bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Iodination of Thyroglobulin Facilitates Processing and Presentation of a Cryptic Pathogenic Peptide
Authors: Dai Yang D. , Rao Varada P. , Carayanniotis George 
Published: April 2014

AbstractIncreased iodine intake has been associated with the development of experimental autoimmune thyroiditis (EAT), but the biological basis for this association remains poorly understood. One hypothesis has been that enhanced incorporation of iodine in thyroglobulin (Tg) promotes the generation of pathogenic T cell determinants. In this study we sought to test this by using the pathogenic nondominant As-binding Tg peptides p2495 and p2694 as model Ags. SJL mice challenged with highly iodinated Tg (I-Tg) developed EAT of higher severity than Tg-primed controls, and lymph node cells (LNC) from I-Tg-primed hosts showed a higher proliferation in response to I-Tg in vitro than Tg-primed LNC reacting to Tg. Interestingly, I-Tg-primed LNC proliferated strongly in vitro against p2495, but not p2694, indicating efficient and selective priming with p2495 following processing of I-Tg in vivo. Tg-primed LNC did not respond to either peptide. Similarly, the p2495-specific, IL-2-secreting T cell hybridoma clone 5E8 was activated when I-Tg-pulsed, but not Tg-pulsed, splenocytes were used as APC, whereas the p2694-specific T cell hybridoma clone 6E10 remained unresponsive to splenic APC pulsed with Tg or I-Tg. The selective in vitro generation of p2495 was observed in macrophages or dendritic cells, but not in B cells, suggesting differential processing of I-Tg among various APC. These data demonstrate that enhanced iodination of Tg facilitates the selective processing and presentation of a cryptic pathogenic peptide in vivo or in vitro and suggest a mechanism that can at least in part account for the association of high iodine intake and the development of EAT.
Diesel Exposure Favors Th2 Cell Recruitment by Mononuclear Cells and Alveolar Macrophages from Allergic Patients by Differentially Regulating Macrophage-Derived Chemokine and IFN-γ-Induced Protein-10 Production
Authors: Fahy Olivier , Sénéchal Stéphanie , Pène Jérôme , Scherpereel Arnaud , Lassalle Philippe , Tonnel André-Bernard , Yssel Hans , Wallaert Benoı̂t , Tsicopoulos Anne 
Published: April 2014

AbstractDiesel exhausts and their associated organic compounds may be involved in the recent increase in the prevalence of allergic disorders, through their ability to favor a type 2 immune response. Type 2 T cells have been shown to be preferentially recruited by the chemokines eotaxin (CCL11), macrophage-derived chemokine (MDC, CCL22), and thymus activation-regulated chemokine (CCL17) through their interaction with CCR3 and CCR4, respectively, whereas type 1 T cells are mainly recruited by IFN-γ-induced protein-10 (CXCL10) through CXCR3 binding. The aim of the study was to evaluate the effect of diesel exposure on the expression of chemokines involved in type 1 and 2 T cell recruitment. PBMC and alveolar macrophages from house dust mite allergic patients were incubated with combinations of diesel extracts and Der p 1 allergen, and chemokine production was analyzed. Diesel exposure alone decreased the constitutive IP-10 production, while it further augmented allergen-induced MDC production, resulting in a significantly increased capacity to chemoattract human Th2, but not Th1 clones. Inhibition experiments with anti-type 1 or type 2 cytokine Abs as well as cytokine mRNA kinetic evaluation showed that the chemokine variations were not dependent upon IL-4, IL-13, or IFN-γ expression. In contrast, inhibition of the B7:CD28 pathway using a CTLA-4-Ig fusion protein completely inhibited diesel-dependent increase of allergen-induced MDC production. This inhibition was mainly dependent upon the CD86 pathway and to a lesser extent upon the CD80 pathway. These results suggest that the exposure to diesel exhausts and allergen may likely amplify a deleterious type 2 immune response via a differential regulation of chemokine production through the CD28 pathway.
The Kinetics of In Vivo Priming of CD4 and CD8 T Cells by Dendritic/Tumor Fusion Cells in MUC1-Transgenic Mice
Authors: Koido Shigeo , Tanaka Yasuhiro , Chen Dongshu , Kufe Donald , Gong Jianlin 
Published: April 2014

AbstractPrevious work has demonstrated that dendritic/tumor fusion cells induce potent antitumor immune responses in vivo and in vitro. However, little is known about the migration and homing of fusion cells after s.c. injection or the kinetics of CD4+ and CD8+ T cell activation. In the present study, fluorescence-labeled dendritic/MUC1-positive tumor fusion cells (FC/MUC1) were injected s.c. into MUC1-transgenic mice. The FC/MUC1 migrated to draining lymph nodes and were closely associated with T cells in a pattern comparable with that of unfused dendritic cells. Immunization of MUC1-transgenic mice with FC/MUC1 resulted in proliferation of T cells and induced MUC1-specific CD8+ CTL. Moreover, CD4+ T cells activated by FC/MUC1 were multifunctional effectors that produced IL-2, IFN-γ, IL-4, and IL-10. These findings indicate that both CD4+ and CD8+ T cells can be primed in vivo by FC/MUC1 immunization.
Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs
Authors: Erdmann Iris , Scheidegger E. Paul , Koch Frauke K. , Heinzerling Lucie , Odermatt Bernhard , Burg Günter , Lowe John B. , Kündig Thomas M. 
Published: April 2014

Abstract
The first step of leukocyte extravasation, leukocyte rolling, is mediated by E-, P-, and L-selectins. Mice deficient for α-1,3-fucosyltransferase VII (FucTVII)−/− are characterized by deficiency of E-, P-, and L-selectin ligand activity. This model system was used to evaluate the role of the interactions of selectins with their ligands in T and B cell responses. In the present study, FucTVII−/− mice showed reduced CD4+ T cell-mediated contact hypersensitivity reactions of the ears to FITC as well as reduced CD8+ T cell-mediated delayed-type hypersensitivity reactions of the footpads against lymphocytic choriomeningitis virus infection. As Langerhans cell migration to local lymph nodes as well as CD4+ and CD8+ T cell induction were found to be normal, the afferent arm of these reactions was not impaired. The reduced inflammatory reactions of the skin were due to inefficient lymphocyte extravasation into the skin. In contrast, extravasation of CD4+ and CD8+ T cells into visceral organs, such as the ovaries or the brain, was not impaired in FucTVII−/− mice. Elimination of vaccinia virus and of lymphocytic choriomeningitis virus from ovaries and brain, as well as elimination of tumor cells from several visceral organs was normal. Thus, interactions of selectins with their ligands are important for lymphocyte homing into the skin, but not for lymphocyte extravasation into visceral organs.
Defective Fas Ligand Expression and Activation-Induced Cell Death in the Absence of IL-2-Inducible T Cell Kinase
Authors: Miller Andrew T. , Berg Leslie J. 
Published: April 2014

AbstractThe Tec family tyrosine kinase, IL-2-inducible T cell kinase (Itk), plays an important role in TCR signaling. Studies of T cells from Itk-deficient mice have demonstrated that Itk is critical for the activation of phospholipase-Cγ1, leading to calcium mobilization in response to TCR stimulation. This biochemical defect results in reduced IL-2 production by Itk-deficient T cells. To further characterize the downstream effects of the Itk deficiency, we crossed Itk−/− mice to a TCR-transgenic line and examined T cell responses to stimulation by peptide plus APC. These studies show that Itk is required for maximal activation of early growth responses 2 and 3 and Fas ligand transcription after TCR stimulation. These transcriptional defects lead to reduced activation-induced cell death of stimulated Itk−/− T cells, both in vitro and in vivo. Together these studies define an important role for Itk in TCR signaling, leading to cytokine gene expression and activation-induced cell death.
IL-12 Induces Monocyte IL-18 Binding Protein Expression Via IFN-γ
Authors: Veenstra Korina G. , Jonak Zdenka L. , Trulli Stephen , Gollob Jared A. 
Published: April 2014

Abstract
IL-18 is a Th1 cytokine that synergizes with IL-12 and IL-2 in the stimulation of lymphocyte IFN-γ production. IL-18 binding protein (IL-18BP) is a recently discovered inhibitor of IL-18 that is distinct from the IL-1 and IL-18 receptor families. In this report we show that IL-18BPa, the IL-18BP isoform with the highest affinity for IL-18, was strongly induced by IL-12 in human PBMC. Other Th1 cytokines, including IFN-γ, IL-2, IL-15, and IL-18, were also capable of augmenting IL-18BPa expression. In contrast, IL-1α, IL-1β, TNF-α, IFN-γ-inducible protein-10, and Th2 cytokines such as IL-4 and IL-10 did not induce IL-18BPa. Although monocytes were found to be the primary source of IL-18BPa, the induction of IL-18BPa by IL-12 was mediated through IFN-γ derived predominantly from NK cells. IL-18BPa production was observed in cancer patients receiving recombinant human IL-12 and correlated with the magnitude of IFN-γ production. The IFN-γ/IL-18BPa negative feedback loop identified in this study may be capable of broadly controlling immune activation by cytokines that synergize with IL-18 to induce IFN-γ and probably plays a key role in the modulation of both innate and adaptive immunity.
Evidence for the Murine IgH μ Locus Acting as a Hot Spot for Intrachromosomal Homologous Recombination
Authors: Raynard Steven J. , Read Leah R. , Baker Mark D. 
Published: April 2014

Abstract
Homologous recombination accomplishes the exchange of genetic information between two similar or identical DNA duplexes. It can occur either by gene conversion, a process of unidirectional genetic exchange, or by reciprocal crossing over. Homologous recombination is well known for its role in generating genetic diversity in meiosis and, in mitosis, as a DNA repair mechanism. In the immune system, the evidence suggests a role for homologous recombination in Ig gene evolution and in the diversification of Ab function. Previously, we reported the occurrence of homologous recombination between repeated, donor and recipient alleles of the Ig H chain μ gene C (Cμ) region residing at the Ig μ locus in mouse hybridoma cells. In this study, we constructed mouse hybridoma cell lines bearing Cμ region heteroalleles to learn more about the intrachromosomal homologous recombination process. A high frequency of homologous recombination (gene conversion) was observed for markers spanning the entire recipient Cμ region, suggesting that recombination might initiate at random sites within the Cμ region. The Cμ region heteroalleles were equally proficient as either conversion donors or recipients. Remarkably, when the same Cμ heteroalleles were tested for recombination in ectopic genomic positions, the mean frequency of gene conversion was reduced by at least 65-fold. These results are consistent with the murine IgH μ locus behaving as a hot spot for intrachromosomal homologous recombination.
Xenopus laevis Stromal Cell-Derived Factor 1: Conservation of Structure and Function During Vertebrate Development
Authors: Braun Mike , Wunderlin Markus , Spieth Kathrin , Knöchel Walter , Gierschik Peter , Moepps Barbara 
Published: April 2014

Abstract
Transmembrane signaling of the CXC chemokine stromal cell-derived factor-1 (SDF-1) is mediated by CXCR4, a G protein-coupled receptor initially identified in leukocytes and shown to serve as a coreceptor for the entry of HIV into lymphocytes. Characterization of SDF-1- and CXCR4-deficient mice has revealed that SDF-1 and CXCR4 are of vital developmental importance. To study the role of the SDF-1/CXCR4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cDNA encoding SDF-1 of the lower vertebrate Xenopus laevis (xSDF-1). Recombinant xSDF-1 was produced in insect cells, purified, and functionally characterized. Although xSDF-1 is only 64–66% identical with its mammalian counterparts, it is indistinguishable from human (h)SDF-1α in terms of activating both X. laevis CXCR4 and hCXCR4. Thus, both xSDF-1 and hSDF-1α promoted CXCR4-mediated activation of heterotrimeric Gi2 in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells. Analysis of the time course of xSDF-1 mRNA expression during Xenopus embryogenesis revealed a tightly coordinated regulation of xSDF-1 and X. laevis CXCR4. xSDF-1 mRNA was specifically detected in the developing CNS, incipient sensory organs, and the embryonic heart. In Xenopus, CXCR4 mRNA appears to be absent from the heart anlage, but present in neural crest cells. This observation suggests that xSDF-1 expressed in the heart anlage may attract cardiac neural crest cells expressing CXCR4 to migrate to the primordial heart to regulate both septation of the cardiac outflow tract and differentiation of the myocardium during early heart development.
Transient Association of Ku with Nuclear Substrates Characterized Using Fluorescence Photobleaching
Authors: Rodgers William , Jordan Stephen J. , Capra J. Donald 
Published: April 2014

Abstract
The autoantigen Ku, composed of subunits Ku70 and Ku86, is necessary for repair of DNA double-strand breaks by nonhomologous end joining. Similarly, Ku participates in repair of DNA double-strand breaks that occur during V(D)J recombination, and it is therefore required for the development of B and T lymphocytes. Although previous studies have identified the DNA-binding activities of Ku, little is known concerning its dynamics, such as the mobility of Ku in the nucleus and its rate of association with substrates. To address this question, fluorescence photobleaching experiments were performed using HeLa cells and B cells expressing a green fluorescent protein (GFP) fusion construct of either Ku70 or Ku86. The results show that Ku moves rapidly throughout the nucleus even following irradiation of the cells. However, the rate of diffusion of Ku was ∼100-fold slower than that predicted from its size. Association of Ku-GFP with a filamentous nuclear structure was also evident, and nuclear extraction experiments suggest that this represents nuclear matrix. A central domain of Ku70 containing its DNA-binding and heterodimerization regions and its nuclear localization signal shows that this alone is sufficient for the observed mobility of Ku70-GFP and its association with nuclear matrix. These data suggest the mobility of Ku is characterized by a transient, high flux association with nuclear substrates that includes both DNA and the nuclear matrix and may represent a mechanism for repair of double-strand breaks using the nuclear matrix as a scaffold.
Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response
Authors: Nair Deepak T. , Singh Kavita , Siddiqui Zaved , Nayak Bishnu P. , Rao Kanury V. S. , Salunke Dinakar M. 
Published: April 2014

Abstract
Crystal structures of distinct mAbs that recognize a common epitope of a peptide Ag have been determined and analyzed in the unbound and bound forms. These Abs display dissimilar binding site structures in the absence of the Ag. The dissimilarity is primarily expressed in the conformations of complementarity-determining region H3, which is responsible for defining the epitope specificity. Interestingly, however, the three Abs exhibit similar complementarity-determining region conformations in the Ag binding site while recognizing the common epitope, indicating that different pathways of binding are used for Ag recognition. The epitope also exhibits conformational similarity when bound to each of these Abs, although the peptide Ag was otherwise flexible. The observed conformational convergence in the epitope and the Ag binding site was facilitated by the plasticity in the nature of interactions.
IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection
Authors: Schopf Lisa R. , Hoffmann Karl F. , Cheever Allen W. , Urban Joseph F. , Wynn Thomas A. 
Published: April 2014

Abstract
Resistance to many intestinal nematodes is dependent on the induction of polarized type 2 cytokine responses, whereas type 1 responses can exacerbate these infections. The contributions of IL-4 and IL-13 to the development of resistance have been well described for a variety of intestinal parasites; however, the role of IL-10 has not been previously investigated. In this study we infected IL-10-, IL-10/IL-4-, IL-10/IL-12-, IL-4-, and IL-12-deficient mice with Trichuris muris to determine whether IL-10 contributes to the development of immunity. Interestingly, T. muris-infected IL-10-, IL-4-, and IL-10/IL-4-deficient mice failed to expel the parasite, and animals deficient in IL-10 displayed marked morbidity and mortality. In contrast, double IL-10/IL-12-deficient mice were completely resistant and mounted a highly polarized type 2 cytokine response, demonstrating that the increased susceptibility of IL-10-deficient mice was dependent on IL-12. Further study suggested that the susceptibility of IL-10- and IL-10/IL-4-deficient mice was probably attributable to a marked increase in type 1 cytokine production in those animals. The mortality observed in T. muris-infected IL-10- and IL-10/IL-4-deficient mice correlated with increased inflammation, loss of Paneth cells, and absence of mucus in the cecum. Interestingly, survival was enhanced in T. muris-infected IL-10/IL-4-deficient mice if a broad spectrum antibiotic was administered, suggesting that an outgrowth of opportunistic bacteria was contributing to the high degree of morbidity and mortality. Overall, these studies reveal a critical role for IL-10 in the polarization of Th2 responses, development of resistance during T. muris infection, and maintenance of barrier function in the colon.
Identification of BING-4 Cancer Antigen Translated From an Alternative Open Reading Frame of a Gene in the Extended MHC Class II Region Using Lymphocytes From a Patient With a Durable Complete Regression Following Immunotherapy
Authors: Rosenberg Steven A. , Tong-On Panida , Li Yong , Riley John P. , El-Gamil Mona , Parkhurst Maria R. , Robbins Paul F. 
Published: April 2014

Abstract
Multiple human cancer Ags have been identified, although little is known concerning which would be most effectively used in cancer immunotherapy. To gain insight into the selection of appropriate Ags, the immunologic reactivity of a patient who had a durable complete regression of melanoma metastases was measured. PBMCs were directly cloned using the monoclonal anti-CD3 Ab OKT3 and IL-2 without any bias introduced by previous culture. A lymphocyte clone recognized a previously unknown shared melanoma Ag that was identified as the BING-4 protein encoded in a gene-rich region of the extended class II MHC. The HLA-A2-restricted BING-4 immunodominant peptide was translated from a 10-aa-long alternative open reading frame. In vitro sensitization against this peptide generated lymphocytes reactive against HLA-A2+ melanomas. Real-time semiquantitative RT-PCR analysis revealed that 8 of 15 melanoma cell lines overexpressed BING-4, and this correlated with recognition by lymphocytes. Overexpression was not found in normal tissues or other tumor types. Thus, BING-4 represents another candidate Ag for possible use in the immunotherapy of patients with melanoma.
A Unique Combination of Inflammatory Cytokines Enhances Apoptosis of Thyroid Follicular Cells and Transforms Nondestructive to Destructive Thyroiditis in Experimental Autoimmune Thyroiditis
Authors: Wang Su He , Bretz James D. , Phelps Ellen , Mezosi Emese , Arscott Patricia L. , Utsugi Saho , Baker James R. 
Published: April 2014

Abstract
Treatment of cultured primary human thyroid cells with IFN-γ and TNF-α uniquely allows the induction of Fas-mediated apoptosis. To investigate the role of this cytokine combination in vivo, CBA/J mice were immunized with thyroglobulin and then injected with IFN-γ and TNF-α. Compared with control animals, mice treated with IFN-γ and TNF-α showed significantly sustained lymphocytic infiltration in the thyroid, which was associated with the destruction of portions of the follicular architecture at wk 6 after initial immunization. Furthermore, the number of apoptotic thyroid follicular cells was increased only in the thyroids from mice treated with the IFN-γ and TNF-α. We also analyzed the function of the Fas pathway in vivo in cytokine-treated mice by using an agonist anti-Fas Ab injected directly into the thyroid. Minimal apoptosis of thyroid epithelial cells was observed unless the mice were pretreated with IFN-γ and TNF-α. These data demonstrate that this unique combination of inflammatory cytokines facilitates the apoptotic destruction of thyroid follicular cells in experimental autoimmune thyroiditis, in a manner similar to what is observed in Hashimoto’s thyroiditis in humans.
A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness
Authors: Zuo Li , Cullen Constance M. , DeLay Monica L. , Thornton Sherry , Myers Linda K. , Rosloniec Edward F. , Boivin Gregory P. , Hirsch Raphael 
Published: April 2014

Abstract
T cells play a central role in many autoimmune diseases. A method to specifically target the function of autoreactive T cell clones would avoid the global immunosuppression associated with current therapies. To develop a molecule capable of inhibiting autoreactive T cell responses in vivo, single-chain peptide-I-A-IgG3 fusion proteins were constructed and expressed in both mammalian and insect cells. The fusion proteins were designed with an IgG3 Fc moiety to make them divalent, allowing TCR cross-linking, while lacking FcR binding and costimulation. The fusion proteins stimulated T cell hybridomas in vitro in a peptide-specific, MHC-restricted manner but failed to do so in soluble form. In vivo administration of an I-Aq fusion protein, containing an immunodominant collagen II peptide, significantly delayed the onset and reduced the severity of collagen-induced arthritis in DBA/1 mice by induction of Ag-specific hyporesponsiveness. Such fusion proteins may be useful to study novel therapeutic approaches for T cell-mediated autoimmune diseases.
Cutting Edge: DNA Polymerases μ and λ Are Dispensable for Ig Gene Hypermutation
Authors: Bertocci Barbara , De Smet Annie , Flatter Eric , Dahan Auriel , Bories Jean-Christophe , Landreau Catherine , Weill Jean-Claude , Reynaud Claude-Agnès 
Published: April 2014

AbstractMutations arising in Ig V genes during an immune response are most likely introduced by one or several error-prone DNA polymerases. Many of the recently described nonreplicative DNA polymerases have an intrinsic fidelity compatible with such an activity, the strongest candidates being polymerase (pol) η, pol ι, pol ζ, and pol μ. We report in this work that mice inactivated for either of the two polymerases related to pol β (i.e., pol μ and pol λ) are viable and fertile and display a normal hypermutation pattern.