bluuebunny/crossref_metadata_2025_split huggingface dataset:
A functionally significant allelic polymorphism in a T cell receptor Vβ gene segment
Authors: Vessey S. J. Rupert , Bell John I. , Jakobsen Bent K. 
Published: March 2007

AbstractThe effect of an allelic polymorphism in the BV1S1 gene segment on recognition of major histocompatibility complex (MHC)‐peptide complexes by a specific T cell receptor (TCR) was studied using RBL 2H3 cells transfected with TCR‐CD3ζ chimeric receptors. An HLA‐A2‐restricted human immunodeficiency virus (HIV) pol‐specific cytotoxic T lymphocyte (CTL) clone utilizing the BV1S1A2 gene in combination with AV2S1A2 was identified and the extracellular domains of the TCR were fused to CD3ζ. In degranulation assays RBL 2H3 transfectants expressing this receptor maintained the specificity of the parental CTL clone. The allelic variant BV1S1A1N1 containing a glutamine for histidine substitution at position 48 in the loop of the second complementarity‐determining region was generated by site‐directed mutagenesis. Transfection of this molecule as a CD3ζ chimera together with the original AV2S1A2 CD3ζ molecule resulted in cell surface expression of both chains but a loss of recognition of HLA‐A2 HIV pol peptide‐pulsed targets. The effect of this polymorphism on MHC‐peptide recognition supports current models of TCR MHC‐peptide interaction and provides evidence for a functional role for polymorphism in the TCRV genes.
Lipid vesicle‐entrapped influenza A antigen modulates the influenza A‐specific human antibody response in immune reconstituted SCID‐human mice
Authors: Walker William , Brewer James M. , Alexander James 
Published: March 2007

AbstractThis study was designed to investigate the capacity of purified influenza antigen in the presence and absence of adjuvant to induce human antibody responses in human‐PBL‐SCID mice. Non‐ionic surfactant vesicles (NISV) were used as adjuvant as they have been shown to promote the development of Th1 responses in mouse studies. Human peripheral blood lymphocyte‐SCID mice were inoculated with either purified influenza antigen (A/Texas, H3N2) or influenza antigen entrapped in NISV. Both vaccinated groups produced significantly higher plasma levels of influenza‐specific human IgG when individually compared with non‐vaccinated controls. However, similar comparisons revealed that specific IgM levels were significantly higher only in the group challenged with purified antigen. Further analysis of IgG subclasses also demonstrated an adjuvant‐dependent dichotomy in the responses of the vaccine groups when compared with non‐vaccinated controls. Thus, only influenza‐specific IgG1 antibodies (associated with Th1 responses in humans) were significantly increased above control levels using antigen with adjuvant, while both this subclass and antigen‐specific IgG4 (Th2 associated) were significantly increased with antigen alone. These results illustrate the suitability of this model for use in human vaccination studies and demonstrates that influenza antigen applied with NISV selectively promotes only Th1 responses, unlike free antigen which also promotes Th2 responses in vivo.
Co‐localization of the neonatal Fcγ receptor and IgG in human placental term syncytiotrophoblasts
Authors: Kristoffersen Einar K. , Matre Roald 
Published: March 2007

AbstractTransfer of maternal IgG through the human placenta furnishes the newborn with passive immunity to a number of infectious agents. The exact mechanism of this transfer is still unknown, but it is agreed that it involves active receptor‐mediated transport. The neonatal Fc receptor is a major histocompatibility complex class I‐like receptor originally identified in the intestines of newborn rodents. A similar receptor has recently been detected in human placental syncytiotrophoblasts. Using multilabeling fluorescence immunohistochemistry and confocal laser scanning microscopy, we found that the neonatal Fc receptor co‐localizes with IgG and β2‐microglobulin in granules of human placental syncytiotrophoblast. The Fc receptor is not detected on syncytiotrophoblast apical plasma membrane. Localization to the outermost cellular barrier between the fetal and maternal blood further strengthens the role of the Fc receptor in transplacental transport of IgG.
Role of tumor necrosis factor‐α and platelet‐activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis
Authors: Lupia Enrico , Montrucchio Giuseppe , Battaglia Edda , Modena Vittorio , Camussi Giovanni 
Published: March 2007

AbstractThe aim of the present study was to investigate in vivo in a mouse model the stimulation of neoangiogenesis by synovial fluids of patients with rheumatoid arthritis (RA) and to determine the role of tumor necrosis factor (TNF)‐α and platelet‐activating factor (PAF) in the formation of new vessels. Angiogenesis was studied in a mouse model in which Matrigel, injected subcutaneously, was used as a vehicle for the delivery of potential angiogenic stimuli. Synovial fluids of patients with RA but not with osteoarthritis (OA) were shown to induce neoangiogenesis. Since synovial fluid of patients with RA contained significantly higher levels of TNF‐α‐like bioactivity and of PAF than that of patients with OA, the role of these mediators was evaluated by using an anti‐TNF‐α neutralizing monoclonal antibody (mAb) and a PAF receptor antagonist, WEB 2170. When added to Matrigel, anti‐TNF‐α mAb and particularly WEB 2170 significantly reduced neoangiogenesis induced by synovial fluids of RA patients. Moreover, PAF extracted and purified from synovial fluid induced angiogenesis. These results suggest that the neoangiogenesis observed in rheumatoid synovitis may be due, at least in part, to the angiogenic effect of locally produced TNF‐α and PAF.
Transporter (TAP)‐independent processing of a multiple membrane‐spanning protein, the Epstein‐Barr virus latent membrane protein 2
Authors: Lee Steven P. , Thomas Wendy A. , Blake Neil W. , Rickinson Alan B. 
Published: March 2007

AbstractAntigen presentation to CD8+ cytotoxic T lymphocytes (CTL) usually involves proteolytic cleavage of antigen in the cytosol and the delivery of epitope peptides onto major histocompatibility complex class I molecules in the endoplasmic reticulum (ER) via the heterodimeric peptide transporter TAP1/TAP2. In the few exceptional cases where TAP‐independent presentation of an endogenously expressed protein has been observed, the epitope‐containing domain of the protein either has naturally accessed or has been directed into the ER lumen where it is thought to become susceptible to ER proteases. Here, we describe a novel example of TAP‐independent processing involving the Epstein‐Barr virus (EBV) latent membrane protein LMP2, a multiple membrane‐spanning protein with minimal projection into the ER. Expression of LMP2 in the TAP− T2 cell line, whether from the resident EBV genome or from a recombinant vaccinia virus vector vacc‐LMP2, rendered the cells sensitive to recognition by CTL clones specific for two HLA‐A2.1‐restricted peptide epitopes, LMP2 329–337 or 426–434. Vacc‐LMP2‐mediated sensitization to lysis required expression of the antigen de novo in T2 cells and was blocked by brefeldin A. In the same experiments, two other EBV‐specific CTL epitopes, one derived from LMP2 but restricted through a different HLA allele (A11), the other restricted through A2.1 but derived from a different viral protein (BMLF1), did not display TAP‐independent processing. The results are discussed in relation to the unusual topology of LMP2 in the membrane and the position of the epitope peptides within that structure.
Peptide binding specificity of major histocompatibility complex class I resolved into an array of apparently independent subspecificities: quantitation by peptide libraries and improved prediction of binding
Authors: Stryhn Anette , Pedersen Lars Østergaard , Romme Tina , Holm Charlotte Bisgaard , Holm Arne , Buus Søren 
Published: March 2007

AbstractConsiderable interest has focused on understanding how major histocompatibility complex (MHC) specificity is generated and characterizing the specificity of MHC molecules with the ultimate goal being to predict peptide binding. We have used a strategy where all possible peptides of a particular size are distributed into positional scanning combinatorial peptide libraries (PSCPL) to develop a highly efficient, universal and unbiased approach to address MHC specificity. The PSCPL approach appeared qualitatively and quantitatively superior to other currently used strategies. The average effect of any amino acid in each position was quantitated, allowing a detailed description of extended peptide binding motifs including primary and secondary anchor residues. It also identified disfavored residues which were found to be surprisingly important in shaping MHC class I specificity. Assuming that MHC class I specificity is the result of largely independently acting subsites, the binding of unknown peptides could be predicted. Conversely, this argues that MHC class I specificities consist of an array of subspecificities acting in a combinatorial mode.
Somatic hypermutation occurs in B cells of terminal deoxynucleotidyl transferase‐, CD23‐, interleukin‐4‐, IgD‐ and CD30‐deficient mouse mutants
Authors: Texidó Gemma , Jacobs Heinz , Meiering Myriam , Kühn Ralf , Roes Jürgen , Müller Werner , Gilfillan Susan , Fujiwara Hiroshi , Kikutani Hitoshi , Yoshida Nobuaki , Amakawa Ryuichi , Benoist Christophe , Mathis Diane , Kishimoto Tadamitsu , Mak Tak W. , Rajewsky Klaus 
Published: March 2007

AbstractWe show through sequence analysis of rearranged immunoglobulin variable (Ig‐V) region genes from memory B cells of mouse mutants generated by gene targeting that terminal deoxynucleotidyl transferase, CD23, interleukin‐4, IgD and CD30 are dispensable for somatic hypermutation.
Subepithelial B cells in the human palatine tonsil. I. Morphologic, cytochemical and phenotypic characterization
Authors: Dono Mariella , Burgio Vito L. , Tacchetti Carlo , Favre Anna , Augliera Adriano , Zupo Simona , Taborelli Giuseppe , Chiorazzi Nicholas , Grossi Carlo E. , Ferrarini Manlio 
Published: March 2007

AbstractThis study describes the purification of a subset of tonsillar B cells which share phenotypic, morphologic and cytochemical features with subepithelial (SE) B cells. These cells, which represented the 5–10% of the total tonsillar B cells, were found in the Percoll gradient fraction of highest density, together with resting follicular mantle (FM) B cells. The latter B cells, however, expressed surface CD5 and could be removed by an immune rosetting procedure. The remaining small CD5− B cells had a surface phenotype (IgM+, IgD+, CD23−, CD38±, CD10−, CD44+) that was different from that of FM (IgM+, IgD+, CD23+, CD39+, CD38−, CD10−, CD44±) and of germinal center (GC) (CD23−, CD39−, CD38+, CD10+, CD44±, IgG+) B cells isolated from the same cell suspensions. Furthermore, the absence of surface activation markers (CD71 and CD69) and of surface IgG allowed us to distinguish small CD5− B cells from activated and memory cells migrating within Percoll fractions of lower density. In situ immunohistochemical studies revealed that B cells with an identical phenotype as that of small CD5− B cells could be detected predominantly in the SE region (lamina propria) of the tonsil, and also within the epithelium lining the cryptae. This area was also comprised of a relatively minor proportion of activated B cells, not found in the small CD5− B cell fraction owing to the separation procedure used. Consistent with the notion that the SE area could be a site of B cell activation was also the presence of activated macrophages and of plasma cells. Thirty to forty percent of small CD5− B cells isolated in suspension were positive for the endogeneous alkaline phosphatase (ALP) activity. In contrast, only a few FM B cells were ALP+, while GC cells were consistently ALP−. In situ studies also demonstrated a prevalent expression of ALP activity by the B cells in the SE area. At the ultrastructural level, small CD5− B cells were clearly different from both FM and GC B cells. They displayed a cytoplasm more extended than that of FM B cells with abundant endosomes and plasma membrane projections, and a speckled pattern of nuclear heterochromatin distribution. When fixed tissue sections were examined, cells with identical ultrastructural features could be demonstrated in the tonsillar lamina propria. Collectively, the above data demonstrate an identity of features between the small CD5− B cells isolated in suspension and SE B cells analyzed in situ. Since tonsillar SE B cells are generally thought to represent the homolog of the extrafollicular B cells (including those of the splenic marginal zone), these studies may provide new opportunities for functional studies on this so far incompletely characterized B cell subset.
Epitopes recognized by neutralizing therapy‐induced human anti‐interferon‐α antibodies are localized within the N‐terminal functional domain of recombinant interferon‐α2
Authors: Nolte Klaus‐Ulrich , Günther Gero , von Wussow Peter 
Published: March 2007

AbstractDuring prolonged recombinant interferon (rIFN)‐α2 therapy, a minority of patients develop high‐titer neutralizing IFN‐α antibodies. Sera from nine IFN‐α antibody‐positive patients were studied to characterize the specificity of anti‐IFN‐α neutralizing antibodies by their ability to inhibit the antiviral and antiproliferative activity of different rIFN‐α subtypes and rIFN‐α1/α2 hybrids. These therapy‐induced antibodies (Tab) were compared with IFN‐α‐specific autoantibodies (Aab) from two patients with systemic lupus erythematosus who had never received any exogenous IFN‐α. Although IFN‐α subtypes are closely related in structure, Tab inhibited the antiviral activity of only recombinant (r)IFN‐α2 and rIFN‐α6, but not or slightly that of rIFN‐α1, ‐α7, ‐α8 and ‐α14. Furthermore, of four different rIFN‐α1/α2 hybrids tested, Tab inhibited only those which contained the N‐terminal residues 17–64 of rIFN‐α2. Comparison of the primary sequences of neutralized and not neutralized subtypes suggests an epitope involving the residues 22–31 of IFN‐α2 is recognized. Thus, Tab block rIFN‐α2 by reacting with only one of two functional domains. In contrast, Aab possessed a broad specificity and neutralized both the antiviral and antiproliferative activity of rIFN‐α2, ‐α6, ‐α7, ‐α8 and ‐α14. They also neutralized all four rIFN‐α1/α2 hybrids tested. These data demonstrate that Tab are highly specific for the therapeutic IFN‐α subtype and specifically neutralize rIFN‐α2 by binding to its N‐terminal functional domain.
Cyclosporin A sensitivity of the HIV‐1 long terminal repeat identifies distinct p56lck‐dependent pathways activated by CD4 triggering
Authors: di Somma M. Maddalena , Majolini M. Bernardetta , Burastero Samuele E. , Telford John L. , Baldari Cosima T. 
Published: March 2007

AbstractThe CD4 co‐receptor interacts with nonpolymorphic regions of major histocompatibility complex class II molecules on antigen‐presenting cells. This interaction results in the mobilization of a number of signaling mediators shared by the T cell receptor (TcR) signaling pathway and thus amplifies TcR‐generated signals. We have investigated the outcome of CD4 engagement on the activation of both cellular transcription factors and the HIV‐1 long terminal repeat (LTR). We show that CD4 triggering activates different pathways of HIV LTR activation which can be identified by their sensitivity to the immunosuppressant cyclosporin A. The response of the inducible cellular transcription factors involved in HIV LTR activation shows that both nuclear factor (NF)‐ϰB and NF‐AT mediate a cyclosporin A‐sensitive response to CD4, while AP‐1 is at least in part responsible for the cyclosporin A‐insensitive response. Both pathways can, however, be blocked by a kinase‐defective dominant negative p56lck mutant, supporting an essential role for p56lck kinase activity in CD4‐dependent signal transduction. A functional analysis of different CD4 epitopes using either anti‐CD4 mAb or HIV‐1 gp120 reveals a common epitope‐specific activation of both the LTR and of the transcription factors NF‐ϰB and NF‐AT.
Distinct mechanisms for rescue from apoptosis in Ramos human B cells by signaling through CD40 and interleukin‐4 receptor: role for inhibition of an early response gene, Berg36
Authors: Ning Zhi‐Qiang , Norton John D. , Li Jin , Murphy John J. 
Published: March 2007

AbstractThe role of interleukin‐4 (IL‐4) and CD40 signaling in negative regulation of apoptosis in human Ramos B cells induced in response to different agents was investigated. CD40 ligation protected cells from apoptosis induced by calcium ionophore through an initial, rapid and apparently Bcl‐2‐independent mechanism, associated with up‐regulation of Bcl‐xL. However, rescue from apoptosis induced by inhibition of macromolecular synthesis required several hours of prior stimulation with CD40 ligand/antibody and was accompanied by up‐regulation of Bcl‐2. In contrast, IL‐4 did not up‐regulate Bcl‐2 or Bcl‐xL and did not inhibit apoptosis induced by inhibitors of macromolecular synthesis. However, IL‐4 did protect Ramos cells from apoptosis induced by calcium ionophore and this effect was accompanied by inhibition of ionophore‐induced expression of an immediate early gene encoding a 36‐kDa zinc‐finger protein, Berg36. Anti‐sense blockade of Berg36 expression partially inhibited ionophore‐induced apoptosis to an extent commensurate with the level of IL‐4 protection, implicating Berg36 function as a requirement for apoptosis induced through calcium signaling and as a target for IL‐4 through which this cytokine inhibits apoptosis in Ramos B cells. These distinct mechanisms for rescue from apoptosis by CD40 and IL‐4 may help explain the co‐operative roles of these T cell‐derived signals for B cell survival.
Human follicular dendritic cells and vascular cells produce interleukin‐7: a potential role for interleukin‐7 in the germinal center reaction
Authors: Kröncke Rolf , Loppnow Harald , Flad Hans‐Dieter , Gerdes Johannes 
Published: March 2007

AbstractInterleukin‐7 (IL‐7) has long been known as a potent growth factor in lymphocyte development. However, recent data obtained in vitro revealed additional functions for this cytokine, e.g. IL‐7 influences the generation of cytotoxic T cells and NK cells, and in higher concentrations, activates monocytes in a manner similar to bacterial lipopolysaccharide. Furthermore, human tonsillar B cells are able to proliferate upon stimulation by IL‐7 and cross‐linking of the B cell receptor. Considering the latter role of IL‐7 for B cell proliferation, we investigated which cells of the human immune system express IL‐7 in vivo. mRNA expression of tonsillar cells was analyzed using the reverse transcription polymerase chain reaction, and protein expression was assessed by immunohistochemical staining of frozen sections. Among a variety of different immune cell types isolated from human tonsils, only follicular dendritic cells (FDC) expressed specific IL‐7 products, whereas B and T cells were consistently negative. Immunohistochemical staining of tonsillar sections revealed the expression of immunoreactive IL‐7 protein on FDC, and a pronounced expression could also be detected in oral mucosa and vascular endothelial cells. For the latter, we could also demonstrate mRNA expression in primary cultured cells. In light of the previous finding that IL‐7 can act as a co‐stimulus for the induction of proliferation in tonsillar B cells, these data suggest a role of IL‐7 in the germinal center reaction. It is tempting to speculate that FDC may function as regulatory cells in B cell development in the tonsil, as epithelial nurse cells are thought to govern T cell development in the thymus.
Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99)
Authors: Vergelli Marco , Hemmer Bernhard , Utz Ursula , Vogt Anne , Kalbus Matthias , Tranquill Laura , Conlon Paul , Ling Nicholas , Steinman Lawrence , McFarland Henry F. , Martin Roland 
Published: March 2007

AbstractWe have examined the functional consequences induced by interaction of DR2a‐restricted myelin basic protein (MBP) (87–99)‐specific T cell clones (TCC) with altered peptide ligands (APL) derived from MBP peptide (87–99). The immunodominant MBP peptide (87–99) has been implicated as a candidate antigen in multiple sclerosis (MS) by several lines of evidence. In the present study, we have defined the T cell receptor (TCR) contact residues for DR2a‐restricted, (87–99)‐specific T helper type 1 T cells to design APL suitable to modify the functions of such T cells potentially relevant for the pathogenesis of MS. We show that neutral (L‐alanine substitutions) or conservative exchanges of the primary and secondary TCR contact residues lead to various alterations of T cell function, ranging from differences in interleukin‐2 receptor up‐regulation to anergy induction and TCR antagonism. The potential usefulness of APL as an immunomodulating therapy for DR2+ MS patients is discussed.
Cellular competition modulates survival and selection of CD8+ T cells
Authors: Freitas António A. , Agenes Fabien , Coutinho Graça C. 
Published: March 2007

AbstractIn this investigation we compare the repopulation of the CD8+ T cell compartments of bone marrow (BM) chimeras by either normal nontransgenic or T cell receptor (TcR) αβ‐transgenic (TG) CD8+ T cells, the fate of TG and non‐TG CD8+ T cells in different parabionts and the survival of TG and non‐TG peripheral CD8+ T cells after transfer into athymic hosts. We found that cellular competition among CD8 T cells occurs at several steps of T cell differentiation including (a) during the DN to DP transition, (b) positive selection in the thymus, (c) export from the thymus and (d) in the periphery. Comparison of the results obtained in the BM chimeras and in the parabionts shows that an important step of T cell selection occurs during seeding of peripheral lymphoid tissues. Once established, peripheral T cells resist replacement by recent thymus migrants, i.e. in the periphery, selection of T cell repertoires follows the rule “first come, first served”. Peripheral dominance correlates with T cell activation and division. Cell cycling and CD44 expression are more frequent among non‐TG CD8 T cells than TG CD8 T cells and within the latter, more frequent among P14 TG CD8 T cells than anti‐HYTG CD8 T cells. Thus, in the absence of intentional immunization, the frequencies of CD8+ T cells follow a hierarchy of selection in which non‐TG ⩾ P14 TG > anti‐HY TG. We also show that the equilibrium size and the fate of one CD8 T cell population differs according to the presence or absence of other CD8 T cell populations. Under these circumstances, selection of T cell repertoires and T cell survival and memory rely not only on the interactions of each T cell with their respective ligands, but also on the nature and number of other competing cells.