bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Sequence Assembly and Characterization of the C57BL/6 Mouse Ig Heavy Chain V Region
Authors: Johnston Colette M. , Wood Andrew L. , Bolland Daniel J. , Corcoran Anne E. 
Published: April 2014

Abstract
The mechanisms that regulate variable (V) gene selection during the development of the mouse IgH repertoire are not fully understood, due in part to the absence of the complete locus sequence. To better understand these processes, we have assembled the entire 2.5-Mb mouse IgH (Igh) V region sequence of the C57BL/6 strain from public sequences and present the first complete annotated map of the region, including V genes, pseudogenes, repeats, and nonrepetitive intergenic sequences. In so doing, we have discovered a new V gene family, VH16. We have identified clusters of conserved region-specific intergenic sequences and have verified our assembly by genic and intergenic Southern blotting. We have observed that V pseudogenes are not evenly spread throughout the V region, but rather cluster together. The largest J558 family, which spans more than half of the locus, has two strikingly different domains, which suggest points of evolutionary divergence or duplication. The 5′ end contains widely spaced J558 genes interspersed with 3609 genes and is pseudogene poor. The 3′ end contains closely spaced J558 genes, no 3609 genes, and is pseudogene rich. Each occupies a different branch of the phylogenetic tree. Detailed analysis of 500-bp upstream of all functional genes has revealed several conserved binding sites, general and B cell-specific, as well as key differences between families. This complete and definitive assembly of the mouse Igh V region will facilitate detailed study of promoter function and large-scale mechanisms associated with V(D)J recombination including locus contraction and antisense intergenic transcription.
Agonistic Antibody to TLR4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by TNF-α
Authors: Akashi-Takamura Sachiko , Furuta Takahisa , Takahashi Koichiro , Tanimura Natsuko , Kusumoto Yutaka , Kobayashi Toshihiko , Saitoh Shin-ichiroh , Adachi Yoshiyuki , Doi Takahiro , Miyake Kensuke 
Published: April 2014

Abstract
LPS is recognized by a heterodimer consisting of TLR4 and its coreceptor MD-2. LPS signal causes excessive inflammation and tissue damage. In this study, we show that a mAb to TLR4/MD-2 protected mice from acute lethal hepatitis caused by LPS/d-galactosamine. The protective effect of the mAb was not due to inhibition of LPS response, because serum TNF-α, which was induced by LPS and caused lethal hepatitis, was 10 times up-regulated by the mAb pretreatment. Moreover, this mAb induced antiapoptotic genes in liver in a TLR4/MD-2-dependent manner. These results demonstrated that an agonistic mAb to TLR4/MD-2 protected mice from LPS/d-galactosamine-induced acute lethal hepatitis by delivering a protective signal activating NF-κB through TLR4/MD-2.
Hemin Activation Ameliorates HIV-1 Infection via Heme Oxygenase-1 Induction
Authors: Devadas Krishnakumar , Dhawan Subhash 
Published: April 2014

Abstract
Hemin, a critical component of hemoglobin, is an active ingredient of a biologic therapeutic approved by the Food and Drug Administration for the treatment of acute porphyries. This report describes a biological function of this molecule in inducing host defense against HIV-1 infection via heme oxygenase-1 (HO-1) induction. Treatment of monocytes with hemin substantially inhibited HIV replication, as evident by nearly undetectable viral RNA and cell-free HIV-1 p24 protein in a dose-dependent manner. Hemin exposure of these cells before infection, at the time of infection, or after infection caused &gt;90% reduction of HIV DNA with substantially low levels of HIV-1 p24 and HIV-associated cytopathic effects. In addition, hemin treatment significantly suppressed infection of both monocytes and T cells inoculated with R5, X4, R5X4 tropic strains, and reverse transcriptase-resistant, azidothymidine-resistant, ddC/ddI-resistant, nivirapine-resistant, and other clinical HIV isolates. Intraperitoneal administration of hemin 4 days after HIV infection reduced viral load in the serum of human PBMC-reconstituted nonobese diabetic SCID mice by &gt;6-fold. Suppression of HIV replication in hemin-activated cells correlated with the induction of HO-1 and was attenuated by tin protoporphyrin (SnPP) IX, an inhibitor of HO-1 activity, suggesting a pivotal role of this endogenous enzyme in the regulation of HIV infection. Hemin-induced HO-1 induction in the CCR-5, CXCR-4, and CD4 coexpressing GHOST(3) cells was consistent with the inhibition of Tat-dependent activation of long terminal repeat promoter leading to reduced GFP expression. These findings suggest an important role of hemin-induced HO-1 activity as a host defense mechanism against HIV-1 infection.
Homing and Function of Human Skin γδ T Cells and NK Cells: Relevance for Tumor Surveillance
Authors: Ebert Lisa M. , Meuter Simone , Moser Bernhard 
Published: April 2014

Abstract
Normal (noninflamed) human skin contains a network of lymphocytes, but little is known about the homing and function of these cells. The majority of αβ T cells in normal skin express CCR8 and produce proinflammatory cytokines. In this study we examined other subsets of cutaneous lymphocytes, focusing on those with potential function in purging healthy tissue of transformed and stressed cells. Human dermal cell suspensions contained significant populations of Vδ1+ γδ T cells and CD56+CD16− NK cells, but lacked the subsets of Vδ2+ γδ T cells and CD56+CD16+ NK cells, which predominate in peripheral blood. The skin-homing receptors CCR8 and CLA were expressed by a large fraction of both cell types, whereas chemokine receptors associated with lymphocyte migration to inflamed skin were absent. Neither cell type expressed CCR7, although γδ T cells up-regulated this lymph node-homing receptor upon TCR triggering. Stimulation of cutaneous Vδ1+ γδ T cell lines induced secretion of large amounts of TNF-α, IFN-γ, and the CCR8 ligand CCL1. In contrast to cutaneous αβ T cells, both cell types had the capacity to produce intracellular perforin and displayed strong cytotoxic activity against melanoma cells. We therefore propose that γδ T cells and NK cells are regular constituents of normal human skin with potential function in the clearance of tumor and otherwise stressed tissue cells.
Lung-Restricted Macrophage Activation in the Pearl Mouse Model of Hermansky-Pudlak Syndrome
Authors: Young Lisa R. , Borchers Michael T. , Allen Holly L. , Gibbons Reta S. , McCormack Francis X. 
Published: April 2014

Abstract
Pulmonary inflammation, abnormalities in alveolar type II cell and macrophage morphology, and pulmonary fibrosis are features of Hermansky-Pudlak Syndrome (HPS). We used the naturally occurring “pearl” HPS2 mouse model to investigate the mechanisms of lung inflammation observed in HPS. Although baseline bronchoalveolar lavage (BAL) cell counts and differentials were similar in pearl and strain-matched wild-type (WT) mice, elevated levels of proinflammatory (MIP1γ) and counterregulatory (IL-12p40, soluble TNFr1/2) factors, but not TNF-α, were detected in BAL from pearl mice. After intranasal LPS challenge, BAL levels of TNF-α, MIP1α, KC, and MCP-1 were 2- to 3-fold greater in pearl than WT mice. At baseline, cultured pearl alveolar macrophages (AMs) had markedly increased production of inflammatory cytokines. Furthermore, pearl AMs had exaggerated TNF-α responses to TLR4, TLR2, and TLR3 ligands, as well as increased IFN-γ/LPS-induced NO production. After 24 h in culture, pearl AM LPS responses reverted to WT levels, and pearl AMs were appropriately refractory to continuous LPS exposure. In contrast, cultured pearl peritoneal macrophages and peripheral blood monocytes did not produce TNF-α at baseline and had LPS responses which were no different from WT controls. Exposure of WT AMs to heat- and protease-labile components of pearl BAL, but not WT BAL, resulted in robust TNF-α secretion. Similar abnormalities were identified in AMs and BAL from another HPS model, pale ear HPS1 mice. We conclude that the lungs of HPS mice exhibit hyperresponsiveness to LPS and constitutive and organ-specific macrophage activation.
Critical Role for Mast Cells in the Pathogenesis of 2,4-Dinitrobenzene-Induced Murine Colonic Hypersensitivity Reaction
Authors: Rijnierse Anneke , Koster Andries S. , Nijkamp Frans P. , Kraneveld Aletta D. 
Published: April 2014

Abstract
The immunological mechanisms underlying the role of mast cells in the pathogenesis of inflammatory bowel disease (IBD) are poorly defined. In this study, non-IgE mediated colonic hypersensitivity responses in BALB/c mice induced by skin sensitization with dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dinitrobenzene sulfonic acid featured as a model to study the role of mast cells in the development of IBD. Vehicle- or DNFB-sensitized mice were monitored for clinical symptoms and inflammation 72 h after dinitrobenzene sulfonic acid challenge. DNFB-sensitized mice developed diarrheic stool, increased colonic vascular permeability, hypertrophy of colonic lymphoid follicles (colonic patches), and showed cellular infiltration at the microscopic level. Increased numbers of mast cells were found in the colon of DNFB-sensitized mice located in and around colonic patches associated with elevated levels of mouse mast cell protease-1 in plasma indicating mast cell activation. Colonic patches of DNFB mice, stimulated in vitro with stem cell factor indicated that an increase in TNF-α levels in the colon is mainly mast cell originated. Finally, neutrophil infiltration was observed in the colon of DNFB-sensitized mice. Induction of this model in mast cell-deficient WBB6F1 W/Wv mice shows a profound reduction of characteristics of the colonic hypersensitivity reaction. Reconstitution with bone marrow-derived mast cells in WBB6F1 W/Wv mice fully restored the inflammatory response. This study demonstrates the importance of mast cells in the development of clinical symptoms and inflammation in the presented murine model for IBD.
Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-γ Production in CXCR3−/− Mice with Experimental Autoimmune Encephalomyelitis
Authors: Liu LiPing , Huang DeRen , Matsui Masaru , He Toby T. , Hu Taofang , DeMartino Julie , Lu Bao , Gerard Craig , Ransohoff Richard M. 
Published: April 2014

Abstract
Experimental autoimmune encephalomyelitis (EAE) is a CD4+ Th1 T cell-mediated disease of the CNS, used to study certain aspects of multiple sclerosis. CXCR3, the receptor for CXCL10, CXCL9, and CXCL11, is preferentially expressed on activated Th1 T cells and has been proposed to govern the migration of lymphocytes into the inflamed CNS during multiple sclerosis and EAE. Unexpectedly, CXCL10-deficient mice were susceptible to EAE, leaving uncertain what the role of CXCR3 and its ligands might play in this disease model. In this study, we report that CXCR3−/− mice exhibit exaggerated severity of EAE compared with wild-type (CXCR3+/+) littermate mice. Surprisingly, there were neither quantitative nor qualitative differences in CNS-infiltrating leukocytes between CXCR3+/+ and CXCR3−/− mice with EAE. Despite these equivalent inflammatory infiltrates, CNS tissues from CXCR3−/− mice with EAE showed worsened blood-brain barrier disruption and more von Willebrand factor-immunoreactive vessels within inflamed spinal cords, as compared with CXCR3+/+ mice. Spinal cords of CXCR3−/− mice with EAE demonstrated decreased levels of IFN-γ, associated with reduced inducible NO synthase immunoreactivity, and lymph node T cells from CXCR3−/− mice primed with MOG35–55 secreted less IFN-γ in Ag-driven recall responses than cells from CXCR3+/+ animals. CXCR3−/− lymph node T cells also showed enhanced Ag-driven proliferation, which was reduced by addition of IFN-γ. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 in EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN-γ production and downstream events that affect disease severity.
The Vast Majority of CLA+ T Cells Are Resident in Normal Skin
Authors: Clark Rachael A. , Chong Benjamin , Mirchandani Nina , Brinster Nooshin K. , Yamanaka Kei-ichi , Dowgiert Rebecca K. , Kupper Thomas S. 
Published: April 2014

Abstract
There are T cells within normal, noninflamed skin that most likely conduct immunosurveillance and are implicated in the development of psoriasis. We isolated T cells from normal human skin using both established and novel methods. Skin resident T cells expressed high levels of CLA, CCR4, and CCR6, and a subset expressed CCR8 and CXCR6. Skin T cells had a remarkably diverse TCR repertoire and were mostly Th1 memory effector cells with smaller subsets of central memory, Th2, and functional T regulatory cells. We isolated a surprising number of nonexpanded T cells from normal skin. To validate this finding, we counted T cells in sections of normal skin and determined that there are ∼1 × 106 T cells/cm2 normal skin and an estimated 2 × 1010 T cells in the entire skin surface, nearly twice the number of T cells in the circulation. Moreover, we estimate that 98% of CLA+ effector memory T cells are resident in normal skin under resting conditions. These findings demonstrate that there is a large pool of memory T cells in normal skin that can initiate and perpetuate immune reactions in the absence of T cell recruitment from the blood.
Iodination of Tyrosyls in Thyroglobulin Generates Neoantigenic Determinants That Cause Thyroiditis
Authors: Li Haiyan S. , Carayanniotis George 
Published: April 2014

Abstract
Thyroglobulin (Tg) is unique in its ability to incorporate and store available iodine in the form of iodotyrosyl residues. Iodination of Tg has been known to increase its immunopathogenicity in experimental animals, presumably through the formation of iodine-containing neoantigenic determinants that can elicit an autoimmune response, but defined pathogenic Tg peptides carrying iodotyrosyls have not yet been identified. We report in this study that a systematic, algorithm-based search of mouse Tg has delineated three iodotyrosyl-containing peptides that activate autoreactive T cells and cause experimental autoimmune thyroiditis in normal CBA/J mice. These peptides (aa 117–132, 304–318, and 1931–1945) were not immunogenic in their native form, and iodination of tyrosyls facilitated either peptide binding to MHC or T cell recognition of the peptide. These results demonstrate that iodotyrosyl formation in normal Tg confers pathogenic potential to certain peptides that may otherwise remain innocuous and undetectable by conventional mapping methods.
The Multiple Personalities of the Chemokine Receptor CCR7 in Dendritic Cells
Authors: Sánchez-Sánchez Noelia , Riol-Blanco Lorena , Rodríguez-Fernández José Luis 
Published: April 2014

AbstractCCR7 was described initially as a potent leukocyte chemotactic receptor that was later shown to be responsible of directing the migration of dendritic cells (DCs) to the lymph nodes where these cells play an important role in the initiation of the immune response. Recently, a variety of reports have indicated that, apart from chemotaxis, CCR7 controls the cytoarchitecture, the rate of endocytosis, the survival, the migratory speed, and the maturation of the DCs. Some of these functions of CCR7 and additional ones also have been described in other cell types. Herein we discuss how this receptor may contribute to modulate the immune response by regulating different functions in DCs. Finally, we also suggest a possible mechanism whereby CCR7 may control its multiple tasks in these cells.
Selection of Anti-Double-Stranded DNA B Cells in Autoimmune MRL-lpr/lprMice
Authors: Chen Ching , Li Hui , Tian Qi , Beardall Michael , Xu Yang , Casanova Nina , Weigert Martin 
Published: April 2014

AbstractAbs to DNA and nucleoproteins are expressed in systemic autoimmune diseases, whereas B cells producing such Abs are edited, deleted, or inactivated in healthy individuals. Why autoimmune individuals fail to regulate is not well understood. In this study, we investigate the sources of anti-dsDNA B cells in autoimmune transgenic MRL-lpr/lpr mice. These mice are particularly susceptible to lupus because they carry a site-directed transgene, H76R that codes for an anti-DNA H chain. Over 90% of the B cells are eliminated in the bone marrow of these mice, and the few surviving B cells are associated with one of two Vκ editors, Vκ38c and Vκ21D. Thus, it appears that negative selection by deletion and editing are intact in MRL-lpr/lpr mice. However, a population of splenic B cells in the H76R MRL-lpr/lpr mice produces IgG anti-nuclear Abs, and these mice have severe autoimmune organ damage. These IgG Abs are not associated with editors but instead use a unique Vκ gene, Vκ23. The H76R/Vκ23 combination has a relatively high affinity for dsDNA and an anti-nuclear Ab pattern characteristic of lupus. Therefore, this Vκ gene may confer a selective advantage to anti-DNA Abs in diseased mice.
Regulation of Intestinal Dendritic Cell Migration and Activation by Plasmacytoid Dendritic Cells, TNF-α and Type 1 IFNs after Feeding a TLR7/8 Ligand
Authors: Yrlid Ulf , Milling Simon W. F. , Miller Joanna L. , Cartland Sian , Jenkins Christopher D. , MacPherson G. Gordon 
Published: April 2014

Abstract
Dendritic cells (DCs) migrating via lymph are the primary influence regulating naive T cell differentiation, be it active immunity or tolerance. How DCs achieve this regulation in vivo is poorly understood. Intestinal DCs are in direct contact with harmless or pathogenic luminal contents, but may also be influenced by signals from epithelial cells, macrophages, or other resident or immigrant cells. To understand the role of TLR7 and TLR8 in regulating intestinal DC function, we fed a TLR7/8 ligand (resiquimod (R-848)) to rats and mice and examined DC in pseudoafferent lymph (rat) and mesenteric lymph nodes (MLNs). Oral R-848 induced a 20- to 30-fold increase in DC output from the intestine within 10 h due to a virtually total release of lamina propria DCs. This resulted in an accumulation of DCs in the MLNs that in mice was completely TNF-α dependent. Surprisingly, intestinal lymph DCs (iL-DCs) released by R-848 did not up-regulate CD86, but did up-regulate CD25. In contrast, MLN-DCs from R-848-stimulated rats and mice expressed high levels of CD86. This DC activation in MLNs was dependent on type 1 IFNs. The major source of these rapidly released cytokines is plasmacytoid DCs (pDCs) and not classical DCs, because depletion of pDCs significantly reduces the R-848-stimulated increase in serum cytokine levels as well as the accumulation and activation of DCs in MLNs. These experiments show that TLR-mediated regulation of iL-DC functions in vivo is complex and does not depend only on direct iL-DC stimulation, but can be regulated by pDCs.
Antigen-Induced IL-10+ Regulatory T Cells Are Independent of CD25+ Regulatory Cells for Their Growth, Differentiation, and Function
Authors: Nicolson Kirsty S. , O’Neill Emma J. , Sundstedt Anette , Streeter Heather B. , Minaee Sophie , Wraith David C. 
Published: April 2014

Abstract
Recent studies have emphasized the importance of T cells with regulatory/suppressor properties in controlling autoimmune diseases. A number of different types of regulatory T cells have been described with the best characterized being the CD25+ population. In addition, it has been shown that regulatory T cells can be induced by specific Ag administration. In this study, we investigate the relationship between peptide-induced, CD4+ regulatory T cells and naturally occurring CD4+CD25+ cells derived from the Tg4 TCR-transgenic mouse. Peptide-induced cells were FoxP3− and responded to Ag by secreting IL-10, whereas CD25+ cells failed to secrete this cytokine. Both cell types were able to suppress the proliferation of naive lymphocytes in vitro although with distinct activation sensitivities. Depletion of CD25+ cells did not affect the suppressive properties of peptide-induced regulators. Furthermore, peptide-induced regulatory/suppressor T cells could be generated in RAG−/−, TCR-transgenic mice that do not spontaneously generate CD25+ regulatory cells. These results demonstrate that these natural and induced regulatory cells fall into distinct subsets.
CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway
Authors: Ndungu Francis M. , Sanni Latifu , Urban Britta , Stephens Robin , Newbold Christopher I. , Marsh Kevin , Langhorne Jean 
Published: April 2014

AbstractWe have studied the human CD4 T cell response to a functionally conserved domain of Plasmodium falciparum erythrocyte membrane protein-1, cysteine interdomain region-1α (CIDR-1α). Responses to CIDR-1α were striking in that both exposed and nonexposed donors responded. The IFN-γ response to CIDR-1α in the nonexposed donors was partially independent of TCR engagement of MHC class II and peptide. Contrastingly, CD4 T cell and IFN-γ responses in malaria-exposed donors were MHC class II restricted, suggesting that the CD4 T cell response to CIDR-1α in malaria semi-immune adults also has a TCR-mediated component, which may represent a memory response. Dendritic cells isolated from human peripheral blood were activated by CIDR-1α to produce IL-12, IL-10, and IL-18. IL-12 was detectable only between 6 and 12 h of culture, whereas the IL-10 continued to increase throughout the 24-h time course. These data strengthen previous observations that P. falciparum interacts directly with human dendritic cells, and suggests that the interaction between CIDR-1α and the host cell may be responsible for regulation of the CD4 T cell and cytokine responses to P. falciparum-infected erythrocytes reported previously.
Expression of Functionally Different Dectin-1 Isoforms by Murine Macrophages
Authors: Heinsbroek Sigrid E. M. , Taylor Philip R. , Rosas Marcela , Willment Janet A. , Williams David L. , Gordon Siamon , Brown Gordon D. 
Published: April 2014

Abstract
Dectin-1 is a specific receptor for β-glucans and a major receptor for fungal particles on macrophages (Mφ). It is a type II membrane receptor that has a C-terminal, NK-like, C-type lectin-like domain separated from the cell membrane by a short stalk region and a cytoplasmic immunoreceptor tyrosine-based activation-like motif. We observed functional differences in dectin-1-dependent recognition of fungal particles by Mφ from different mouse strains. RT-PCR analysis revealed that mice have at least two splice forms of dectin-1, generated by differential usage of exon 3, encoding the full-length dectin-1A and a stalkless Mφ dectin-1B. Mφ from BALB/c mice and genetically related mice expressed both isoforms in similar amounts, whereas Mφ from C57BL/6 and related mice mainly expressed the smaller isoform. NIH-3T3 fibroblast and RAW264.7 macrophage cell lines stably expressing either isoform were able to bind and phagocytose zymosan at 37°C. However, binding by the smaller dectin-1B isoform was significantly affected at lower temperatures. These properties were shared by the equivalent human isoforms. The relative ability of each of the isoforms to induce TNF-α production in RAW264.7 Mφ was also found to be different. These results are the first evidence that dectin-1 isoforms are functionally distinct and indicate that differential isoform usage may represent a mechanism of regulating cellular responses to β-glucans.