bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tolerance to Noninherited Maternal MHC Antigens in Mice
Authors: Andrassy Joachim , Kusaka Satoshi , Jankowska-Gan Ewa , Torrealba Jose R. , Haynes Lynn D. , Marthaler Brodie R. , Tam Robert C. , Illigens Ben M.-W. , Anosova Natalie , Benichou Gilles , Burlingham William J. 
Published: April 2014

AbstractThe phenomenon of tolerance to noninherited maternal Ags (NIMA) is poorly understood. To analyze the NIMA effect C57BL/6 (H-2b/b) males were mated with B6D2F1 (H-2b/d) females, whereby 50% of the offspring are H-2b/b mice that have been exposed to maternal H-2d alloantigens. Controls were H-2b/b offspring of C57BL/6 mothers, either inbred C57BL/6 mice or F1 backcross mice from breedings with H-2b/d fathers. We found that 57% of the H-2b/b offspring of semiallogeneic (H-2b/d) mothers accepted fully allogeneic DBA/2 (H-2d/d) heart grafts for &gt;180 days, while similar transplants were all rejected by day 11 in controls (p &lt; 0.0004). Foster nursing studies showed that both oral and in utero exposure to NIMA are required for this tolerogenic effect. An effect of NIMA was also found to extend the survival of skin grafts from a semiallogeneic donor (p &lt; 0.02). Pretransplant analysis of splenocytes showed a 40–90% reduction of IL-2-, IL-5-, and IFN-γ-producing T cells responding to H-2d-expressing APC in NIMAd-exposed vs control mice. Injection of pregnant BALB/c-dm2 (H-2Ld-negative) female mice i.v. with H-2Ld61–80 peptide profoundly suppressed the offspring’s indirect pathway alloreactive CD4+ T cell response to H-2Ld. These results suggest that the natural exposure of the fetus and newborn to maternal cells and/or soluble MHC Ags suppresses NIMA-allospecific T cells of the offspring, predisposing to organ transplant tolerance in adult mice.
Impaired Germinal Center Maturation in Adenosine Deaminase Deficiency
Authors: Aldrich Melissa B. , Chen Wilma , Blackburn Michael R. , Martinez-Valdez Hector , Datta Surjit K. , Kellems Rodney E. 
Published: April 2014

AbstractMice deficient in the enzyme adenosine deaminase (ADA) have small lymphoid organs that contain reduced numbers of peripheral lymphocytes, and they are immunodeficient. We investigated B cell deficiency in ADA-deficient mice and found that B cell development in the bone marrow was normal. However, spleens were markedly smaller, their architecture was dramatically altered, and splenic B lymphocytes showed defects in proliferation and activation. ADA-deficient B cells exhibited a higher propensity to undergo B cell receptor-mediated apoptosis than their wild-type counterparts, suggesting that ADA plays a role in the survival of cells during Ag-dependent responses. In keeping with this finding, IgM production by extrafollicular plasmablast cells was higher in ADA-deficient than in wild-type mice, thus indicating that activated B cells accumulate extrafollicularly as a result of a poor or nonexistent germinal center formation. This hypothesis was subsequently confirmed by the profound loss of germinal center architecture. A comparison of levels of the ADA substrates, adenosine and 2′-deoxyadenosine, as well resulting dATP levels and S-adenosylhomocysteine hydrolase inhibition in bone marrow and spleen suggested that dATP accumulation in ADA-deficient spleens may be responsible for impaired B cell development. The altered splenic environment and signaling abnormalities may concurrently contribute to a block in B cell Ag-dependent maturation in ADA-deficient mouse spleens.
A Blunted Blood Plasmacytoid Dendritic Cell Response to an Acute Systemic Viral Infection Is Associated with Increased Disease Severity
Authors: Pichyangkul Sathit , Endy Timothy P. , Kalayanarooj Siripen , Nisalak Ananda , Yongvanitchit Kosol , Green Sharone , Rothman Alan L. , Ennis Francis A. , Libraty Daniel H. 
Published: April 2014

Abstract
At least two distinct human dendritic cell (DC) subsets are produced in the bone marrow and circulate in the peripheral blood-precursor myeloid DCs (pre-mDCs) and plasmacytoid DCs (PDCs). Both lineages of DCs are instrumental in antiviral innate immunity and shaping Th1 adaptive immune responses. PDCs are the most potent IFN-α-producing cells to viral pathogens. Dengue, an acute flavivirus disease, provides a model to study DC responses to a self-limited human viral infection. We analyzed circulating DC subsets in a prospective study of children with dengue across a broad range of illness severities: healthy controls; mild, nondengue, presumed viral infections; moderately ill dengue fever; and, the most severe form of illness, dengue hemorrhagic fever. We also examined PDC responses in monkeys with asymptomatic dengue viremia and to dengue virus exposure in vitro. The absolute number and frequency of circulating pre-mDCs early in acute viral illness decreased as illness severity increased. Depressed pre-mDC blood levels appeared to be part of the typical innate immune response to acute viral infection. The frequency of circulating PDCs trended upward and the absolute number of circulating PDCs remained stable early in moderately ill children with dengue fever, mild other, nondengue, febrile illness, and monkeys with asymptomatic dengue viremia. However, there was an early decrease in circulating PDC levels in children who subsequently developed dengue hemorrhagic fever. A blunted blood PDC response to dengue virus infection was associated with higher viremia levels, and was part of an altered innate immune response and pathogenetic cascade leading to severe disease.
Unopposed Matrix Metalloproteinase-9 Expression in Human Tuberculous Granuloma and the Role of TNF-α-Dependent Monocyte Networks
Authors: Price Nicholas M. , Gilman Robert H. , Uddin Jasim , Recavarren Sixto , Friedland Jon S. 
Published: April 2014

AbstractTuberculosis is characterized by granuloma formation and caseous necrosis, but the factors causing tissue destruction are poorly understood. Matrix metalloproteinase (MMP)-9 (92-kDa gelatinase) secretion from monocytes is stimulated by Mycobacterium tuberculosis (M. tb) and associated with local tissue injury in tuberculosis patients. We demonstrate strong immunohistochemical MMP-9 staining in monocytic cells at the center of granuloma and adjacent to caseous necrosis in M. tb-infected patient lymph nodes. Minimal tissue inhibitor of MMPs-1 staining indicated that MMP-9 activity is unopposed. Because granulomas characteristically contain few mycobacteria, we investigated whether monocyte-monocyte cytokine networks amplify MMP-9 secretion. Conditioned medium from M. tb-infected primary human monocytes or THP-1 cells (CoMTB) stimulated MMP-9 gene expression and a &gt;10-fold increase in MMP-9 secretion by monocytes at 3–4 days (p &lt; 0.009, vs controls). Although CoMTB stimulated dose-dependent MMP-9 secretion, MMP-1 (52-kDa collagenase) was not induced. Anti-TNF-α Ab but not IL-1R antagonist pretreatment decreased CoMTB-induced MMP-9 secretion by 50% (p = 0.0001). Anti-TNF-α Ab also inhibited MMP-9 secretion from monocytic cells by 50%, 24 h after direct M. tb infection (p = 0.0002). Conversely, TNF-α directly stimulated dose-dependent MMP-9 secretion. Pertussis toxin inhibited CoMTB-induced MMP-9 secretion and enhanced the inhibitory effect of anti-TNF-α Ab (p = 0.05). Although chemokines bind to G protein-linked receptors, CXCL8, CXCL10, CCL2, and CCL5 did not stimulate monocyte MMP-9 secretion. However, the response to cholera toxin confirmed that G protein signaling pathways were intact. In summary, MMP-9 within tuberculous granuloma is associated with tissue destruction, and TNF-α, critical for antimycobacterial granuloma formation, is a key autocrine and paracrine regulator of MMP-9 secretion.
Peptide-MHC Class II Dimers as Therapeutics to Modulate Antigen-Specific T Cell Responses in Autoimmune Diabetes
Authors: Masteller Emma L. , Warner Matthew R. , Ferlin Walter , Judkowski Valeria , Wilson Darcy , Glaichenhaus Nicolas , Bluestone Jeffrey A. 
Published: April 2014

AbstractType 1 diabetes is an autoimmune disorder caused by autoreactive T cells that mediate destruction of insulin-producing β cells of the pancreas. Studies have shown that T cell tolerance can be restored by inducing a partial or altered signal through the TCR. To investigate the potential of bivalent peptide-MHC class II/Ig fusion proteins as therapeutics to restore Ag-specific tolerance, we have developed soluble peptide I-Ag7 dimers for use in the nonobese diabetic mouse model of diabetes. I-Ag7 dimers with a linked peptide specific for islet-reactive BDC2.5 TCR transgenic CD4+ T cells were shown to specifically bind BDC2.5 T cells as well as a small population of Ag-specific T cells in nonobese diabetic mice. In vivo treatment with BDC2.5 peptide I-Ag7 dimers protected mice from diabetes mediated by the adoptive transfer of diabetogenic BDC2.5 CD4+ T cells. The dimer therapy resulted in the activation and increased cell death of transferred BDC2.5 CD4+ T cells. Surviving cells were hypoproliferative to challenge by Ag and produced increased levels of IL-10 and decreased levels of IFN-γ compared with cells from control I-Ag7 dimer-treated mice. Anti-IL-10R therapy reversed the tolerogenic effects of the dimer. Thus, peptide I-Ag7 dimers induce tolerance of BDC2.5 TCR T cells through a combination of the induction of clonal anergy and anti-inflammatory cytokines.
IFN-γ Polymorphisms (IFN-γ +2109 and IFN-γ +3810) Are Associated with Severe Hepatic Fibrosis in Human Hepatic Schistosomiasis (Schistosoma mansoni)
Authors: Chevillard Christophe , Moukoko Carole Eboumbou , Elwali Nasr-Eldin M. A. , Bream Jay H. , Kouriba Bourema , Argiro Laurent , Rahoud Siddig , Mergani Adil , Henri Sandrine , Gaudart Jean , Mohamed-Ali Qurashi , Young Howard A. , Dessein Alain J. 
Published: April 2014

Abstract
Schistosome infection is a major public health concern affecting millions of people living in tropical regions of Africa, Asia, and South America. Schistosomes cause mild clinical symptoms in most subjects, whereas a small proportion of individuals presents severe clinical disease (as periportal fibrosis (PPF)) that may lead to death. Severe PPF results from an abnormal deposition of extracellular matrix proteins in the periportal spaces due to a chronic inflammation triggered by eggs and schistosome Ags. Extracellular matrix protein production is regulated by a number of cytokines, including IFN-γ. We have now screened putative polymorphic sites within this gene in a population living in an endemic area for Schistosoma mansoni. Two polymorphisms located in the third intron of the IFN-γ gene are associated with PPF. The IFN-γ +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-γ +3810 G/A polymorphism is associated with less PPF. The polymorphisms result in changes in nuclear protein interactions with the intronic regions of the gene, suggesting that they may modify IFN-γ mRNA expression. These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the α-chain of the IFN-γ receptor, and low IFN-γ producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN-γ expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).
Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients
Authors: Coker Heather A. , Durham Stephen R. , Gould Hannah J. 
Published: April 2014

AbstractImmunoglobulin E is produced by nasal B cells in response to allergen. We have analyzed IgE VH region sequences expressed in the nasal mucosa of patients suffering from allergic rhinitis. VH region sequences were amplified by RT-PCR from IgE+ B cells from nasal biopsies. In two of six patients, sequence analysis clearly demonstrated the presence of closely related IgE+ B cell clones: cells displaying identical signature regions across CDR3/FWR4, indicating a common clonal ancestry, but a mixture of shared and diverse somatic mutations across the VH region. Furthermore, in one of the two patients exhibiting related IgE+ B cell clones, five IgA+ B cell clones, related to the IgE+ B cell family, were also isolated from the patient’s nasal mucosa. This evidence, combined with the local expression of mRNA transcripts encoding activation-induced cytidine deaminase, suggests that local somatic hypermutation, clonal expansion, and class switch recombination occur within the nasal mucosa of allergic rhinitics. The presence of related B cells in the nasal mucosa does not appear to result from the random migration of IgE+ cells from the systemic pool, as analysis of a nonatopic subject with highly elevated serum IgE did not exhibit any detectable VH-Cε transcripts in the nasal mucosa. We have provided evidence that suggests for the first time that the nasal mucosa of allergic rhinitics is an active site for local somatic hypermutation, clonal expansion, and class switch recombination, making it of major significance for the targeting of future therapies.
Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1
Authors: Wilson Cara C. , McKinney Denise , Anders Michelle , MaWhinney Samantha , Forster Jeri , Crimi Claire , Southwood Scott , Sette Alessandro , Chesnut Robert , Newman Mark J. , Livingston Brian D. 
Published: April 2014

AbstractEpitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-γ ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.
Conversion of Monophasic to Recurrent Autoimmune Disease by Autoreactive T Cell Subsets
Authors: Shao Hui , Lei Song , Sun Sheher L. , Kaplan Henry J. , Sun Deming 
Published: April 2014

AbstractAutoimmune uveitis has been elicited in susceptible rodents by several ocular-specific Ags. In most of these animal models the induced uveitis is acute and monophasic. Because recurrent uveitis poses the highest risk for blinding ocular complications in human disease, a spontaneous relapsing animal model would be most helpful in understanding the disease pathogenesis. In our current study we have observed that the adoptive transfer of interphotoreceptor retinoid-binding protein residues 1177–1191-specific T cells to naive Lewis rats induced a chronic relapsing disease, in contrast to the monophasic disease induced by immunization with interphotoreceptor retinoid-binding protein residues 1177–1191 emulsified in CFA. The chronic relapsing uveitis induced by autoreactive T cell subsets is dependent on the number of autoreactive T cells generated as well as their activation status. Our study documented a spontaneous model of recurrent uveitis in the rat, which should assist us in the study of disease pathogenesis and the design of specific therapy.
Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity
Authors: Rodríguez Dunia , Keller Alexandre C. , Faquim-Mauro Eliana L. , de Macedo Mahasti S. , Cunha Fernando Q. , Lefort Jean , Vargaftig B. Boris , Russo Momtchilo 
Published: April 2014

Abstract
Asthma results from an intrapulmonary allergen-driven Th2 response and is characterized by intermittent airway obstruction, airway hyperreactivity, and airway inflammation. An inverse association between allergic asthma and microbial infections has been observed. Microbial infections could prevent allergic responses by inducing the secretion of the type 1 cytokines, IL-12 and IFN-γ. In this study, we examined whether administration of bacterial LPS, a prototypic bacterial product that activates innate immune cells via the Toll-like receptor 4 (TLR4) could suppress early and late allergic responses in a murine model of asthma. We report that LPS administration suppresses the IgE-mediated and mast cell-dependent passive cutaneous anaphylaxis, pulmonary inflammation, airway eosinophilia, mucus production, and airway hyperactivity. The suppression of asthma-like responses was not due to Th1 shift as it persisted in IL-12−/− or IFN-γ−/− mice. However, the suppressive effect of LPS was not observed in TLR4- or NO synthase 2-deficient mice. Our findings demonstrate, for the first time, that LPS suppresses Th2 responses in vivo via the TLR4-dependent pathway that triggers NO synthase 2 activity.
IL-18 Enhances Collagen-Induced Arthritis by Recruiting Neutrophils Via TNF-α and Leukotriene B4
Authors: Cannetti Claudio A. , Leung Bernard P. , Culshaw Shauna , McInnes Iain B. , Cunha Fernando Q. , Liew Foo Y. 
Published: April 2014

Abstract
IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-α induction, which drives the production of leukotriene B4 (LTB4), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB4 and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB4 synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB4 production could also be blocked by a neutralizing anti-TNF-α Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55−/− mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB4 that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.
Matrix Metalloproteinase-9-Mediated Dendritic Cell Recruitment into the Airways Is a Critical Step in a Mouse Model of Asthma
Authors: Vermaelen Karim Y. , Cataldo Didier , Tournoy Kurt , Maes Tania , Dhulst An , Louis Renaud , Foidart Jean-Michel , Noël Agnès , Pauwels Romain 
Published: April 2014

AbstractDendritic cells (DCs) appear to be strategically implicated in allergic diseases, including asthma. Matrix metalloproteinase (MMP)-9 mediates transmigration of inflammatory leukocytes across basement membranes. This study investigated the role of MMP-9 in airway DC trafficking during allergen-induced airway inflammation. MMP-9 gene deletion affected the trafficking of pulmonary DCs in a specific way: only the inflammatory transmigration of DCs into the airway lumen was impaired, whereas DC-mediated transport of airway Ag to the thoracic lymph nodes remained unaffected. In parallel, the local production of the Th2-attracting chemokine CC chemokine ligand 17/thymus and activation-regulated chemokine, which was highly concentrated in purified lung DCs, fell short in the airways of allergen-exposed MMP-9−/− mice. This was accompanied by markedly reduced peribronchial eosinophilic infiltrates and impaired allergen-specific IgE production. We conclude that the specific absence of MMP-9 activity inhibits the development of allergic airway inflammation by impairing the recruitment of DCs into the airways and the local production of DC-derived proallergic chemokines.
The RhoA Effector mDia Is Induced During T Cell Activation and Regulates Actin Polymerization and Cell Migration in T Lymphocytes
Authors: Vicente-Manzanares Miguel , Rey Mercedes , Pérez-Martínez Manuel , Yáñez-Mó María , Sancho David , Cabrero José Román , Barreiro Olga , de la Fuente Hortensia , Itoh Kazuyuki , Sánchez-Madrid Francisco 
Published: April 2014

Abstract
Regulation of actin polymerization is critical for many different functions of T lymphocytes, including cell migration. Here we show that the RhoA effector mDia is induced in vitro in activated PBL and is highly expressed in vivo in diseased tissue-infiltrating activated lymphocytes. mDia localizes at the leading edge of polarized T lymphoblasts in an area immediately posterior to the leading lamella, in which its effector protein profilin is also concentrated. Overexpression of an activated mutant of mDia results in an inhibition of both spontaneous and chemokine-directed T cell motility. mDia does not regulate the shape of the cell, which involves another RhoA effector, p160 Rho-coiled coil kinase, and is not involved in integrin-mediated cell adhesion. However, mDia activation blocked CD3- and PMA-mediated cell spreading. mDia activation increased polymerized actin levels, which resulted in the blockade of chemokine-induced actin polymerization by depletion of monomeric actin. Moreover, mDia was shown to regulate the function of the small GTPase Rac1 through the control of actin availability. Together, our data demonstrate that RhoA is involved in the control of the filamentous actin/monomeric actin balance through mDia, and that this balance is critical for T cell responses.