bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor‐α in the central nervous system
Authors: Taupin Véronique , Renno Toufic , Bourbonnière Lyne , Peterson Alan C. , Rodriguez Moses , Owens Trevor 
Published: March 2007

AbstractTumor necrosis factor‐α (TNF‐α) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF‐α in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes are a target of immune attack. TNF‐α also regulates macrophage activity which could contribute to autoimmune inflammation. We have expressed TNF‐α at disease‐equivalent levels in the central nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage/microglial reactivity was evident in demyelinating lesions in spinal cord, but T cells were not detected during chronic disease. The participation of TNF‐α in the demyelinating process is thus more probably due to the perpetuation of macrophage/microglial activation than to direct cytotoxicity of myelin or oligodendroglia.
Chemoattractant receptors for interleukin‐8 and C5a: expression on peripheral blood leukocytes and differential regulation on HL‐60 and AML‐193 cells by vitamin D3 and all‐trans rètinoic acid
Authors: Zahn Stefan , Zwirner JÖRg , Spengler Hans‐Peter , Götze Otto 
Published: March 2007

AbstractTwo homologous high‐affinity receptors for the chemoattractant interleukin‐8, IL‐8RA and IL‐8RB, and one for the chemoattractant C5a (C5aR) have been cloned. These membrane proteins are members of the rhodopsin superfamily of G‐protein coupled seven‐transmembrane segment receptors. New monoclonal antibodies (mAb) directed against the deduced N‐terminal sequences of the IL‐8RA (mAb SE2) and IL‐8RB (mAb HC2) were generated to determine the IL‐8R expression on human blood leukocytes and two human myeloid cell lines. The C5aR expression was detected using the mAb W17/1. Approximately 107000 C5aR, 55000 IL‐8RA, and 25000 IL‐8RB molecules per cell could be detected on human granulocytes by flow cytometric analysis. On peripheral blood monocytes, 42000 C5aR molecules/cell and 3000 IL‐8RB molecules/cell were expressed. However, we were unable to quantitate IL‐8RA expression, which was detectable but below 2500 molecules per cell and thus outside the standard range for the quantitation of receptor molecules by flow cytometry. On AML‐193 cells, only the IL‐8RB was constitutively expressed, whereas on HL‐60 cells, we could not detect expression of any of the three receptors. Vitamin D3 (250 ng/ml, 7 days), which has been shown to induce differentiation of AML‐193 and HL‐60 cells into the monocytic phenotype, led to an up‐regulation of IL‐8RB and C5aR in both cell lines in the absence of any expression of IL‐8RA. In contrast, all‐trans retinoic acid (0.1 μM, 7 days), which induces differentiation into the granulocytic phenotype, led to an up‐regulation of IL‐8RB in AML‐193 cells and to an expression of IL‐8RB and C5aR in HL‐60 cells. Again, neither cell line expressed IL‐8RA. These findings suggest that regulation of IL‐8RA expression differs from that of its IL‐8RB homolog and may be a late event in leukocyte maturation.
Epitope cleavage byLeishmaniaendopeptidase(s) limits the efficiency of the exogenous pathway of major histocompatibility complex class I‐associated antigen presentation
Authors: Garcia Maria R. , Graham Shek , Harris Robert A. , Beverley Stephen M. , Kaye Paul M. 
Published: March 2007

AbstractThe activation of CD8+T cell responses is commonplace during infection with a number of nonviral pathogens. Consequently, there has been much interest in the pathways of presentation of such exogenous antigens for major histocompatibility complex class I‐restricted recognition. We had previously shown thatLeishmaniapromastigotes transfected with the ovalbumin (OVA) gene could efficiently target OVA to the parasitophorous vacuole (PV), with subsequent recognition by class II‐restricted T cells. We now report the results of studies aimed at evaluating the PV as a route of entry into the exogenous class I pathway. Bone marrow‐derived macrophages can present soluble OVA (albeit at high concentrations) to the OVA257–264‐specific T cell hybridoma 13.13. In contrast, infection with OVA‐transfectedLeishmaniapromastigotes failed to result in the stimulation of this hybridoma. This appeared unrelated to variables such as antigen concentration, parasite survival, and macrophage activation status. These results prompted an analysis of the effects of promastigotes on class I peptide binding using RMA‐S cells and OVA257–264. Our data indicate that the major surface protease ofLeishmania, gp63, inhibits this interaction by virtue of its endopeptidase activity against the OVA257–264peptide. The data suggest that this activity, if maintained within the PV, would result in loss of the OVA257–264epitope. Although we can therefore draw no conclusions from these studies regarding the efficiency of the PV as a site of entry of antigen into the exogenous class I pathway, we have identified a further means by which parasites may manipulate the immune repertoire of their host.
Activation and activation‐induced death of human tonsillar B cells and Burkitt lymphoma cells: lack of CD95 (Fas/APO‐1) ligand expression and function
Authors: Daniel Peter T. , Oettinger Ulrich , Mapara Markus Y. , Bommert Kurt , Bargou Ralf , Dörken Bernd 
Published: March 2007

AbstractActivation of T cells was shown to up‐regulate the Fas ligand (FasL) which binds to the CD95 (APO‐1/Fas) antigen and mediates activation‐induced cell death (AICD) of activated T cells and T lymphoma cells. A recent report showed that mouse B cells express the FasL upon activation with lipopolysaccharide (LPS). We therefore asked whether activation of human B cells induces expression of FasL and whether AICD is mediated, as in T cells, through autocrine production of the FasL. We used human tonsillar B cells and Burkitt lymphoma cell lines which were activated by CD40 ligand, surface (s)IgM cross‐linking, or LPS. Northern and Western blot analysis failed to detect FasL during B cell activation or AICD of both normal and malignant B cells. Low‐level expression of FasL was detected by reverse transcriptase‐polymerase chain reaction. Functional experiments, however, showed that FasL is not functionally expressed upon activation. IgM‐mediated AICD in the tonsillar or Burkitt lymphoma B cells could not be inhibited by FasL blocking. Thus, our data show that, in contrast to T cells, activation of normal or malignant human B cells does not lead to functional FasL expression.
CD43 (leukosialin, sialophorin) expression is differentially regulated by retinoic acids
Authors: Babina Magda , Weber Sylvia , Henz Beate M. 
Published: March 2007

AbstractCD43 (leukosialin, sialophorin), a cell‐surface associated mucin that is constitutively expressed at high levels on most leukocytes, is thought to be involved in cell activation and adhesion. We here provide evidence that the vitamin A metabolites all‐trans and 13‐cis retinoic acid up‐regulate CD43 on human leukemic (HMC‐1) mast cells, as determined by flow cytometry, Western blot analysis, and by semiquantitative reverse transcriptase‐polymerase chain reaction. Enhanced CD43 expression was accompanied by a strong increase in anti‐CD43‐mediated, LFA‐1‐dependent homotypic aggregation of HMC‐1 cells, demonstrating that newly synthesized CD43 is functionally active in transmitting signals across the plasma membrane which result in enhanced cellular adhesion. CD43 expression was also enhanced in response to retinoic acids on isolated human skin mast cells and human monocytes, but not on cells of the basophilic cell line KU‐812 and promyelocytic HL‐60 cells, indicating that these agents might act in a cell‐type specific manner. These combined result point to a novel aspect in the regulation of CD43. Possibly, vitamin A metabolites act directly on the CD43 gene, since putative retinoic acid response elements have been detected within its regulatory regions.
Resistance of cultured peripheral T cells towards activation‐induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death‐inducing signaling complex
Authors: Peter Marcus E. , Kischkel Frank C. , Scheuerpflug Christian G. , Medema Jan Paul , Debatin Klaus‐Michael , Krammer Peter H. 
Published: March 2007

AbstractPhytohemagglutinin‐activated peripheral CD95+ T cells (day 1 T cells) are resistant to CD95‐mediated apoptosis. After prolonged interleukin‐2 treatment, these T cells become CD95‐mediated apoptosis‐sensitive (day 6T cells). To elucidate the molecular mechanism of apoptosis resistance, day 1 and day 6 T cells were tested for formation of the CD95 death‐inducing signaling complex (DISC). DISC‐associated active Fas‐associated DD protein (FADD)‐like interleukin‐1β‐converting enzyme‐like protease (FLICE) also referred to as MACH/caspase 8 was only found in apoptosis‐sensitive day 6 T cells. Further analysis of mRNA and protein expression levels of apoptosis‐signaling molecules FADD, receptor interacting protein, hematopoietic cell protein tyrosine phosphatase, Fas‐associated phosphatase‐1, FLICE, bcl‐2, bcl‐xL, and, bax‐α showed that only the expression level of bcl‐xL correlated with T cell resistance to CD95‐mediated apoptosis (day 1 T cells: bcl‐xhiL; day 6 T cells: bcl‐xloL). In T cells activated in vitro, up‐regulation of bcl‐xL has previously been correlated with general apoptosis resistance. However, the experiments presented suggest that resistance to CD95‐mediated apoptosis in T cells can also be regulated at the level of recruitment of FLICE to the DISC.
Effect of interleukin‐10 on dendritic cell maturation and function
Authors: de Smedt Thibaut , van Mechelen Marcelle , De Becker Geneviève , Urbain Jacques , Leo Oberdan , Moser Muriel 
Published: March 2007

AbstractThe main function of dendritic cells (DC) is to induce the differentiation of naive T lymphocytes into helper cells producing a large array of lymphokines, including interleukin (IL)‐2; interferon‐γ (IFN‐γ), IL‐4, IL‐5 and IL‐10. The potent immunostimulatory properties of DC develop during a process of maturation that occurs spontaneously in vitro. Since IL‐10 has been shown to inhibit Th1 responses, we determined its effect on DC maturation and accessory function. Our data show that DC that have undergone maturation in vitro in the presence of IL‐10, have an impaired capacity to induce a Th1‐type response in vivo, leading to the development of Th2 lymphocytes. Their inability to promote the synthesis of IFN‐γ seems to correlate with a decreased production of IL‐12, an heterodimeric cytokine necessary for optimal generation of Th1‐type cells. These results suggest that IL‐10 skews the Th1/Th2 balance to Th2 in vivo by selectively blocking IL‐12 synthesis by the antigen‐presenting cells that play a role of adjuvant of the primary immune response. The cytokines present in the environment at the presentation step may, therefore, determine the class of the immune response induced by DC in vivo, i.e. Th0 Th1 and/or Th2.
Immunoglobulin lambda light chain orphons on human chromosome 8q11.2
Authors: Frippiat Jean‐Pol , Dard Patricia , Marsh Sharon , Winter Greg , Lefranc Marie‐Paule 
Published: March 2007

AbstractWe have identified two Vλ genes outside the major lambda locus on chromosome 22q11.2, and shown that they reside on chromosome 8q11.2. One gene (Orphéel), hybridizing strongly to the Vλ probes, was sequenced and found to belong to the Vλ8 family; the other gene (Orphée2) only hybridized weakly. Orphée1 was present in all individuals tested (140) from three different populations, and was also found in gorillas. We envisage that these genes were generated by duplication and translocation of the Vλ8a gene (and a Vλ pseudogene) from the major locus, and that this event occurred before the evolutionary divergence of humans and gorillas. As there is no other evidence for Vλ genes outside the major locus, it appears that the human lambda locus has undergone considerably less evolutionary shuffling than either the human light chain kappa locus or the heavy chain locus.
Cleavage of caspase family members by granzyme B: a comparative study in vitro
Authors: Van De Craen Marc , Van Den Brande Ilse , Declercq Wim , Irmler Martin , Beyaert Rudi , Tschopp Jürg , Fiers Walter , Vandenabeele Peter 
Published: March 2007

AbstractThe aspartase granzyme B is one of the major components of the granules involved in cell killing by cytotoxic T lymphocytes. Granzyme B has been shown to activate the apoptotic death pathway in the target cell, and this involves activation of members of the caspase (CASP) protein family. Therefore, activational cleavage of mouse (m) CASP proforms by granzyme B was examined in vitro. CASP can be subdivided in the CASP‐1 (interleukin‐1β‐converting enzyme; ICE) subfamily, the CASP‐2 (Ich1) subfamily, and the CASP‐3 (CPP32) subfamily. Our results reveal that the proforms of the CASP‐3 subfamily members mCASP‐3 and mCASP‐7 are hydrolyzed by granzyme B, while proforms of CASP‐2 and CASP‐1 subfamily members are not directly cleaved. Only one CASP‐3 subfamily member, pro‐mCASP‐6, was not proteolytically cleaved by granzyme B. These results indicate that two members of the CASP‐3 subfamily, but no others, become activated by granzyme B.
A retro‐inverso analog mimicks the cognate peptide epitope of a CD4+ T cell clone
Authors: Bartnes Kristian , Hannestad Kristian , Guichard Gilles , Briand Jean Paul 
Published: March 2007

AbstractSynthetic analogs of peptide epitopes may activate specific T helper cells, antagonize their antigen receptors, or block recognition by competing for major histocompatibility complex (MHC) class II binding sites. Rationally designed peptides may therefore prove useful as vaccines and for treatment of autoimmune diseases and allergies mediated by CD4+ T cells. However, their susceptibility to proteolytic degradation limits the applicability of conventional peptides in vivo. By contrast, retro‐inverso analogs, in which a native sequence is substituted with D‐amino acids linked with a reversed backbone, resist proteolysis and still maintain the side chain topology of the corresponding natural peptide. We report here that an end group‐modified retro‐inverso analog of the IgG2ab heavy chain allopeptide determinant γ2ab 435–447 was recognized by an I‐Ad‐restricted, γ2ab 435–447‐reactive T cell clone. The pseudopeptide elicited near‐maximal interleukin‐2 responses, although 300‐fold higher concentrations were needed than the native determinant. The weaker antigenicity of the retro‐inverso analog could be fully accounted for by an impaired I‐Ad binding capacity, which might reflect reduced ability of the distorted main chain to form hydrogen bonds with I‐Ad. Glycine substitution at the residue corresponding to the first primary anchor (P1) of the native peptide abrogated I‐Ad binding and antigenicity of the retro‐inverso analog. Thus, the pseudopeptide resembled the native determinant with respect to orientation in the class II binding site, configuration of the epitopic side chains, and the constraints that governed the interactions between a major anchoring side chain and I‐Ad. In conclusion, proteolytically resistant compounds with predefined capacity to interact with MHC class II allelic products and T cell antigen receptors may be designed by retro‐inverso modification of native determinants.
Activation of protein kinase C attenuates early signals in Fas‐mediated apoptosis
Authors: Ruiz‐Ruiz María Del Carmen , Izquierdo Manuel , de Murcia Gilbert , López‐Rivas Abelardo 
Published: March 2007

AbstractActivation of protein kinase C (PKC) has been reported to inhibit Fas (APO‐1, CD95)‐mediated apoptosis in different cellular systems. Human Jurkat leukemic T cells express the Fas antigen in the cell membrane and undergo apoptosis upon cross‐linking by anti‐Fas monoclonal antibodies (mAb). Cleavage of the apoptosis‐associated protease CPP32 and its substrate poly(ADP‐ribose)polymerase are observed after the engagement of Fas antigen with mAb. In this report, we show that all these effects are substantially inhibited by the activation of PKC with a phorbol ester. Bisindolylmaleimide, an inhibitor of PKC, prevents phorbol ester‐induced down‐regulation of Fas signaling. Inhibition of Fas‐mediated cell death by phorbol ester is also observed in other human leukemic T cell lines. Cross‐linking of Fas antigen by mAb results in the rapid increase in tyrosine phosphorylation of several protein substrates which is further elevated in the presence of the protein tyrosine phosphatase inhibitor, orthovanadate. Furthermore, orthovanadate markedly enhances the cell death response to Fas mAb in different human leukemic T cell lines and human T cell blasts. These effects of orthovanadate on early tyrosine phosphorylation and cell death are clearly diminished by PKC activation. These results strongly suggest that tyrosine phosphorylation is involved in Fas signaling in apoptosis and that PKC plays a negative role in Fas‐mediated apoptosis by counteracting at a very early stage the signals generated following cross‐linking of this receptor.
Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor‐α‐mediated shock
Authors: Sparwasser Tim , Miethke Thomas , Lipford Grayson , Erdmann Andreas , Häcker Hans , Heeg Klaus , Wagner Hermann 
Published: March 2007

AbstractCell surface components of pathogens, such as lipopolysaccharide (LPS), are an important signal for receptor‐mediated activation of immune cells. Here we demonstrate that DNA of gram‐positive and gram‐negative bacteria or certain synthetic oligonucleotides displaying unmethylated CpG‐motifs can trigger macrophages in vitro to induce nuclear translocation of nuclear factor‐xB, accumulate tumor necrosis factor (TNF)‐α mRNA and release large amounts of TNF‐α. In vivo these events culminate in acute cytokine‐release syndrome which includes systemic but transient accumulation of TNF‐α. D‐Galactosamine (D‐GalN)‐sensitized mice succumb to lethal toxic shock due to macrophage‐derived TNF‐α resulting in fulminant apoptosis of liver cells. LPS and a specific oligonucleotide synergized in vivo as measured by TNF‐α‐release, suggesting that macrophages integrate the respective signals. The ability of macrophages to discriminate and to respond to bacterial DNA with acute release of pro‐inflammatory cytokines may point out an important and as yet unappreciated sensing mechanism for foreign DNA.
Dominance of the BV17 element in nickel‐specific human T cell receptors relates to severity of contact sensitivity
Authors: Vollmer Jörg , Fritz Michaela , Dormoy Anne , Weltzien Hans Ulrich , Moulon Corinne 
Published: March 2007

AbstractHypersensitivity to nickel (Ni) represents the most common manifestation of contact allergy in humans. The role of metal‐specific T cells in this disease is well established, but the molecular interactions involved in their activation are poorly understood. We examined the T cell receptor (TCR) repertoire in T cells activated with either NiSO4 or NiSO4‐treated human serum albumin from six allergic patients. For the three most hyperreactive donors, we found a strong over‐represention of the TCR BV17 element. TCR sequencing for one of these donors revealed an additional skewing for AV1 as well as a selection for an N region encoded argine at position 95 of the BV17 complementarity determining region (CDR)3. Since Arg is not known to participate in Ni complexing, we suppose that this selection is driven by contacts with peptide rather than nickel. However, the CDR1 of BV17 contains a unique combination of amino acids (HDA) that bears similarities to known motifs in Ni‐binding proteins or peptides. We therefore propose that the severe hypersensitivity reactions found in BV17 over‐expressors may be the result of Ni2+ ions bridging the germ‐line‐encoded BV17 CDR1 loop to corresponding sites in the major histocompatibility complex/peptide complex and thereby creating a superantigen‐like enhancement of weak TCR‐peptide contacts.
Cytotoxic T cell reactivity and HLA‐B35 binding of the variant Plasmodium falciparum circumsporozoite protein CD8+ CTL epitope in naturally exposed Kenyan adults
Authors: Udhayakumar Venkatachalam , Ongecha John M. , Shi Ya‐Ping , Aidoo Michael , Orago A. S. S. , Oloo Aggrey J. , Hawley William A. , Nahlen Bernard L. , Hoffman Stephen L. , Weiss Walter R. , Lal Altaf A. 
Published: March 2007

AbstractIn this study, we have investigated the extent of natural polymorphism in the CD8+ cytotoxic T lymphocyte (CTL) determinant (amino acids 368–390) of circumsporozoite (CS) protein of Plasmodium falciparum field isolates from a holoendemic region of Kenya, and determined how this variation affects the CTL reactivities in clinically immune adults and binding specificities to human histocompatibility leukocyte antigen (HLA)‐B35. Among the eight variant sequences that were found in this region, four were new and not seen in parasites from other geographical regions. When synthetic peptides corresponding to the eight variants were used to test the presence of CTL response in different donors, a different spectrum of CTL reactivity to these variants was noticed. While CTL from some donors recognized the P1 sequence (the most prevalent type of sequence) but not P8 (another major variant), other donors showed a reverse pattern of reactivity. Although none of the donors was able to recognize all the variants, CTL responses to all the eight variant sequences were found in this population. An octamer peptide with P1 sequence KPKDELDY in this polymorphic determinant was known to bind HLA‐B35. When we tested the effect of natural variation in this octamer sequence on HLA‐B35 binding, it became evident that SP13 with D → N substitution retained its binding specificity to HLA‐B35. On the other hand, the SP12 octamer sequence which had two substitutions did not bind HLA‐B35. The most interesting finding was the observation that a D → G substitution at position 374 rescued the binding ability of SP14, which otherwise could not bind to this HLA molecule due to E → Q amino acid substitution at position 372. To our knowledge, this is the first demonstration showing that a natural polymorphism can rescue the binding specificity to an HLA‐class I molecule that was lost due to another natural amino acid substitution. Altogether, these results demonstrate that natural polymorphism in the CS protein affects both the CTL reactivity and the ability to bind to HLA‐B35.