeys produced a broadly cross-reactive, Ag-specific IFN-γ response equivalent to that induced by experimental infection. Immunized monkeys exhibited a significant decrease in infectious burden during the early peak shedding periods (days 3–14). However, at later time points, they exhibited no difference from control animals in either burden or duration of infection. Immunization had no effect on the progression of ocular disease. These results show that systemically administered nMOMP is highly immunogenic in nonhuman primates and elicits partially protective immunity against ocular chlamydial challenge. This is the first time a subunit vaccine has shown a significant reduction in ocular shedding in nonhuman primates. A partially protective vaccine, particularly one that reduces infectious burden after primary infection of children, could interrupt the natural trachoma reinfection cycle. This would have a beneficial effect on the transmission between children and sensitized adults which drives blinding inflammatory disease.
Cooperation between Mast Cells and Neurons Is Essential for Antigen-Mediated Bronchoconstriction
Authors: Cyphert Jaime M. , Kovarova Martina , Allen Irving C. , Hartney John M. , Murphy Dennis L. , Wess Jürgen , Koller Beverly H. 
Published: June 2009

Abstract
Mast cells are important sentinels guarding the interface between the environment and the body: a breach in the integrity of this interface can lead to the release of a plethora of mediators that engage the foreign agent, recruit leukocytes, and initiate adaptive physiological changes in the organism. While these capabilities make mast cells critical players in immune defense, it also makes them important contributors to the pathogenesis of diseases such as asthma. Mast cell mediators induce dramatic changes in smooth muscle physiology, and the expression of receptors for these factors by smooth muscle suggests that they act directly to initiate constriction. Contrary to this view, we show herein that mast cell-mediated bronchoconstriction is observed only in animals with intact innervation of the lung and that serotonin release alone is required for this action. While ablation of sensory neurons does not limit bronchoconstriction, constriction after Ag challenge is absent in mice in which the cholinergic pathways are compromised. Linking mast cell function to the cholinergic system likely provides an important means of modulating the function of these resident immune cells to physiology of the lung, but may also provide a safeguard against life-threatening anaphylaxis during mast cell degranulation.
Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1
Authors: Ko Hyun-Mi , Oh Sin-Hye , Bang Hwa-Suk , Kang Nam-In , Cho Baik-Hwan , Im Suhn-Young , Lee Hern-Ku 
Published: June 2009

Abstract
The nonessential amino acid l-glutamine (Gln) is the most abundant amino acid in plasma. Clinical trials have demonstrated that Gln therapy is safe and improves clinical outcomes in critically ill patients. We have previously shown that Gln protect animals from endotoxic shock through the inhibition of cytosolic phospholipase A2 activity. In this study, we investigated how Gln regulates MAPK activation, as the molecular mechanism underlying Gln-induced cytosolic phospholipase A2 inactivation. Gln rapidly (within 10 min) inactivated p38 and JNK, but not ERK, by dephosphorylating them only when these MAPKs were phosphorylated in response to LPS in vivo as well as in vitro. Western blot analysis revealed that Gln administration resulted in rapid (∼5 min) phosphorylation and protein induction of MAP kinase phosphatase-1 (MKP-1). MKP-1 siRNA abrogated the Gln-mediated 1) inactivation of p38 and JNK, 2) induction of MKP-1, and 3) protection against endotoxic shock. The ERK inhibitor U0126 blocked Gln-induced MKP-1 phosphorylation and protein induction, as well as Gln’s protective activity against endotoxic shock. These data suggest that Gln exerts a beneficial effect on endotoxic shock by inactivating p38 and JNK via a rapid induction of MKP-1 protein in an ERK-dependent way.
The Immunomodulatory Action of Sialostatin L on Dendritic Cells Reveals Its Potential to Interfere with Autoimmunity
Authors: Sá-Nunes Anderson , Bafica André , Antonelli Lis R. , Choi Eun Young , Francischetti Ivo M. B. , Andersen John F. , Shi Guo-Ping , Chavakis Triantafyllos , Ribeiro José M. , Kotsyfakis Michalis 
Published: June 2009

Abstract
Sialostatin L (SialoL) is a secreted cysteine protease inhibitor identified in the salivary glands of the Lyme disease vector Ixodes scapularis. In this study, we reveal the mechanisms of SialoL immunomodulatory actions on the vertebrate host. LPS-induced maturation of dendritic cells from C57BL/6 mice was significantly reduced in the presence of SialoL. Although OVA degradation was not affected by the presence of SialoL in dendritic cell cultures, cathepsin S activity was partially inhibited, leading to an accumulation of a 10-kDa invariant chain intermediate in these cells. As a consequence, in vitro Ag-specific CD4+ T cell proliferation was inhibited in a time-dependent manner by SialoL, and further studies engaging cathepsin S−/− or cathepsin L−/− dendritic cells confirmed that the immunomodulatory actions of SialoL are mediated by inhibition of cathepsin S. Moreover, mice treated with SialoL displayed decreased early T cell expansion and recall response upon antigenic stimulation. Finally, SialoL administration during the immunization phase of experimental autoimmune encephalomyelitis in mice significantly prevented disease symptoms, which was associated with impaired IFN-γ and IL-17 production and specific T cell proliferation. These results illuminate the dual mechanism by which a human disease vector protein modulates vertebrate host immunity and reveals its potential in prevention of an autoimmune disease.
Reduced Expression of the Mevalonate Pathway Enzyme Farnesyl Pyrophosphate Synthase Unveils Recognition of Tumor Cells by Vγ9Vδ2 T Cells
Authors: Li Jianqiang , Herold Marco J. , Kimmel Brigitte , Müller Ingrid , Rincon-Orozco Bladimiro , Kunzmann Volker , Herrmann Thomas 
Published: June 2009

Abstract
Human Vγ9Vδ2 T cells are characterized by a unique specificity for certain tumors (e.g., Daudi), cells presenting so-called phosphoantigens such as isopentenyl pyrophosphate (IPP), or cells treated with aminobisphosphonates. We now report conversion of hematopoietic and nonhematopoietic tumor cell lines into Vγ9Vδ2 T cell activators by means of short hairpin RNA-mediated knockdown of expression of the IPP-consuming enzyme, farnesyl pyrophosphate synthase (FPPS). FPPS knockdown cells activated Vγ9Vδ2 T cells, as measured by increased levels of CD69 and CD107a, killing of FPPS knockdown cells, and induction of IFN-γ secretion. The IPP-synthesis-inhibiting drug mevastatin reduced Vγ9Vδ2 T cell activation by FPPS knockdown cells but not activation by the phosphoantigen bromohydrin pyrophosphate. In conclusion, our data support the concept of Vγ9Vδ2 T cells as sensors of a dysregulated isoprenoid metabolism and suggest therapeutic down-modulation of FPPS expression as an additional tool to target tumor cells to Vγ9Vδ2 T cell-mediated immunosurveillance.
Glycolipids Injected into the Skin Are Presented to NKT Cells in the Draining Lymph Node Independently of Migratory Skin Dendritic Cells
Authors: Tripp Christoph H. , Sparber Florian , Hermans Ian F. , Romani Nikolaus , Stoitzner Patrizia 
Published: June 2009

Abstract
APCs, such as dendritic cells (DC), can present glycolipid Ags on CD1d molecules to NKT cells. This interaction activates DC and NKT cells, leading to release of cytokines and enhanced T cell responses. Thus, glycolipid Ags are currently being tested as adjuvants for immunotherapy. We were interested in the interaction of murine skin DC with NKT cells in skin-draining lymph nodes. We observed that all skin DC subsets expressed CD1d upon migration to the lymph nodes. Moreover, skin DC were able to present the synthetic glycolipid Ag α-galactosylceramide (α-GalCer) to the NKT cell hybridoma DN32.D3. Intradermally injected α-GalCer was presented by migratory skin DC and lymph node DC to NKT hybridoma cells in vitro. When we injected α-GalCer intradermally into the skin, the numbers of various leukocyte subsets in the draining lymph nodes did not change significantly. However, T and B cells as well as NKT cells up-regulated the activation marker CD69. Coapplication of α-GalCer with the tumor model Ag OVA induced strong cytolytic CD8+ T cell function that could inhibit the growth of B16 melanoma cells expressing OVA. However, mice that were devoid of migratory skin DC developed similar cytotoxic immune responses after intradermal immunization, indicating that skin DC are not required for the adjuvant properties of NKT cell activation and Ag presentation by this immunization route. In conclusion, migratory skin DC are able to interact with NKT cells; however, intradermally applied glycolipids are presented predominantly by lymph node DC to NKT cells.
A Single Nucleotide Polymorphism inTyk2Controls Susceptibility to Experimental Allergic Encephalomyelitis
Authors: Spach Karen M. , Noubade Rajkumar , McElvany Ben , Hickey William F. , Blankenhorn Elizabeth P. , Teuscher Cory 
Published: June 2009

AbstractGenes controlling immunopathologic diseases of differing etiopathology may also influence susceptibility to autoimmune disease. B10.D1-H2q/SgJ mice with a 2538 G→A missense mutation in the tyrosine kinase-2 gene (Tyk2) are susceptible to Toxoplasma gondii yet resistant to autoimmune arthritis, unlike the wild-type B10.Q/Ai substrain. To understand whether Tyk2 is also important in a second autoimmune model, experimental allergic encephalomyelitis (EAE) was induced in B10.D1-H2q/SgJ (Tyk2A) and B10.Q/Ai (Tyk2G) mice with the myelin oligodendrocyte glycoprotein peptide 79–96. B10.D1-H2q/SgJ mice were resistant to EAE whereas B10.Q/Ai mice were susceptible, and a single copy of the Tyk2G allele conferred EAE susceptibility in F1 hybrids. Furthermore, EAE resistance in B10.D1-H2q/SgJ mice was overridden when pertussis toxin (PTX) was used to mimic the effects of environmental factors derived from infectious agents. Numerous cytokines and chemokines were increased when PTX was included in the immunization protocol. However, only RANTES, IL-6, and IFN-γ increased significantly with both genetic compensation and PTX treatment. These data indicate that Tyk2 is a shared autoimmune disease susceptibility gene whose genetic contribution to disease susceptibility can be modified by environmental factors. Single nucleotide polymorphisms like the one that distinguishes Tyk2 alleles are of considerable significance given the potential role of gene-by-environment interactions in autoimmune disease susceptibility.
Identification and Biochemical Characterization of Human Plasma Soluble IL-7R: Lower Concentrations in HIV-1-Infected Patients
Authors: Rose Thierry , Lambotte Olivier , Pallier Coralie , Delfraissy Jean-François , Colle Jean-Hervé 
Published: June 2009

Abstract
The IL-7R α-chain and the common γ-chain (γc) are both components of IL-7R. Human plasma harbors soluble forms of IL-7R (sIL-7Rα and sγc) that are detected and assayed by Western blotting, showing that the levels of sIL-7Rα are higher than the levels of sγc (47.5 ng/ml and 1.5 ng/ml, respectively). Gel electrophoresis and tandem mass spectrometry used to analyze deglycosylated, affinity-purified protein showed that sIL-7Rα is generated through differentially spliced mRNA, not by membrane receptor shedding. Plasma sIL-7Rα and sγc are present as heterocomplexes and sγc was found to be mainly associated with sIL-7Rα. The affinities of two IL-7 binding sites (Kd = 35 ± 8 pM and Kd = 3 ± 1 nM) were similar to that of the membrane receptor, suggesting that the sIL-7Rα/sγc complex retains high affinity for IL-7. sIL-7Rα mRNA is constitutively present among peripheral T lymphocytes and is down-modulated in vitro by IL-7. Chronically HIV-1-infected patients (n = 20) showed no significant (p &gt; 0.714) variation in sγc levels and a significant (p &lt; 0.0014) 2-fold decrease in plasma sIL-7Rα levels compared with those in control healthy individuals. Plasma IL-7 and sIL-7Rα levels did not show any obvious relationship.
Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-Transgenic Mice Expressing Specific Anti-Gliadin CD4+ T Cells
Authors: de Kauwe Andrea L. , Chen Zhenjun , Anderson Robert P. , Keech Catherine L. , Price Jason D. , Wijburg Odilia , Jackson David C. , Ladhams Jodi , Allison Janette , McCluskey James 
Published: June 2009

Abstract
Celiac disease is a chronic inflammatory enteropathy caused by cellular immunity to dietary gluten. More than 90% of patients carry HLA-DQ2 encoded by HLA-DQA1*05 and DQB1*02, and gluten-specific CD4+ T cells from intestinal biopsies of these patients are HLA-DQ2-restricted, produce Th1 cytokines and preferentially recognize gluten peptides deamidated by tissue transglutaminase. We generated mice lacking murine MHC class II genes that are transgenic for human CD4 and the autoimmunity and celiac disease-associated HLA-DR3-DQ2 haplotype. Immunization with the α-gliadin 17-mer that incorporates the overlapping DQ2-α-I and DQ2-α-II epitopes immunodominant in human celiac disease generates peptide-specific HLA-DQ2-restricted CD4+ T cells. When exposed to dietary gluten, naive or gliadin-primed mice do not develop pathology. Coincident introduction of dietary gluten and intestinal inflammation resulted in low-penetrance enteropathy and tissue transglutaminase-specific IgA. Two further strains of transgenic mice expressing HLA-DR3-DQ2 and human CD4, one with a NOD background and another TCR transgenic having over 90% of CD4+ T cells specific for the DQ2-α-II epitope with a Th1 phenotype, were also healthy when consuming gluten. These humanized mouse models indicate that gluten ingestion can be tolerated without intestinal pathology even when HLA-DQ2-restricted CD4+ T cell immunity to gluten is established, thereby implicating additional factors in controlling the penetrance of celiac disease.
Selective Up-Regulation of Intact, but Not Defective env RNAs of Endogenous Modified Polytropic Retrovirus by the Sgp3 Locus of Lupus-Prone Mice
Authors: Yoshinobu Kumiko , Baudino Lucie , Santiago-Raber Marie-Laure , Morito Naoki , Dunand-Sauthier Isabelle , Morley Bernard J. , Evans Leonard H. , Izui Shozo 
Published: June 2009

Abstract
Endogenous retroviruses are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Because four different classes of endogenous retroviruses, i.e., ecotropic, xenotropic, polytropic, or modified polytropic (mPT), are expressed in mice, we investigated the possibility that a particular class of endogenous retroviruses is associated with the development of murine SLE. We observed &gt;15-fold increased expression of mPT env (envelope) RNA in livers of all four lupus-prone mice, as compared with those of nine nonautoimmune strains of mice. This was not the case for the three other classes of retroviruses. Furthermore, we found that in addition to intact mPT transcripts, many strains of mice expressed two defective mPT env transcripts which carry a deletion in the env sequence of the 3′ portion of the gp70 surface protein and the 5′ portion of the p15E transmembrane protein, respectively. Remarkably, in contrast to nonautoimmune strains of mice, all four lupus-prone mice expressed abundant levels of intact mPT env transcripts, but only low or nondetectable levels of the mutant env transcripts. The Sgp3 (serum gp70 production 3) locus derived from lupus-prone mice was responsible for the selective up-regulation of the intact mPT env RNA. Finally, we observed that single-stranded RNA-specific TLR7 played a critical role in the production of anti-gp70 autoantibodies. These data suggest that lupus-prone mice may possess a unique genetic mechanism responsible for the expression of mPT retroviruses, which could act as a triggering factor through activating TLR7 for the development of autoimmune responses in mice predisposed to SLE.
Suppression of IgE B Cells and IgE Binding to FcεRI by Gene Therapy with Single-Chain Anti-IgE
Authors: Ota Takayuki , Aoki-Ota Miyo , Duong Bao Hoa , Nemazee David 
Published: June 2009

AbstractIgE plays a pivotal role in allergic reactions and asthma through its ability to bind to the mast cell FcR for IgE (FcεRI). Current therapies to suppress such reactions include passive treatment with neutralizing Abs to IgE that block its binding to FcεRI. In theory, induction of immune tolerance in the B lymphocytes that carry IgE Ag receptors and give rise to IgE-secreting cells should provide longer term efficacy. However, recent data have suggested that such memory cells may lack cell surface IgE. Using a gene therapy approach, we show that a recombinant single-chain neutralizing anti-IgE could not only neutralize circulating IgE, but also reduce IgE+ B cell numbers and H chain transcripts. Therapeutic anti-IgE stimulated a calcium response in primary B cells or in a B cell line expressing membrane IgE and suppressed IgE secretion in vitro, suggesting that active signaling through membrane IgE likely promoted tolerance. Interestingly, upon subsequent challenge of anti-IgE-treated mice with an IgE cross-linking reagent capable of inducing activation of IgE-decorated mast cells, an anaphylaxis reaction was induced, apparently via a FcγRIII pathway involving recognition of anti-IgE Ab itself. These studies have important implications for the optimal design of safe and effective anti-IgE therapies and suggest that the IgE memory B cells may be targeted by such genetic Ab therapies.
SP-A Preserves Airway Homeostasis During Mycoplasma pneumoniae Infection in Mice
Authors: Ledford Julie G. , Goto Hisatsugu , Potts Erin N. , Degan Simone , Chu Hong Wei , Voelker Dennis R. , Sunday Mary E. , Cianciolo George J. , Foster William M. , Kraft Monica , Wright Jo Rae 
Published: June 2009

Abstract
The lung is constantly challenged during normal breathing by a myriad of environmental irritants and infectious insults. Pulmonary host defense mechanisms maintain homeostasis between inhibition/clearance of pathogens and regulation of inflammatory responses that could injure the airway epithelium. One component of this defense mechanism, surfactant protein-A (SP-A), exerts multifunctional roles in mediating host responses to inflammatory and infectious agents. SP-A has a bacteriostatic effect on Mycoplasma pneumoniae (Mp), which occurs by binding surface disaturated phosphatidylglycerols. SP-A can also bind the Mp membrane protein, MPN372. In this study, we investigated the role of SP-A during acute phase pulmonary infection with Mp using mice deficient in SP-A. Biologic responses, inflammation, and cellular infiltration, were much greater in Mp infected SP-A−/− mice than wild-type mice. Likewise, physiologic responses (airway hyperresponsiveness and lung compliance) to Mp infection were more severely affected in SP-A−/− mice. Both Mp-induced biologic and physiologic changes were attenuated by pharmacologic inhibition of TNF-α. Our findings demonstrate that SP-A is vital to preserving lung homeostasis and host defense to this clinically relevant strain of Mp by curtailing inflammatory cell recruitment and limiting an overzealous TNF-α response.
The C-Type Lectin Clec12A Present on Mouse and Human Dendritic Cells Can Serve as a Target for Antigen Delivery and Enhancement of Antibody Responses
Authors: Lahoud Mireille H. , Proietto Anna I. , Ahmet Fatma , Kitsoulis Susie , Eidsmo Liv , Wu Li , Sathe Priyanka , Pietersz Suzanne , Chang Hsuen-Wen , Walker Ian D. , Maraskovsky Eugene , Braley Hal , Lew Andrew M. , Wright Mark D. , Heath William R. , Shortman Ken , Caminschi Irina 
Published: June 2009

Abstract
We have cloned the mouse and human C-type lectin Clec12A, expressed both, and produced mAb recognizing both. Mouse Clec12A is highly expressed on splenic CD8+ dendritic cells (DC) and plasmacytoid DC. A proportion of CD8−DC also expresses lower levels of Clec12A, as do monocytes, macrophages, and B cells. Human CLEC12A, like the mouse counterpart, is expressed on blood monocytes and DC, including pDC and BDCA-3+DC, the proposed equivalent of mouse CD8+DC. To determine whether Ag targeted to Clec12A could induce immune responses, mice were injected with a rat mAb recognizing Clec12A, or a control rat mAb, then production of anti-rat Ig was measured. Anti-Clec12A mAb alone produced only moderate responses, but these were amplified by coinjecting only small amounts of LPS as a DC activation agent. Furthermore, when OVA was conjugated to anti-Clec12A mAb, OVA-specific T cells were induced to proliferate. This Ag presentation to naive T cells was due to targeting conventional DC, because their ablation eliminated T cell activation. The potent Ab responses induced using microgram amounts of anti-Clec12A and minimal amounts of adjuvant demonstrate that this molecule can be used as an Ag-delivery target to enhance Ab responses to vaccines.
α9 Integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis
Authors: Kanayama Masashi , Kurotaki Daisuke , Morimoto Junko , Asano Tsuyoshi , Matsui Yutaka , Nakayama Yosuke , Saito Yoshinari , Ito Koyu , Kimura Chiemi , Iwasaki Norimasa , Suzuki Koji , Harada Tanenobu , Li Hong Mei , Uehara Jun , Miyazaki Tadaaki , Minami Akio , Kon Shigeyuki , Uede Toshimitsu 
Published: June 2009

Abstract
Osteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, α9 integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express α9 integrin, and autocrine and paracrine interactions of α9 integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. α9 integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of α9 integrin function with an anti-α9 integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified α9 integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.