bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ability of murine dendritic cell subsets to direct T helper cell differentiation is dependent on microbial signals
Authors: Manickasingham Shivanthi P. , Edwards Alexander D. , Schulz Oliver , Sousa Caetano Reis e 
Published: February 2003

AbstractDendritic cells (DC) initiate T cell responses and direct the class of T cell immunity through the production of Th‐polarizing cytokines. In the mouse, immunization with CD8α+ DC has led to Th1 priming whereas immunization with CD8α– DC has been associated with Th2 induction. Here, we use a direct T cell priming assay in vitro to re‐examine the Th‐directing potential of total DC or purified CD4+ DC, CD8α+ DC or CD4– CD8α– (double‐negative; DN) DC subsets from mouse spleen. We show that the default Th effector phenotype induced by priming with DC depends on the protocol used for T cell purification, the T cell:antigen‐presenting cell ratio and the antigen dose but is only marginally affected by DC subtype. All DC subsets can direct increased Th1 development in response to microbial stimuli known to elicit IL‐12 production. Similarly, all subsets can suppress Th1 development and allow Th2 cellsto expand upon exposure to IL‐10‐inducing microbial agents. The flexibility of DC in directing Th development in function of microbial signals argues against the notion of pre‐determined "DC1" and "DC2" subsets and suggests that multiple DC subtypes can direct an appropriate Th response to different classes of infectious agents.
β‐Catenin expression in thymocytes accelerates thymic involution
Authors: Xu Youyuan , Sen Jyoti 
Published: February 2003

AbstractAge‐related thymic involution in mammals is accompanied by decreased generation of naïve T cells without significant reduction in the number of peripheral T cells. This leads to inefficient immune responses and inadequate combating of infections and other challenges to the immune system in older mammals. The molecular mechanisms that underlie this phenomenon are not known. In this report we show that expression of β‐catenin in thymocytes enhances thymic involution. The effect of β‐catenin expression is seen in all the thymic sub‐populations, suggesting that an age‐related developmental process is accelerated. We also show that, as in normal mice, thymic involution does not lead to a drastic reduction in splenic T cells in β‐catenin‐transgenic mice. This study identifies β‐catenin expression in thymocytes as a molecular target of age‐related thymic involution.
Severe Mycobacterium bovis BCG infections in a large series of novel IL–12 receptor β1 deficient patients and evidence for the existence of partial IL–12 receptor β1 deficiency
Authors: Lichtenauer‐Kaligis Elgin G. R. , de Boer Tjitske , Verreck Frank A. W. , van Voorden Sjaak , Hoeve Marieke A. , Vosse Esther van de , Ersoy Fugen , Tezcan Ilhan , van Dissel Jaap T. , Sanal Ozden , Ottenhoff Tom H. M. 
Published: February 2003

AbstractCell mediated immunity plays a critical role in human host defence against intracellular bacteria. In patients with unusual, severe infections caused by poorly pathogenic species of mycobacteria and salmonellae, genetic deficiencies have been identified in key genes in the type‐1 cytokine pathway, especially in IFNGR1 and IL12RB1. Here, we analyzed 11 patients originating from Turkey and suffering from unusual Mycobacterium bovis Bacille Calmette‐Guerin infections following vaccination, and found that most patients (n=8) are deficient in IL‐12Rβ1 expression and function. No defects were found in patients' IFN‐γR or IL‐18R. In addition, a first patient suffering from partial IL‐12Rβ1 deficiency is described. This patient presented with an intermediate cellular and immunological phenotype: a consistent, low response to IL‐12 was found, which could be further augmented by IL‐18. Despite a lack of cell surface IL‐12Rβ1 expression, normal levels of intracellular IL‐12Rβ1 protein were detectable, which was not seen in the other, completely IL‐12Rβ1 deficient patients examined. Moreover, this patient had a relatively mild clinical phenotype and was the only individual with a single homozygous amino acid substitution in IL‐12Rβ1 (C198R). Collectively, our findings indicate that idiopathic, unusually severe infections due to M. bovis BCG can be caused by complete as well as partial IL‐12Rβ1 deficiency.
Clonally expanded CD4+CD28null T cells in rheumatoid arthritis use distinct combinations of T cell receptor BV and BJ elements
Authors: Wagner Ulf , Pierer Matthias , Kaltenhäuser Sylke , Wilke Bernd , Seidel Wolfram , Arnold Sybille , Häntzschel Holm 
Published: February 2003

AbstractClonally expanded, autoreactive CD4+CD28null cells can be found in the peripheral blood of patients with rheumatoid arthritis and have been shown to be associated with severeextra‐articular disease manifestations. We investigated the size of the CD4+CD28null compartment and the TCR β chain repertoire of expanded CD4+ clonotypes in 94 rheumatoid arthritis patients by complementarity‐determining region 3 (CDR3) length analysis (spectratyping) in the BV6 and BV14 TCR families, with primers specific for three arbitrarily chosen β chain joining elements (BJ1S2, BJ2S3 and BJ2S7). The spectratyping results showed a strong correlation of the size of the CD4+CD28null compartment with the detected number of BV14 clonotypes, whereas no association with BV6 oligoclonality was found. Only clones using the BV14–BJ1S2 and BV14–BJ2S3 combinations contributed to this correlation, however, whereas BV14–BJ2S7 clones did not. This preferential correlation implies a role for the TCR β chain in stimulating clonal outgrowth and argues against the previously suggested superantigenic stimulation of in‐vivo‐expanded clones. Instead, since no evidence for shared antigen specificity could be detected, clonal expansion of T cells in rheumatoid arthritis might be influenced by the BJ elements because of changes in the flexibility of the protein backbone of the β‐chain.
Dok protein family members are involved in signaling mediated by the type 1 Fcϵ receptor
Authors: Abramson Jakub , Rozenblum Guido , Pecht Israel 
Published: February 2003

AbstractAggregation of type 1 Fcϵ receptors (FcϵRI) on mast cells activates a biochemical cascade that culminates in secretion of inflammatory mediators, as well as in changes of cell morphology and adhesion properties. Some of the intracellular components involved in the early coupling events are still unidentified. Here we show that two adaptor proteins, downstream of tyrosine kinases (Dok)‐1 and Dok‐2, are involved in the FcϵRI coupling cascade in the rat mucosal‐type mast cells of the RBL‐2H3 line. Dok‐1 is found to be constitutively associated with the FcϵRI, even in untreated cells, and this interaction is not affected by this receptor's aggregation. Both Dok forms undergo a fast and relatively long‐term tyrosyl‐phosphorylation. This modification of Dok‐1 increases its association with RasGAP, suggesting that it is modulating Ras activity. Indeed, we further found that FcϵRI‐mediated Ras/Raf1/Erk signaling as well as the de novo synthesis of TNF‐α are markedly reduced in cells overexpressing Dok‐1. Moreover, FcϵRI clustering causes both Dok‐1 and Dok‐2 to become docking sites for other signaling molecules including Nck, CrkL and Cas. The latter proteins have been implicated particularly in regulation of the actin‐cytoskeletal reorganization. Hence Dok‐1/Dok‐2 may also be involved in the FcϵRI‐stimulated processes of cytoskeleton rearrangement required for cell adhesion, membrane ruffling and exocytosis.
Natural killer cell‐mediated lysis of dorsal root ganglia neurons via RAE1/NKG2D interactions
Authors: Backström Eva , Chambers Benedict J. , Ho Emily L. , Naidenko Olga V. , Mariotti Raffaella , Fremont Daved H. , Yokoyama Wayne M. , Kristensson Krister , Ljunggren Hans‐Gustaf 
Published: February 2003

AbstractNatural killer cells have been reported to be able to kill various transformed and virus‐infected target cells. It was recently observed that NK cells also could kill syngeneic dorsal root ganglia (DRG) neurons by a perforin‐dependent mechanism. We demonstrate here that this phenomenon does not reflect a general ability of NK cells to kill neurons in culture. While DRG neurons of the peripheral nervous system were readily killed, ventral spinal cord neurons and hippocampal neurons of the central nervous system (CNS) were resistant to lysis. The resistance to NK cell‐mediated lysis of the latter neurons was not related to protection by MHC class I molecules, since similar β2‐microglobulin–/– neurons were equally resistant to lysis. While exploring other possible molecular mechanisms for the selective triggering of lysis of DRG neurons, we observed that the retinoic acid early inducible gene‐1 (RAE‐1), the product of which is a ligand for the NK cell‐activating receptor NKG2D, was expressed at high levels in the DRG neurons. In contrast, RAE‐1 was expressed only at very low levels in the resistant CNS‐derived neurons. Blocking NK cells withanti‐NKG2D antibodies inhibited NK cell‐mediated killing of the DRG neurons. Thus, we demonstrate that NK cell‐mediated lysis of DRG neurons correlates with the expression of RAE‐1 and that this lysis is dependent on activation of NK cells via NKG2D. This observation demonstrates that NK cells can kill non‐pathogen‐infected or non‐transformed syngeneic cells through activation of the NKG2D receptor.
Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer
Authors: Bauernhofer Thomas , Kuss Iris , Henderson Brent , Baum Andrew S. , Whiteside Theresa L. 
Published: February 2003

AbstractNatural killer (NK) cells (CD56+/CD3–) in the circulation of cancer patients were reported to have low NK activity and undergo spontaneous apoptosis. A possible relationship between apoptosis and impaired NK activity was studied by Annexin V‐binding and NK‐cell assays performed with peripheral blood mononuclear cells of patients with head and neck cancer (HNC), breast cancer (BC) and normal controls (NC). Cells stained with Annexin V (Anx) and antibodies to CD56, CD3, CD95, CD25, CD122 or CD132 were examined by flow cytometry. NK activity was tested against K562 targets in 4‐h 51Cr‐release assays. The ratio of CD56dim/CD56bright NK cells was significantly different in patients vs. controls (10 vs. 16; p<0.01). A significantly greater percentage of CD56dim NK cells bound Anx in HNC patients (27±17%, median ± SD) or BC (46±18%) than in NC (15±18%, p<0.04and p<0.0002, respectively). CD56dim NK cells were preferentially targeted for apoptosis. NK activity was significantly lower in patients with HNC and BC than in NC (p<0.009). An inverse correlation between NK activity and the percent of Anx+CD56dim NK cells was observed in cancer patients (p =0.002) but not in NC. In patients, circulating CD56dim NK cells were targeted for apoptosis, leading to low levels of NK activity.
Increased expression of DC‐SIGN+IL‐12+IL‐18+ and CD83+IL‐12–IL‐18– dendritic cell populations in the colonic mucosa of patients with Crohn's disease
Authors: Velde Anje A. te , van Kooyk Yvette , Braat Henri , Hommes Daan W. , Dellemijn Trees A. M. , Slors J. Frederik M. , van Deventer Sander J. H. , Vyth‐Dreese Florry A. 
Published: February 2003

AbstractDentritic cells (DC) as antigen‐presenting cells are most likely responsible for regulation of abnormal T cell activation in Crohn's disease (CD), a chronic inflammatory bowel disease. Wehave analyzed the expression of activation and maturation markers on DC in the colon mucosa from patients with CD compared with normal colon, using immunohistochemical techniques. We found two distinct populations of DC present in CD patients: a DC‐specific ICAM‐3 grabbing non‐integrin (DC‐SIGN)+ population that was present scattered throughout the mucosa, and a CD83+ population that was present in aggregated lymphoid nodules and as single cells in the lamina propria. In normal colon the number of DC‐SIGN+ DC was lower and CD83+ DC were detected only in very few solitary lymphoid nodules. Co‐expression of activation markers and cytokine synthesis was analyzed with three‐color confocal laser scanning microscopy analysis. CD80 expression was enhanced on the majority of DC‐SIGN+ DC in CD patients, whereas only a proportion of the CD83+ DC co‐expressed CD80 in CD as well as in normal tissue. Surprisingly, IL‐12 and IL‐18were only detected in DC‐SIGN+ DC and not in CD83+ DC. A similar pattern of cytokine production was observed in normal colon albeit to a much lesser extent. The characteristics ofthese in‐situ‐differentiated DC markedly differ from the in‐vitro‐generated DC that simultaneously express DC‐SIGN, CD83 and cytokines.
The kidney as a second site of human C‐reactive protein formation in vivo
Authors: Jabs Wolfram J. , Lögering Birgit A. , Gerke Peter , Kreft Burkhard , Wolber Eva‐Maria , Klinger Matthias Heinrich Friedrich , Fricke Lutz , Steinhoff Jürgen 
Published: February 2003

AbstractC‐reactive protein (CRP) is the main acute phase reactant in humans. Its production is presumably restricted to the liver but extrahepatic expression by inflamed tissue has not been studied indetail. By real‐time PCR and immunohistochemistry we here show that renal cortical tubular epithelial cells (TEC) express CRP mRNA and protein within 6 h after stimulation with conditioned medium (CM) or IL‐6, but not IL‐1α or TNF‐α. Western blot analysis with monoclonal anti‐CRP antibody that recognizes native CRP revealed protein secretion into supernatants of CM‐stimulated TEC cultures. While hepatoma‐derived Hep3B cells could be induced similarly, peripheral blood mononuclear cells could not. CRP mRNA transcripts were observed in nephrectomized renal allografts with severe acute rejection but not with chronic allograft nephropathy (CAN). Of 19 needle biopsies of acutely rejecting kidney transplants, 15 demonstrated CRP mRNA production with the relative expression levels increasing with the severity of rejection. On the other hand, none of 7 graft biopsies with acute tubular necrosis (ATN) or CAN showed CRP mRNA expression. By using monoclonal anti‐CRP antibody, cortical tubules as well as glomerular cells were shown to locally express CRP in rejecting, but not in ATN kidneys. We conclude that inflamed kidneys represent a so far unknown site of CRP formation in vivo. These data shed new light on the acute phase reaction not merely representing a systemic inflammatory pathway but probably being part of the local immune response.
Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal model for autoimmune disease studies
Authors: Chen Dan , Ueda Roanna , Harding Fiona , Patil Namrata , Mao Yifan , Kurahara Carole , Platenburg Gerard , Huang Manley 
Published: February 2003

AbstractLinkage studies indicate close associations of certain HLA alleles with autoimmune diseases. To better understand how specific HLA alleles are related to disease pathogenesis, we have generated an HLA DR3/DQ2 transgenic mouse utilizing a 550‐kb yeast artificial chromosome (YAC) construct containing the complete DRα, DRβ1, DRβ3, DQα, and DQβ regions. The transgenic mouse (4D1/C2D) in an I‐Aβo background appears healthy with no signs of autoimmune diseases. Lymphoid tissues as well as CD4+ T cells develop normally. Characterization of the transgene expression demonstrates that ∼90% of B cells express high levels of DR3 and 50–70% of B cells express DQ2. CD11c+ dendritic cells express high levels of DR and DQ. Approximately12–18% of resting T cells are positive for DR expression, and further up‐regulation to 40–50% expression is seen upon activation with anti‐CD3/anti‐CD28 mAb. These results suggest that the transgenic construct confers a high fidelity to the normal human temporal and spatial expression profile. Analysis of T cell receptor repertoire in transgenic mice confirms that DR3/DQ2 are able to mediate thymic selection. Furthermore, transgenic mice respond to a DR3‐restricted antigen, demonstrating antigen processing and presentation by antigen‐presenting cells (APC). Purified T cells from ovalbumin (OVA)‐immunized 4D1 mice respond to human APC co‐cultured with OVA, suggesting appropriate antigen/DR3 or DQ2 recognition by murine T cells. Immunoglobulin isotype switching is also observed, indicating functional T‐B cognate interactions. Thus, the DR3/DQ2 transgenic mouse has normal lymphoid development and functionality that are mediated by HLA transgenes and can be used to investigate HLA‐associated immunological questions.
Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways
Authors: Feito Maria Jose , Vaschetto Rosanna , Criado Gabriel , Sánchez Alejandra , Chiocchetti Annalisa , Jiménez‐Periáñez Arturo , Dianzani Umberto , Portoles Pilar , Rojo Jose M. 
Published: February 2003

AbstractH4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR signals have been analyzed in mouse CD4+ Th2 cells, expressing H4/ICOS at higher levels than Th1 clones. Anti‐H4/ICOS antibodies strongly enhanced CD3‐mediated tyrosine phosphorylation of ZAP‐70, ζ, or Vav, as well as extracellular signal‐regulated kinase (ERK), Jun N‐terminal kinase (JNK) and p38 MAP kinase activation in these cells. The association of phosphoinositide 3‐kinase (PI‐3K) to H4/ICOS was enhanced by H4/ICOS cross‐linking, and PI‐3K inhibitors inhibited ERK and JNK activation andIL‐4/IL‐10 secretion, but not p38 MAP kinase or ZAP‐70 activation. H4/ICOS‐mediated activation of JNK, but not ERK or p38, is partially dependent on the expression of CD4 by the cells, whereas H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP‐70, MAP kinase activation, or IL‐4/IL‐10 secretion. Neither cyclosporin A nor inhibitors of PKC produced detectable inhibition of ZAP‐70 phosphorylation or MAP kinase activation in these Th2 cells. Cyclosporin A strongly inhibited IL‐4, but not IL‐10 secretion. ERK or JNKinhibitors partially inhibited IL‐4 and IL‐10 secretion, while PKC or p38 inhibitors had no significant effects on IL‐4 or IL‐10 secretion. Taken together, our data show clear similarities of costimulation mechanisms between H4/ICOS and CD28 during the early steps of TCR activation.
Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis
Authors: Cao Duojia , Malmström Vivianne , Baecher‐Allan Clare , Hafler David , Klareskog Lars , Trollmo Christina 
Published: February 2003

AbstractIn the homeostasis of the immune system regulatory cells play a major role. Removal of one group of regulatory cells, the CD25+CD4+ T cells, leads to autoimmune manifestations in experimental animal models, and reintroduction of this population prevents disease. This study addresses the role of such regulatory T cells in humans with an autoimmune disease, where we demonstrate the presence of CD25brightCD4+ T cells in the target organ of patients with active rheumatoid arthritis. The patients displayed an enrichment of CD25brightCD4+ T cells in synovial fluid as compared to peripheral blood. These cells are functional regulatory cells, as they were able to suppress in vitro proliferation of autologous T cells, bothfrom synovial and peripheral blood origin. Although the frequency of CD25brightCD4+ T cells varied between patients, it was found to be constant over time in any one joint during each relapse. Numbers were also comparable in two inflamed knee joints of one and the same patient, emphasizing the symmetry of the disease. In summary, it is striking that in addition to all activated, potentially pathological T cells the synovial fluid from RA patients also contains CD25‐expressing CD4+ T cells with a regulatory capacity.
Prevention of mucosally induced uveitis with a HSP60‐derived peptide linked to cholera toxin B subunit
Authors: Phipps Paula A. , Stanford Miles R. , Sun Jia‐Bin , Xiao Bao‐Guo , Holmgren Jan , Shinnick Thomas , Hasan Adam , Mizushima Yutaka , Lehner Thomas 
Published: February 2003

AbstractOral administration of the uveitogenic peptide (aa 336‐351) derived from human HSP60 induced clinical and histological manifestations of uveitis in 65.8% (48/73) of Lewis rats. Uveitis was significantly decreased to 16.7% (11/66) in parallel experiments with the peptide linked to recombinant cholera toxin B subunit (rCTB), also given by mouth (χ2=34.2, p<0.0001). The protective efficacy between tolerized and immunized animals was 74.7%. Adoptive transfer of mesenteric lymph node cells from tolerized rats prevented the development of uveitis. A significantly higher proportion of regulatory CD4+CD45RClowRT6+ subset of Th2 memory cells were found in the mesenteric lymph nodes (p<0.005) and spleens (p⩽0.05) of tolerized rats without uveitis, as compared with immunized rats and uveitis. In situ hybridization studies of mesenteric lymph nodes and/or the uveal tract showed significant increases in IL‐10 and TGF‐β mRNA but decreases in IFN‐γ and IL‐12 mRNA in tolerized, as compared with immunized animals. Thus, the mechanism of tolerance, preventing the development of uveitis may involve a regulatory subset of memory cells and a shift from Th1 to Th2 and Th3 cytokines. We suggest that mucosally induced uveitis can be prevented by oral administration of the peptide‐rCTB conjugate.
Precautionary motives and portfolio decisions
Authors: Hochguertel Stefan 
Published: February 2003

AbstractThis paper studies the empirical relevance of precautionary and other motives for household portfolio behaviour using recent panel data from the Netherlands. Dutch households' portfolios exhibit low degrees of risk taking and diversification. It is possible that this is the outcome of a rational, precautionary response to unavoidable exposure to background risk (stemming from the labour market or health conditions, etc.). We consider as alternative explanations liquidity needs and habits. The endogenous variable is the fraction of clearly safe in total financial assets at the household level. Parametric and semi‐parametric censored regression models for pooled cross‐sections and random and fixed effects models for panel data show that both heteroscedasticity and unobserved heterogeneity are of major importance in the data. With subjective indicators of income uncertainty we find a limited role for precautionary motives. Copyright © 2002 John Wiley & Sons, Ltd.
Second trimester diagnosis of Neu Laxova syndrome
Authors: Shivarajan M. A. , Suresh S. , Jagadeesh Sujatha , Lata S. , Bhat Lathaa 
Published: February 2003

AbstractThis is the first report of a prenatally diagnosed case of Neu Laxova syndrome (NLS) from India. This also includes a case of NLS in monochorionic diamniotic twins and two more cases in which we were able to detect most of the features of NLS as early as 19 to 20 weeks by routine antenatal ultrasonography. Severe intrauterine growth retardation (IUGR), microcephaly, central nervous system (CNS) abnormality, joint contractures, and abnormal facies are the major diagnostic features observed in prenatal ultrasonography. Risk factors such as consanguinity and history of intrauterine death or stillbirth in siblings have been noted in all the cases, but none of the three families that were reported had previously had an affected fetus. The spectrum of skin manifestations and frequency of occurrence of major clinical features of the syndrome have been discussed. Review of the literature on NLS and possibility of detecting the syndrome in the second trimester is discussed. Copyright © 2002 John Wiley & Sons, Ltd.