bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin‐1 dysregulation is an intrinsic defect in macrophages from MRL autoimmune‐prone mice
Authors: Levine Jerrold S. , Pugh Barbara J. , Hartwell Daqing , Fitzpatrick John M. , Marshak‐Rothstein Ann , Beller David I. 
Published: March 2007

AbstractMacrophages (Mϕ) from pre‐diseased autoimmune‐prone MRL mice (both MRL/+ and MRL/1pr) dramatically underproduce the cytokine interleukin‐1 (IL‐1) in comparison to Mϕ from a number of normal strains. In this study we show that IL‐1 dysregulation by MRL Mϕ is fully expressed at birth, and that this defect does not change with time or the development of disease. We also constructed adult irradiation chimeras (consisting of A/J → MRL and MRL → A/J mice), and show that Mϕ isolated from these chimeras display a pattern of IL‐1 production indistinguishable from that of the donor strain controls. Moreover, when we constructed a mixed chimera (A/J + MRL → A/J), the A/J and MRL Mϕ coexisting within the same animal retained their individual patterns of IL‐1 production when isolated by negative selection. Taken together, these results provide the first substantive evidence for an intrinsic defect (IL‐1 dysregulation) in Mϕ from MRL autoimmune‐prone mice.
Autoimmunity, hyporeactivity to T cell mitogens and lymphoproliferative disorders following neonatal induction of transplantation tolerance in mice
Authors: Jánossy Tamás , Baranyi Lajos , Knulst André C. , Vizier Csaba , Benner Robbert , Kelényi Gábor , Végh Pál 
Published: March 2007

AbstractWe have reported that, in A/J (A) (H‐2a) mice, a partial tolerance to C57BL/10ScSn (B10) (H‐2b) skin allografts and a high incidence of lethal lymphoproliferative disorders (LPD) can be induced by the neonatal i.v. injection of 2 × 107 semiallogeneic (B10 × A)F1 spleen cells (SC) (Végh, P., Baranyi, L. and Jánossy, T., Cell. Immunol. 1990. 129: 56). In this study, we show that the incidence and mortality of LPD were continuously growing from 1 month of age until the end of the experiment at 1 year (64% and 36%, respectively). Based on histology, 27% of the diseased mice suffered from lymphoid malignancies. In the remaining cases (73%), reactive histopathological changes were seen in the spleen, lymph nodes (LN), liver and kidneys. The proportion of CD4+Tcells in the spleen and LN as well as that of splenic B cells decreased, while the percentages of mature and immature myeloid cells doubled. The total cell number of each (sub)population, however, was elevated in both lymphoid organs. The cells taking part in the lymphoproliferation were of host (A) and not of donor (F1) origin. Preceding the development of apparent LPD, the SC, LN cell and thymus cell suspensions of 1‐month‐old tolerized mice showed reduced in vitro proliferative responses to cell and T cell‐dependent B cell mitogens (Con A or PWM), while their reactivity to aT cell‐independent B cell mitogen (lipopolysaccharide) was essentially unimpaired. This hyporeactivity seems to be functional, because neither histology nor immunophenotyping by flow cytometry revealed significant alterations in the spleen and thymus of such animals, apart from a slight reduction in the ratio of CD4+/CD8+ T cell subpopulations in the spleen. The in vivo T cell‐mediated immune response of the tolerized mice was practically normal to third party CBA/Ca (H‐2k) allografts. Antithymocyte autoantibodies (ATA) were detected in the sera of 76% of the tolerized mice at 1 month of age (i.e., even before the mass appearence of LPD). ATA as well as antinuclear Ab were present in 65% of the adult tolerized mice, independently of the presence of LPD. Taken together, in A mice neonatally injected with (B10 × A)F1SC, a partial, specific allograft tolerance and a chronic host‐vs.‐graft disease‐like syndrome developed. The latter is manifested in hyporeactivity to T cell mitogens, development of autoantibodies and, subsequently, in progressive LPD and lymphoid malignancies.
Antigens pre‐bound to the primate erythrocyte complement receptor via cross‐linked bispecific monoclonal antibody heteropolymers are rapidly cleared from the circulation
Authors: Reist Craig J. , Combs Matthew J. , Croft Barbara Y. , Taylor Ronald P. 
Published: March 2007

AbstractWe have used cross‐linked, bispecific monoclonal antibody heteropolymers, specific for primate erythrocyte (E) complement receptor (CR1) and target antigen (Ag), to attach 125I‐labeled Ag to 51Cr‐labeled monkey erythrocytes (E) in vitro. Injection of these sensitized E into monkeys leads to rapid clearance from the circulation of several different 125I‐labeled Ag with little, if any sequestration, lysis, or clearance of the E. It should now be possible, in principle, to use the heteropolymer‐E system to facilitate the clearance of blood‐borne pathogens from the circulation.
Peptide variants reveal how antibodies recognize major histocompatibility complex class I
Authors: Hogquist K. A. , Grandea A. G. , Bevan M. J. 
Published: March 2007

AbstractThe T cell receptor (TcR) on CD8+ T lymphocytes recognizes a complex which consists of a major histocompatibility complex (MHC) heavy chain, β2‐microglobulin (β2M), and peptide on the surface of antigen‐presenting cells. Mutational analyses have suggested that the TcR recognizes both the αl and α2 domains of the heavy chain as well as the peptide. In light of this, it is of interest to know to what extent the heavy chain domains take on distinct conformations when bound to individual peptides.It has recently been shown that antibodies which recognize the Kb MHC complex are sensitive to which peptides are bound in the groove. We have extended this analysis to include eight Kb‐specific antibodies, seven of which are peptide sensitive. These antibodies, all of which are allo‐antibodies, recognize Kb‐bearing cells which, it is now appreciated, have a highly heterogeneous mix of self peptides presented in their grooves. We show that these self peptides also can affect antibody binding.It has been suggested that peptides alter the conformation of the αl and α2 domains of the heavy chain and that this in turn affects the recognition of Kb by antibody. An alternative hypothesis is that solvent‐exposed peptide side chains may prevent the antibody from binding the complex. Using a panel of 128 single‐amino acid variants of a Kb‐binding antigenic peptide from ovalbumin we show that for most Kb‐specific antibodies, the second idea is more likely. Those variants which prevent antibody binding are at solvent exposed positions, and in general, the bulkier the side chain, the greater the inhibition of antibody binding. However, in the case of two antibodies, 100.30 and 34.4.20, the peptide residues which affect antibody recognition are buried, suggesting that these antibodies see an alternate conformation of the peptide/MHC complex.
No independent association between a tumor necrosis factor‐α promotor region polymorphism and insulin‐dependent diabetes mellitus
Authors: Pociot Flemming , Wilson Anthony G. , Nerup Jørn , Duff Gordon W. 
Published: March 2007

AbstractSeveral studies have implicated tumor necrosis factor (TNF)‐α in the pathogenesis of insulin‐dependent diabetes mellitus (IDDM). In the present study we analyzed the first reported TNF‐α gene polymorphism in relation to IDDM. We have made frequence analysis and tested in vitro lipopolysaccharide (LPS)‐induced TNF‐α secretion. A significant difference in allele frequency was observed between patients and controls (p = 0.03). However, a very strong association of the uncommonTNF2 allele was observed with the HLA‐B8, –DR3 alleles. The relative risk (RR) of TNF2 was 2.2 compared to a RRof 3.1 for DR3. One reason for this difference was the identification of the TNF1 allele on the otherwise strongly IDDM‐associated HLA‐DR3 haplotype: DQB1*0201, DQA1*0501, DRB1*0301, TNFc2, TNFB*2, TNFal, TNFb5, B18. Thus, the IDDM‐associated TNF2 allele had no DR3‐independent value as a disease marker. The LPS‐induced TNF‐α production by human monocytes in relation to genotypes demonstrated that TNF1/2 heterozygous individuals had higher, though not statistically significantly (p = 0.08) levels than TNF1‐homozygous subjects. However, this difference was rather small, unlikely to be of biological significance and based on the present material we cannot establish the functional importance of this polymorphism.
Allergy‐associated Iϵ and Fcϵ receptor II (CD23b) genes activated via binding of an interleukin‐4‐induced transcription factor to a novel responsive element
Authors: Köhler Ingrid , Rieber Ernst Peter 
Published: March 2007

AbstractInterleukin‐4 (IL‐4) has important regulatory functions in the immune system, particularly in the generation of immunoglobulin E, the principal mediator of allergic responses. The molecular basis of IL‐4 action has remained elusive so far. Here we report on a novel human transcription factor, termed nuclear factor IL‐4 (NF‐IL4), which is posttranslationally activated by IL‐4 in lymphoid and monocytic cells. Homologous binding sequences for NF‐IL4 were identified in the promoter regions of the IL‐4 controlled CD23b and Iϵ genes. We defined a palindromic 9‐bp consensus sequence (5′‐TYCYRRGAA‐3′) as IL‐4‐responsive element (IL‐4RE). Point mutation analysis of the CD23b promoter showed that binding of NF‐IL4 to the IL‐4RE is essential for the initiation of gene transcription in response to IL‐4. NF‐IL4 was not activated by Ca2+ ionophore, phorbol ester and cAMP either alone or in combination suggesting a non classical pathway for IL‐4 signal transduction.
Cyclosporin A inhibits T cell receptor‐induced interleukin‐2 synthesis of human T lymphocytes by selectively preventing a transmembrane signal transduction pathway leading to sustained activation of a protein kinase C isoenzyme, protein kinase C‐β
Authors: Szamel Marta , Bartels F. , Resch K. 
Published: March 2007

AbstractStimulation of human peripheral blood lymphocytes via T cell receptor/CD3 complex resulted in a bimodal activation of protein kinase(s) C (PKC). Within 10 min of stimulation PKC‐α was translocated to, and thus activated in, the plasma membranes of human lymphocytes, followed by a fast dissociation of this isotype from the plasma membrane. This short term activation and translocation PKC‐α proved to be cyclosporin A (CsA) insensitive. After 90 min of stimulation PKC‐β was translocated to and remained bound to the plasma membranes for up to 4 h. Preincubation of human lymphocytes with 200 ng/ml CsA specifically and completely abolished the sustained activation of PKC‐β. Neither the phorbol ester‐induced direct activation of PKC nor the specific activity of the plasma membrane‐bound enzyme was influenced by CsA, suggesting that a signal transduction pathway leading to sustained activation of PKC‐β was influenced by the immunosuppressive agent. In fact, CsA inhibited, in a concentration‐dependent manner, the activation of lysophosphatid acyltransferase‐catalyzed elevated incorporation of cis‐polyunsaturated fatty acids into plasma membrane phospholipids. While interleukin‐2 (IL‐2) synthesis and cellular proliferation were completely inhibited by 200 ng/ml CsA in BMA 030‐ or BMA 031‐stimulated cells, expression of high‐affinity IL‐2 receptors was not influenced by the immunosuppressive drug. These results suggest that synthesis and expression of high‐affinity IL‐2 receptors might be regulated by a signal‐transducing pathway involving activation and translocation of PKC‐α. Lysophosphatid acyltransferase‐catalyzed incorporation of cis‐polyunsaturated fatty acids might represent another mechanism of signal transduction implicated in the activation and translocation of PKC‐β, which is specifically inhibited by CsA. Neutralization of PKC‐β by introducing anti‐PKC‐β antibodies prevented IL‐2 synthesis and proliferation in stimulated human lymphocytes. The results suggest a possible link between activation of PKC‐β and regulation of IL‐2 synthesis in activated human lymphocytes. Thus, inhibition of the activation and translocation of PKC‐β by CsA may result in inhibition of IL‐2 gene expression in human lymphocytes.
Differential effect of transporter Tap 2 gene introduction into RMA‐S cells on viral antigen processing
Authors: Ossevoort Miriam A. , Sijts Alice J. A. M. , van Veen Karin J. H. , Momburg Frank , Hämmerling Günter J. , Seelig Angela , Butcher Geoffrey W. , Howard Jonathan C. , Kast W. Martin , Melief Cornells J. M. 
Published: March 2007

AbstractThe protein products of the Tap (Transporter associated with antigen processing) 1 and 2 genes are presumed to deliver peptides across the endoplasmic reticulum (ER) for assembly with major histocompatibility complex (MHC) class I molecules. The antigen processing‐defective cell line RMA‐S (H‐2b) has a premature stop in the Tap 2 gene and probably therefore fails to deliver peptides into the ER, which leads to a low level of cell surface MHC class I molecules. Transfection of a Tap 2 gene restores to RMA‐S both MHC class I molecule expression and the ability to present influenza viral antigens. We investigated the ability of RMA‐S cells transfected with a Tap 2 gene to process and present alloantigens, Sendai and Rauscher viral antigens to allogeneic and virus‐specific cytotoxic T lymphocytes. We found that allogeneic peptides as well as Rauscher and Sendai viral peptides can be processed and presented by RMA‐S but at reduced levels. Transfection of a Tap 2 gene of mouse (BALB/c, H‐2d) or rat origin into RMA‐S increased the presentation of Sendai viral antigens and partially restored the presentation of allogeneic antigens. The already low level of Rauscher viral peptides presented by RMA‐S is not elevated by transfection of either Tap 2 gene into RMA‐S. This indicates a differential effect of transfection of a Tap 2 gene of rat or allogeneic mouse origin into RMA‐S on viral antigen processing.
The major histocompatibility complex influences myelin basic protein 63‐88‐induced T cell cytokine profile and experimental autoimmune encephalomyelitis
Authors: Mustafa Maha , Vingsbo Carina , Olsson Tomas , Ljungdahl Åke , Höjeberg Bo , Holmdahl Rikard 
Published: March 2007

AbstractPolymorphism of the major histocompatibility complex (MHC) influences susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP) in rats. Current concepts relate such influences to the capacity of class II molecules to present relevant peptides to autoreactive T cells. We have here analyzed the MHC influence on the immune response and the development of EAE after immunization with the immunodominant peptide MBP‐63–88. Analysis of MHC‐congenic LEWIS strains showed that RT1a, RT1c and RT1l haplotypes are permissive for disease induction, whereas RT1d and RT1u are resistant. All EAE responding strains showed peptide‐specific proliferation and interferon (IFN)‐γ secretion, but no early significant tendency to express interleukin (IL‐4) or transforming growth factor (TGF)‐β mRNA in lymphocytes in response to the MBP 63–88, 7 days post immunization (p.i.). Later, 14 days p.i., peptide‐specific induction of IL‐4 and TGF‐β occurred in RT1l rats. Among the EAE non‐responders strains, only the RT1u rats showed an immune response to MBP 63‐88. This response, however, was qualitatively different from the immune response in the EAE‐susceptible strains. Thus, there was no proliferation and only moderate IFN‐γ production in response to peptide, but in contrast, a significant and early peptide‐induced IL‐4 and TGF‐β response was observed. The data suggest that the MHC‐associated susceptibility to EAE is partly related to the ability to mount a TH1‐like immune response while the MHC‐associated EAE resistance may either be related to MBP peptide non‐responsiveness or to peptide recognition and induction of a qualitatively different and disease down‐regulatory immune response.
The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages
Authors: de Weers Michel , Verschuren Martie C. M. , Kraakman Margriet E. M. , Mensink Rob G. J. , Schuurman Ruud K. B. , van Dongen Jacques J. M. , Hendriks Rudolf W. 
Published: March 2007

AbstractX‐linked agammaglobulinemia (XLA) is an immunodeficiency disease in man, resulting from an arrest in early B cell differentiation. The gene defective in XLA has recently been identified and encodes a cytoplasmic protein tyrosine kinase, named Bruton's tyrosine kinase (btk), essential for cell differentiation and proliferation at the transition from pre‐B to later B cell stages. In this study we investigated btk expression by Northern blotting experiments in a series of human (precursor‐) B cell lines, acute lymphoblastic leukemias and plasmacytomas, btk was found to be already expressed in very early stages of B cell differentiation, even prior to immunoglobulin (Ig) heavy (H) or light (L) chain gene rearrangements. Transcripts were also detected at the pre‐B cell stage and in mature B cells, irrespective of the Ig H chain class expressed. Approximately at the transition from mature B cells to plasma cells, expression of the btk gene is down‐regulated. In addition, the btk gene was found to be expressed in myeloid cell lines and acute myeloid leukemias. btk expression in myeloid cells is probably not a prerequisite for myeloid differentiation, since myeloid cells in XL A patients seem not to be affected. No btk expression was found in T‐lineage cells. The btk expression profile, i.e. from early precursor‐B cell stages preceding Ig rearrangement up to mature B cells, supports the hypothesis that the XLA defect resides in a critical step of B cell development which is independent of the Ig gene recombination machinery.
Increased number of cytotoxic T cells within CD4+8− T cells in β2‐microglobulin, major histocompatibility complex class I‐deficient mice
Authors: Marušić‐Galešić Suzana , Udaka Keiko , Walden Peter 
Published: March 2007

AbstractTargeted disruption of β2‐microgobulin gene results in deficient major histocompatibility complex class I expression and failure to develop CD4−8+ T cells. Despite this, β2M−/− mice reject skin grafts and cope with most viral infections tested. We asked whether CD4+8− cytotoxic T cells could play a role in compensating for the defect in CD4−8+ cytotoxic T cell function. We found that the cytotoxic activity against class II+ targets is significantly higher among CD4+8− T cells of β2M−/− than among those of β2M+/+ mice. In the limiting dilution experiment, we showed that the precursor frequency for the cytotoxic, CD4+8−, class II‐specific T cells is at least fivefold higher in β2M −/−than in β2M+/+ mice. These results suggest that CD4+8− cytotoxic T cells could play a major role in carrying out cytotoxic function in β2M−/− mice.
Phenotypical and functional characterization of Fey receptor I (CD64)‐negative monocytes, a minor human monocyte subpopulation with high accessory and antiviral activity
Authors: Grage‐Griebenow Evelin , Lorenzen Dirk , Fetting Rudolf , Flad Hans‐Dieter , Ernst Martin 
Published: March 2007

AbstractFcγ receptor I‐positive (CD64+) and Fcγ receptor I‐negative (CD64−) monocytes were prepared from highly purified (elutriation‐derived) human monocytes by cytofluorograph cell sorting, and a phenotypical and functional dissociation of the isolated CD64+ and CD64− monocyte subsets is demonstrated. Surface analyses revealed that the surface antigen pattern of CD64+ monocytes corresponds to the phenotype of typical unseparated monocytes. In contrast, CD64− monocytes are characterized by high expression of major histocompatibility complex (MHC) class I antigens (HLA‐A, ‐B, ‐C) and MHC class II antigens (HLA‐DR, ‐DP, ‐DQ), and low expression of the monocyte‐specific marker CD14 which is found on nearly all CD64+ monocytes. However, 75% of the CD64− cells were found to be esterase‐positive, and 85% were positive for the monocyte/macrophage‐specific intracellular antigen CD68. Furthermore, CD64+ monocytes show significantly higher expression of CD45RA and Fcγ receptor III (CD16) than CD64+ monocytes, but lack the natural killer cell markers CD56 and CD57. Functional studies showed that cells of the minor CD64− monocyte subset have a higher accessory cell capacity in antigen‐driven T cell activation than CD64+ monocytes. CD64− monocytes pretreated with PPD (purified protein derivative of tuberculin) induced up to tentimes more interferon‐γ and also higher proliferation in responding autologous T cells than PPD‐pretreated CD64+ monocytes. Similar results were obtained for T cells in mixed leukocyte reaction. Interferon‐γ release and proliferation of allogeneic lymphocytes were consistently higher in the presence of irradiated CD64− monocytes than of irradiated CD64+ monocytes. Furthermore, when CD64− and CD64+ monocytes were stimulated with Newcastle disease virus, we measured an up to 67‐fold higher interferon‐a release from CD64− than from CD64+ monocytes, indicating a higher anti‐viral capacity of this subset. CD64− monocytes showed lower activity in the phagocytosis of unopsonized particles and also lower zymosan‐ or latex‐induced chemiluminescence than CD64+ monocytes. These findings indicate that CD64− monocytes, although comprising only less than 10% of all peripheral blood monocytes, represent a monocyte subpopulation efficiently interacting in vitro with T cells and, additionally, are the major source of interferon‐α.
Antigen‐independent adhesion of CD4 CD45RA T cells from cord blood
Authors: Buzyn‐Veil Agnès , Hivroz Claire , Lecomte Olivia , Barbat Christiane , Mazerolles Fabienne , Fischer Alain 
Published: March 2007

AbstractAntigen‐independent adhesion of resting adult CD4+ CD45RO+ T cells to B lymphocytes has been shown to be transient and can be down‐regulated by CD4 major histocompatibility complex (MHC) class II molecule interactions. Conversely, adhesion of adult CD4+ CD45RA+ subpopulation to B cells is not regulated by ligands of CD4. We have investigated the regulation of adhesion of cord blood CD45RA+ CD4+ T lymphocytes. In contrast to adult CD45RA+ CD4+ T cells, cord blood CD45RA+ CD4+ T cells were strongly sensitive to the down‐regulation of adhesion mediated by the CD4‐HLA class II interaction, since adhesion to MHC class II(+) B cells was transient and inhibited by an anti‐CD4 antibody. In addition, human immunodeficiency virus gpl60, synthetic gpl06‐derived peptides encompassing a CD4 binding site inhibited conjugate formation between cord blood CD45RA+ CD4+ T cells and B cells. Following activation of the cord blood CD4 T cells by an anti‐CD3 antibody, a conversion from a transient to a stable adhesion pattern of cord blood CD4 T cells to B cells occurred in 2 days. The reversal to a transient adhesion occurred at day 8 following anti‐CD3 activation in correlation with a complete shift to a CD45RO phenotype of the cord blood CD4 T cells. These data suggest that CD4 T cell adhesion can be developmentally regulated.