bluuebunny/crossref_metadata_2025_split huggingface dataset:
CR2+ Marginal Zone B Cell Production of Pathogenic Natural Antibodies Is C3 Independent
Authors: Woods Keith M. , Pope Michael R. , Hoffman Sara M. , Fleming Sherry D. 
Published: December 2010

Abstract
Intestinal ischemia-reperfusion (IR)–induced damage requires complement receptor 2 (CR2) for generation of the appropriate natural Ab repertoire. Pathogenic Abs recognize neoantigens on the ischemic tissue, activate complement, and induce intestinal damage. Because C3 cleavage products act as ligands for CR2, we hypothesized that CR2hi marginal zone B cells (MZBs) require C3 for generation of the pathogenic Abs. To explore the ability of splenic CR2+ B cells to generate the damaging Ab repertoire, we adoptively transferred either MZBs or follicular B cells (FOBs) from C57BL/6 or Cr2−/− mice into Rag-1−/− mice. Adoptive transfer of wild type CR2hi MZBs but not CR2lo FOBs induced significant damage, C3 deposition, and inflammation in response to IR. In contrast, similarly treated Rag-1−/− mice reconstituted with either Cr2−/− MZB/B1 B cells (B1Bs) or FOBs lacked significant intestinal damage and displayed limited complement activation. To determine whether C3 cleavage products are critical in CR2-dependent Ab production, we evaluated the ability of the natural Ab repertoire of C3−/− mice to induce damage in response to IR. Infusion of C3−/− serum into Cr2−/− mice restored IR-induced tissue damage. Furthermore, Rag-1−/− mice sustained significant damage after infusion of Abs from C3−/− but not Cr2−/− mice. Finally, adoptive transfer of MZBs from C3−/− mice into Rag-1−/− mice resulted in significant tissue damage and inflammation. These data indicate that CR2 expression on MZBs is sufficient to induce the appropriate Abs required for IR-induced tissue damage and that C3 is not critical for generation of the pathogenic Abs.
Pyk2 Is Required for Neutrophil Degranulation and Host Defense Responses to Bacterial Infection
Authors: Kamen Lynn A. , Schlessinger Joseph , Lowell Clifford A. 
Published: December 2010

Abstract
The appropriate regulation of neutrophil activation is critical for maintaining host defense and limiting inflammation. Polymorphonuclear neutrophils (PMNs) express a number of cytoplasmic tyrosine kinases that regulate signaling pathways leading to activation. One of the most highly expressed, but least studied, kinases in PMNs is proline rich kinase 2 (Pyk2). By analogy to the related focal adhesion kinase, Pyk2 has been implicated in regulating PMN adhesion and migration; however, its physiologic function has yet to be described. Using pyk2−/− mice, we found that this kinase was required for integrin-mediated degranulation responses, but was not involved in adhesion-induced cell spreading or activation of superoxide production. Pyk2-deficient PMNs also manifested reduced migration on fibrinogen-coated surfaces. The absence of Pyk2 resulted in a severe reduction in paxillin and Vav phosphorylation following integrin ligation, which likely accounts for the poor degranulation and cell migration. Pyk2−/− mice were unable to efficiently clear infection with Staphylococcus aureus in a skin abscess model, owing in part to the poor release of granule contents at the site of infection. However, Pyk2-deficient PMNs responded normally to soluble agonists, demonstrating that this kinase functions mainly in the integrin pathway. These data demonstrate the unrealized physiologic role of this kinase in regulating the adhesion-mediated release of PMN granule contents.
Postselection Thymocyte Maturation and Emigration Are Independent of IL-7 and ERK5
Authors: Weinreich Michael A. , Jameson Stephen C. , Hogquist Kristin A. 
Published: December 2010

AbstractThe transcription factor Krüppel-like factor 2 (KLF2) controls the emigration of conventional T cells from the thymus through its regulation of the cell surface receptor S1P1. Prior to KLF2 expression, developing T cells require a positive selection signal through the TCR. However, following positive selection there are time, spatial, and maturational events that occur before KLF2 is finally upregulated and emigration occurs. We are interested in determining the signals that upregulate KLF2 and allow thymocytes to emigrate into circulation and whether they are linked to functional maturation. In endothelial cells KLF2 expression has been shown to be dependent on the mitogen-activated protein kinase ERK5. Furthermore, it has been reported that IL-7 signaling leads to the phosphorylation of ERK5. Thus, we hypothesized that IL-7R signaling through ERK5 could drive the expression of KLF2. In this study, we provide evidence that this hypothesis is incorrect. We also found that CD8 lineage specification occurred normally in the absence of IL-7R signaling, in contrast to a recently proposed model. We showed that both CD4 and CD8 T cells complete maturation and express KLF2 independently of ERK5 and IL-7.
Langerin+ Dermal Dendritic Cells Are Critical for CD8+ T Cell Activation and IgH γ-1 Class Switching in Response to Gene Gun Vaccines
Authors: Stoecklinger Angelika , Eticha Tekalign D. , Mesdaghi Mehrnaz , Kissenpfennig Adrien , Malissen Bernard , Thalhamer Josef , Hammerl Peter 
Published: December 2010

Abstract
The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin+ dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin+ DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin+ DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin+ cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin+ DC abrogated the activation of IFN-γ–producing and cytolytic CD8+ T cells after gene gun vaccination. Moreover, we identified migratory langerin+ dermal DC as the subset that directly activated CD8+ T cells in lymph nodes. Langerin+ DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4+ T helper cells by langerin+ or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin+ DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation.
Gene Expression Patterns of Th2 Inflammation and Intercellular Communication in Asthmatic Airways
Authors: Choy David F. , Modrek Barmak , Abbas Alexander R. , Kummerfeld Sarah , Clark Hilary F. , Wu Lawren C. , Fedorowicz Grazyna , Modrusan Zora , Fahy John V. , Woodruff Prescott G. , Arron Joseph R. 
Published: December 2010

Abstract
Asthma is canonically thought of as a disorder of excessive Th2-driven inflammation in the airway, although recent studies have described heterogeneity with respect to asthma pathophysiology. We have previously described distinct phenotypes of asthma based on the presence or absence of a three-gene “Th2 signature” in bronchial epithelium, which differ in terms of eosinophilic inflammation, mucin composition, subepithelial fibrosis, and corticosteroid responsiveness. In the present analysis, we sought to describe Th2 inflammation in human asthmatic airways quantitatively with respect to known mediators of inflammation and intercellular communication. Using whole-genome microarray and quantitative real-time PCR analysis of endobronchial biopsies from 27 mild-to-moderate asthmatics and 13 healthy controls with associated clinical and demographic data, we found that asthmatic Th2 inflammation is expressed over a variable continuum, correlating significantly with local and systemic measures of allergy and eosinophilia. We evaluated a composite metric describing 79 coexpressed genes associated with Th2 inflammation against the biological space comprising cytokines, chemokines, and growth factors, identifying distinctive patterns of inflammatory mediators as well as Wnt, TGF-β, and platelet-derived growth factor family members. This integrated description of the factors regulating inflammation, cell migration, and tissue remodeling in asthmatic airways has important consequences for the pathophysiological and clinical impacts of emerging asthma therapeutics targeting Th2 inflammation.
Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion
Authors: Renaud Stephen J. , Cotechini Tiziana , Quirt Jill S. , Macdonald-Goodfellow Shannyn K. , Othman Maha , Graham Charles H. 
Published: December 2010

Abstract
Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3–4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.
RIG-I/MDA5/MAVS Are Required To Signal a Protective IFN Response in Rotavirus-Infected Intestinal Epithelium
Authors: Broquet Alexis H. , Hirata Yoshihiro , McAllister Christopher S. , Kagnoff Martin F. 
Published: December 2010

Abstract
Rotavirus is a dsRNA virus that infects epithelial cells that line the surface of the small intestine. It causes severe diarrheal illness in children and ∼500,000 deaths per year worldwide. We studied the mechanisms by which intestinal epithelial cells (IECs) sense rotavirus infection and signal IFN-β production, and investigated the importance of IFN-β production by IECs for controlling rotavirus production by intestinal epithelium and virus excretion in the feces. In contrast with most RNA viruses, which interact with either retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) inside cells, rotavirus was sensed by both RIG-I and MDA5, alone and in combination. Rotavirus did not signal IFN-β through either of the dsRNA sensors TLR3 or dsRNA-activated protein kinase (PKR). Silencing RIG-I or MDA5, or their common adaptor protein mitochondrial antiviral signaling protein (MAVS), significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Overexpression of laboratory of genetics and physiology 2, a RIG-I–like receptor that interacts with viral RNA but lacks the caspase activation and recruitment domains required for signaling through MAVS, significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Rotavirus-infected mice lacking MAVS, but not those lacking TLR3, TRIF, or PKR, produced significantly less IFN-β and increased amounts of virus in the intestinal epithelium, and shed increased quantities of virus in the feces. We conclude that RIG-I or MDA5 signaling through MAVS is required for the activation of IFN-β production by rotavirus-infected IECs and has a functionally important role in determining the magnitude of rotavirus replication in the intestinal epithelium.
Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors
Authors: de Weers Michel , Tai Yu-Tzu , van der Veer Michael S. , Bakker Joost M. , Vink Tom , Jacobs Daniëlle C. H. , Oomen Lukas A. , Peipp Matthias , Valerius Thomas , Slootstra Jerry W. , Mutis Tuna , Bleeker Wim K. , Anderson Kenneth C. , Lokhorst Henk M. , van de Winkel Jan G. J. , Parren Paul W. H. I. 
Published: December 2010

Abstract
CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
Functional Consequences of Natural Sequence Variation of Murine Cytomegalovirus m157 for Ly49 Receptor Specificity and NK Cell Activation
Authors: Corbett Alexandra J. , Coudert Jerome D. , Forbes Catherine A. , Scalzo Anthony A. 
Published: December 2010

Abstract
The Ly49H activating receptor on C57BL/6 (B6) NK cells plays a key role in early resistance to murine cytomegalovirus (MCMV) infection through specific recognition of the MCMV-encoded MHC class I-like molecule m157 expressed on infected cells. The m157 molecule is also recognized by the Ly49I inhibitory receptor from the 129/J mouse strain. The m157 gene is highly sequence variable among MCMV isolates, with many m157 variants unable to bind Ly49HB6. In this study, we have sought to define if m157 variability leads to a wider spectrum of interactions with other Ly49 molecules and if this modifies host susceptibility to MCMV. We have identified novel m157–Ly49 receptor interactions, involving Ly49C inhibitory receptors from B6, BALB/c, and NZB mice, as well as the Ly49HNZB activation receptor. Using an MCMV recombinant virus in which m157K181 was replaced with m157G1F, which interacts with both Ly49HB6 and Ly49CB6, we show that the m157G1F–Ly49C interactions cause no apparent attenuating effect on viral clearance in B6 mice. Hence, when m157 can bind both inhibitory and activation NK cell receptors, the outcome is still activation. Thus, these data indicate that whereas m157 variants predominately interact with inhibitory Ly49 receptors, these interactions do not profoundly interfere with early NK cell responses.
Controlling Herpes Simplex Virus-Induced Ocular Inflammatory Lesions with the Lipid-Derived Mediator Resolvin E1
Authors: Rajasagi Naveen K. , Reddy Pradeep B. J. , Suryawanshi Amol , Mulik Sachin , Gjorstrup Per , Rouse Barry T. 
Published: December 2010

Abstract
Stromal keratitis (SK) is a chronic immunopathological lesion of the eye caused by HSV-1 infection and a common cause of blindness in humans. The inflammatory lesions are primarily perpetuated by neutrophils with the active participation of CD4+ T cells. Therefore, targeting these immune cell types represents a potentially valuable form of therapy to reduce the severity of disease. Resolvin E1 (RvE1), an endogenous lipid mediator, was shown to promote resolution in several inflammatory disease models. In the current report, we determined whether RvE1 administration begun at different times after ocular infection of mice with HSV could influence the severity of SK lesions. Treatment with RvE1 significantly reduced the extent of angiogenesis and SK lesions that occurred. RvE1-treated mice had fewer numbers of inflammatory cells that included Th1 and Th17 cells as well as neutrophils in the cornea. The mechanisms by which RvE1 acts appear to be multiple. These included reducing the influx of neutrophils and pathogenic CD4+ T cells, increasing production of the anti-inflammatory cytokine IL-10, and inhibitory effects on the production of proinflammatory mediators and molecules, such as IL-6, IFN-γ, IL-17, KC, VEGF-A, MMP-2, and MMP-9, that are involved in corneal neovascularization and SK pathogenesis. These findings are, to our knowledge, the first to show that RvE1 treatment could represent a novel approach to control lesion severity in a virally induced immunopathological disease.
Genotype–phenotype correlations of pheochromocytoma in two large von Hippel–Lindau (VHL) type 2A kindreds with different missense mutations
Authors: Nielsen Sarah M. , Rubinstein Wendy S. , Thull Darcy L. , Armstrong Michaele J. , Feingold Eleanor , Stang Michael T. , Gnarra James R. , Carty Sally E. 
Published: December 2010

AbstractVon Hippel–Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype–phenotype correlations but, unlike other familial syndromes such as MEN‐2, the phenotype in VHL has not yet been stratified at the codon level. Over decades, we have managed two very large VHL type 2A regional kindreds with nearly adjacent but distinct VHL missense mutations. We determined the phenotype of Family 2 and compared the clinical and pathologic parameters of pheo between 30 members of Family 1 (Y112H mutation) and 33 members of Family 2 (Y98H mutation) with mean follow‐up of 15.5 and 12.1 years, respectively (P = 0.24). In Family 2, pheo was the most frequent VHL manifestation (79%) and all pheo diagnoses occurred by age 50. Age at first diagnosis was younger in Family 2 than in Family 1 (mean 19.7 vs. 28.8 years; P = 0.02). Pheo expressivity differed by genotype: Family 1 pheo was more likely to be multifocal (P = 0.04), as well as malignant (P < 0.01) and lethal (P = 0.02). Family 1 pheo was also more likely to secrete vanillylmandelic acid (VMA) alone (P = 0.05). This analysis of 130 pheochromocytomas in 63 VHL type 2A patients demonstrates that mutation‐specific malignancy and expression patterns exist within the VHL type 2A subtype, and provides information that may help tailor the screening and management algorithms of affected members and those at risk. © 2010 Wiley‐Liss, Inc.
Association of a p.Pro786Leu variant in COL2A1 with mild spondyloepiphyseal dysplasia congenita in a three‐generation family
Authors: Mark Paul R. , Torres‐Martinez Wilfredo , Lachman Ralph S. , Weaver David D. 
Published: December 2010

AbstractHeterozygous sequence variants of the COL2A1 gene cause a phenotypic spectrum collectively called type II collagenopathies. Here, we describe a COL2A1 sequence variant, c.2957C>T, p.Pro986Leu in the triple helical domain, which is a Y‐position substitution in exon 41 of the repeating triplet sequence Gly‐X‐Y of the proα1(II) chain. This sequence variant was associated with a mild spondyloepiphyseal dysplasia phenotype in three individuals in a three‐generation family. On clinical examination at the age of 19 months, the proband had a flat face, bifid uvula, and a protruding abdomen. Radiographically, he had rhizomelia, mesomelia, and ovoid‐shaped vertebrae. He also had absent mineralization of the epiphyses, the os pubis, tali, and calcanei. His mother had myopia, mild lumbar lordosis, and mild coxa vara. She had a detached retina repaired at age 24 years. The maternal grandmother had cataracts but has had no kyphoscoliosis or lordosis. All three had disproportionate short stature. None had arthritis or hearing loss. The sequence variant in this family is the only reported Y‐position proline substitution in the triple helical domain (Gly‐X‐Y) of the proα1(II) coded by the COL2A1 gene. © 2010 Wiley‐Liss, Inc.
Implications of prenatal diagnosis of the fetus with both interstitial deletion and a small marker ring originating from chromosome 5
Authors: Ohashi Hiroyasu , Suzumori Kaoru , Chisaka Yasushi , Sonta Shinichi , Kobayashi Tomoko , Aoki Yoko , Matsubara Yoichi , Sone Michiko , Shaffer Lisa G. 
Published: December 2010

AbstractWe describe a patient with 47,XY,del(5)(p11p13), +mar observed in prenatal screening. We performed analyses including G‐banding, multi‐color fluorescent in situ hybridization (mFISH) for fetal chromosome detection. After birth array‐based comparative genomic hybridization (aCGH), bacterial artificial chromosome (BAC)‐FISH was carried out to define the chromosomal changes precisely. The mFISH revealed that a ring chromosome that had originated from chromosome 5. The aCGH showed that this fetus had a terminal duplication, an interstitial deletion, and a pericentromeric duplication of the short arm of chromosome 5. This complex alteration resulted in partial trisomy 5p15.33–p15.31, partial monosomy 5p14.3–p13.2, and partial trisomy 5p12–p11. To clarify these alterations, we performed BAC‐FISH using BAC clones related to deleted and duplicated regions, and found that a derivative (der) chromosome 5 showed the presence of hybridization signals from the duplicated region at 5p15.33 and the loss of hybridization signals from the deleted region at 5p14.2. In addition, FISH analysis confirmed the origin of the marker chromosome. Hybridization signals from the second intervening sequence at 5p13.1, between the deleted region and the pericentric duplicated region, were present on the marker ring chromosome. © 2010 Wiley‐Liss, Inc.