Antigen Receptor (antigen + receptor)

Distribution by Scientific Domains

Kinds of Antigen Receptor

  • b cell antigen receptor
  • b-cell antigen receptor
  • cell antigen receptor

  • Selected Abstracts

    Enhanced B-cell activation mediated by TLR4 and BCR crosstalk,

    Susana Minguet
    Abstract Despite the important role of B lymphocytes as a bridge between the innate and the adaptive immune system, little is known regarding lipopolysaccharide (LPS) recognition, activation of signalling networks or conceivable cooperation between LPS and the B-cell antigen receptor (BCR). Here, we show that primary B cells can efficiently discriminate between different LPS chemotypes, responding with at least 100-fold higher sensitivity to rough-form LPS compared with smooth-form LPS. Using genetically modified mice, we demonstrate that B lymphocytes recognize all LPS chemotypes via Toll-like receptor 4 (TLR4). In addition, we dissect the signalling pathways that lead to CD69 upregulation upon TLR4 and BCR activation in primary B cells. Our data suggest that TLR4 and BCR induce CD69 transcription via two distinct sets of signalling molecules, exerting quantitative and qualitative differences in B-cell activation. Finally, we show that simultaneous stimulation of TLR4 and BCR additively elevates B-cell activation. In contrast, co-engagement of TLR4 and BCR by antigen-coupled LPS synergistically enhances activation of B cells, pointing out attractive targets for signalling crosstalk in B lymphocytes. [source]

    Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE-secreting cells

    Alexander Karnowski
    Abstract Immunoglobulin,E (IgE) is the key effector element in allergic diseases ranging from innocuous hay fever to life-threatening anaphylactic shock. Compared to other Ig classes, IgE serum levels are very low. In its membrane-bound form (mIgE), IgE behaves as a classical antigen receptor on B,lymphocytes. Expression of mIgE is essential for subsequent recruitment of IgE-secreting cells. We show that in activated, mIgE-bearing B,cells, mRNA for the membrane forms of both murine and human epsilon (,) heavy chains (HC) are poorly expressed compared to mRNA for the secreted forms. In contrast, in mIgG-bearing B,cells, mRNA for the membrane forms of murine gamma-1 (,1) and the corresponding human ,4 HC are expressed at a much higher level than mRNA for the respective secreted forms. We show that these findings correlate with the presence of deviant polyadenylation signal hexamers in the 3,,untranslated region (UTR) of both murine and human ,,genes, causing inefficient processing of primary transcripts and thus poor expression of the proteins and poor recruitment of IgE-producing cells in the immune response. Thus, we have identified a genetic steering mechanism in the regulation of IgE synthesis that represents a further means to restrain potentially dangerous, high serum IgE levels. [source]

    Expression and function of the adaptor protein Gads in murine B,cells

    Abstract Nearly all hematopoietic receptors are dependent on adaptor proteins for the activation of downstream signaling pathways. The Gads adaptor protein is expressed in many hematopoietic tissues, including bone marrow, lymph node, and spleen. Using intracellular staining, we detected Gads protein in a number cells, including B,cells, T,cells, NK cells, monocytes, and plasmacytoid DC, but not in macrophages, neutrophils, or monocyte-derived DC. In the B,cell compartment, Gads was first expressed after immature B,cells leave the bone marrow and was down-regulated after B,cell antigen receptor (BCR) ligation. Female Gads,/, mice had increased numbers of splenic B,cells, as compared to female Gads+/+ mice, suggesting a role for Gads in B,cell homeostasis. Although B,cell production and turnover of splenic B,cell subsets appeared normal in Gads,/, mice, homeostatic proliferation was significantly impaired in Gads,/, B,cells. Whereas BCR ligation can induce apoptosis in wild-type transitional stage 1 (T1) B,cells, Gads,/, T1 B,cells were resistant to BCR-induced apoptosis. Gads,/, B,cells also showed increased BCR-mediated calcium mobilization. We conclude that Gads may have a negative regulatory role in signaling through survival pathways, and is necessary for normal homeostatic proliferation in B,cells. [source]

    Phosphorylation of Artemis following irradiation-induced DNA damage

    Catherine Poinsignon
    Abstract Artemis is a DNA repair factor required for V(D)J recombination, repair of DNA damage induced by ionizing radiation (IR) or radiomimetic drugs, and the maintenance of genome integrity. During V(D)J recombination, Artemis participates in the resolution of hairpin-sealed coding ends, a step crucial to the constitution of the gene encoding for the antigen receptor of lymphocytes. The precise role of Artemis in the repair of IR-induced DNA damage remains to be elucidated. Here we show that Artemis is constitutively phosphorylated in cultured cells and undergoes additional phosphorylation events after irradiation. The IR-induced phosphorylation is mainly, although not solely, dependent on Ataxia-telangiectasia-mutated kinase (ATM). The physiological role of these phosphorylation events remains unknown, as in vitro -generated Artemis mutants, which present impaired IR-induced phosphorylation, still display an activity sufficient to complement the V(D)J recombination defect and the increased radiosensibility of Artemis-deficient cells. Thus, Artemis is an effector of DNA repair that can be phosphorylated by ATM, and possibly by DNA-PKcs and ATR depending upon the type of DNA damage. [source]

    Apoptosis via the B cell antigen receptor requires Bax translocation and involves mitochondrial depolarization, cytochrome C release, and caspase-9 activation

    Eric Eldering
    Abstract Various routes to apoptosis can be active during B cell development. In a model system of mature B cells, differences in caspase-3 processing have suggested that antigen receptor (BCR)-mediated apoptosis may involve a zVAD-insensitive initiator protease(s). In search of the events leading to caspase-3 activation, we now establish that both CD95- and BCR-mediated apoptosis depend on Bax activation and cytochrome C (cytC) release. Nevertheless, the timing and caspase-dependence of mitochondrial membrane depolarization differed considerably after CD95- or BCR-triggering. To delineate events subsequent to cytC release, we compared apoptosis induced via BCR triggering and via direct mitochondrial depolarization by CCCP. In both cases, partial processing of caspase-3 was observed in the presence of zVAD. By expression in 293 cells we addressed the potential of candidate initiator caspases to function in the presence of zVAD, and found that caspase-9 efficiently processed caspase-3, while caspase-2 or ,8 were inactive. Finally, retroviral expression of dominant-negative caspase-9 inhibited both CD95- and BCR-mediated apoptosis. In conclusion, we obtained no evidence for involvement of a BCR-specific protease. Instead, our data show for the first time that the BCR-signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release. Subsequent caspase-9 activation can solely account for events further downstream. [source]

    CREB function is required for normal thymic cellularity and post-irradiation recovery

    Sven Baumann
    Abstract Recent generation of genetically modified Creb1 mutant mice has revealed an important role for CREB (cAMP responsive element binding protein) and the related proteins CREM (cAMP responsive element modulator) and ATF1 (activating transcription factor 1) in cell survival, in agreement with previous studies using overexpression of dominant-negative CREB (dnCREB). CREB and ATF1 are abundantly expressed in T cells and are rapidly activated by phosphorylation when T cells are stimulated through the T cell antigen receptor. We show that T cell-specific loss of CREB in mice, in combination with the loss of ATF1, results in reduced thymic cellularity and delayed thymic recovery following sublethal irradiation but no changes in T cell development or activation. These data show that loss of CREB function has specific effects on thymic T lymphocyte proliferation and homeostasis in vivo. [source]

    The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B,cells

    Josephine Meade
    Abstract In this study we set out to test whether Syk was required for negative selection of immature B,cells. B,cells expressing a B,cell antigen receptor (BCR) transgene (3,83, anti-H-2Kk) underwent negative selection independently of Syk in both fetal liver organ culture and radiation chimera models. Furthermore, Syk-independent negative selection was not reversed by transgenic overexpression of Bcl-2. Receptor editing was not apparent in Syk-deficient B,cells, presumably as a consequence of the failure of mature edited B,cells to develop in the absence of Syk. Interestingly, light chain isotype exclusion by the BCR transgene failed in the absence of Syk. We observed a dramatic reduction in the overall BCR-mediated tyrosine phosphorylation of cellular proteins in Syk-deficient immature B,cells. However, the tyrosine phosphorylation of a number of substrates including phospholipase,C,2, although reduced, was not completely abrogated. BCR ligation triggered an increase in calcium flux in the absence of Syk. Thus signaling events that mediate negative selection can still occur in the absence of Syk. This may be due to redundancy with zeta-associated protein,70 (ZAP-70), which we demonstrate to be expressed in immature B,cells. [source]

    Identification of pro-interleukin 16 as a novel target of MAP kinases in activated T lymphocytes

    Arian Laurence
    Abstract T lymphocyte activation is controlled by a coordinated web of tyrosine and serine kinases. There is a large body of information about tyrosine kinase substrates in T cells but analysis of serine kinase substrates has been more difficult. Recently we described an antiserum that recognizes serine-phosphorylated peptides corresponding to the substrate sequences for AGC serine kinases. This antiserum, termed PAP-1 (phospho antibody for proteomics-1), has proven useful for probing the serine phosphoproteome of antigen receptor-activated T lymphocytes. The present study shows that PAP-1 can also be used to explore serine kinases activated by cytokines and chemokines in T cells. Using PAP-1, together with proteomic analysis, the precursor form of the cytokine IL-16 (ProIL-16) was shown to be phosphorylated on Ser144 in antigen receptor-, SDF1,- and IL-2-activated T cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of ProIL-16 is dependent on activation of the kinases Erk1/2. IL-16 is secreted by mitogen-activated T cells, and the biochemical link between ProIL-16 and Erk1/2, revealed by studies with PAP-1, prompted analysis of the role of MAP kinases in this response. We show that TCR-mediated secretion of IL-16 is dependent on MAP kinases. The present study thus reveals how phosphoproteomic analysis opens previously unrecognized avenues for research, and yields novel insights about targets for MAP kinases in T lymphocytes. [source]

    IFN-,-mediated inhibition of antigen receptor-induced B cell proliferation and CREB-1 binding activity requires STAT-1 transcription factor

    Frank Frissora
    Abstract We report here a role for cyclic AMP-responsive element-binding protein-1 (CREB-1) in B cell antigen receptor (BCR)-induced growth inhibition by IFN-,. BCR-induced proliferation is negatively regulated by IFN-,. Stimulation through BCR resulted in dose-dependent induction of CREB-1 binding to the consensus cyclic AMP-responsive element. Recombinant IFN-, inhibited the BCR-induced CREB-1 DNA binding activity and cell proliferation in B cells from signal transducer and activator of transcription-1 (STAT-1)+/+, but not STAT-1,/, mice. These studies provide the first evidence for cross-talk between the STAT-1 and CREB-1 signaling pathways in IFN-,-mediated negative regulation of B cell activation. [source]

    NF-ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B cell antigen receptor

    Eisaku Kondo
    Abstract Cross-linking of the B cell antigen receptor (BCR) with an anti-IgM antibody has been shown to induce dramatic apoptosis in type I Burkitt's lymphoma (BL) cells. However, the apoptotic mechanism triggered via BCR remains unknown. Here we reports a mechanism of BCR ligation-induced apoptosis involving protein phosphatase calcineurin and its specific substrate, transcriptional factor NF-AT. In response to BCR cross-linking, endogenous calcineurin was rapidly activated, and this facilitated nuclear translocation of NF-ATc2, a subtype of NF-AT members. Interestingly, nuclear-imported NF-ATc2 functioned pro-apoptotically in BL cells. The effect of NF-ATc2 was efficiently blocked with FK506, which prevented its nuclear translocation through inactivation of calcineurin. In addtion, TR3 induction during BCR cross-linking was reduced by FK506 and the VIVIT peptide, which is a highly selective inhibitor for NF-AT. This strongly suggests that activation of NF-ATc2 by calcineurin is essential for TR3 recruitment, and that TR3 can be considered as a candidate for death effector in BCR-mediated apoptosis. Therefore, NF-ATc2 plays a crucial role in BCR-mediated apoptosis in type IBL, providing greater insight into unique BL characteristics through BCR signaling. [source]

    Surface T-cell antigen receptor expression and availability for long-term antigenic signaling

    Adam G. Schrum
    Summary:, It is important to understand how T-cell antigen receptor (TCR) engagement and signaling are regulated throughout an immune response. This review examines the dynamics of surface TCR expression and signaling capacity during thymic and effector T-cell development. Although the TCR can undergo vast changes in surface expression, T cells remain capable of sustaining TCR engagement for long periods of time. This may be achieved by a combination of mechanisms that involve (a) controlling the quantity of surface TCR available for ligand interaction and (b) controlling the quality of surface TCR expression during T-cell activation. TCR signaling itself appears to be one of the main quantitative modulators of surface TCR expression, and it can cause both downregulation and upregulation at different times of T-cell activation. Recent studies indicate that the degree of upregulation is tunable by the strength of antigenic stimulation. There is evidence that qualitatively distinct forms of the TCR exist, and their potential role in sustained antigenic signaling is also discussed. A goal of future studies will be to better characterize these modulations in surface TCR expression and to clarify their impact on the regulation of immune responses. [source]

    Molecular modifiers of T cell antigen receptor triggering threshold: the mechanism of CD28 costimulatory receptor

    Oreste Acuto
    Summary:, CD28 was thought to represent a prototypic membrane receptor responsible for delivering the classically defined ,second signal' needed to avoid T cell paralysis when recognizing antigen presented by appropriate antigen presenting cells (APCs). Almost two decades after its molecular identification, the mechanism by which this ,second receptor' facilitates clonal expansion and differentiation upon antigen encounter is still not fully elucidated. There may be at least two reasons for this partially gray picture: the use of nonphysiological experimental conditions to study it and the fact that the action of CD28 may be partly masked by the presence of additional T cell surface receptors that also provide some costimulatory signals, although not equivalent to the one delivered through CD28. Thus, instead of aging, the study of CD28 is still a topical subject. What is appearing through work of recent years is that far from being purely qualitative, the CD28 signal provides a key quantitative contribution to potently boost the T cell antigen receptor (TCR) signal. In other words, CD28 is in part a signaling ,sosia' of the TCR. Also, it is clear now that CD28 operates via multiple molecular effects. Still, what we do not understand is the ,qualitative' part of this signal, perhaps due to lack of identification of unique signaling components and/or pathways activated by CD28 only. Here we review a series of recent findings pointing towards novel avenues to better understand the molecular basis of CD28 function. [source]

    Kinetic perspectives of T cell antigen receptor signaling

    Makio Iwashima
    Summary: T-cell activation consists of multiple layers of signaling events. Interleukin-2 production is of interest for many, since its expression determines a critical difference between partial and full T-cell activation. To achieve full activation of T cells, it is necessary for the T-cell antigen receptor (TCR) to be engaged for an extended period of time. However, why extended stimulation is required for full T-cell activation is not understood at the molecular level. In this review, orchestrated events of TCR signal transduction will be analyzed in a kinetic manner and connected toward the understanding of the mechanism of T-cell activation. Based on recent results, a model of the mechanism that dictates the threshold between partial and full T-cell activation is proposed. [source]

    Induction and mechanism of action of transforming growth factor-,-secreting Th3 regulatory cells

    Howard L. Weiner
    Summary: Th3 CD4+ regulatory cells were identified during the course of investigating mechanisms associated with oral tolerance. Different mechanisms of tolerance are induced following oral antigen administration, including active suppression, clonal anergy and deletion. Low doses favor active suppression whereas high doses favor anergy/deletion. Th3 regulatory cells form a unique T-cell subset which primarily secretes transforming growth factor (TGF)-,, provides help for IgA and has suppressive properties for both Th1 and Th2 cells. Th3 type cells are distinct from the Th2 cells, as CD4+ TGF-,-secreting cells with suppressive properties have been generated from interleukin (IL)-4-deficient animals. In vitro differentiation of Th3 cells from Th precursors from T-cell antigen receptor (TCR) transgenic mice is enhanced by culture with TGF-,, IL-4, IL-10, and anti-IL-12. Th3 CD4+ myelin basic protein regulatory clones are structurally identical to Th1 encephalitogenic clones in TCR usage, MHC restriction and epitope recognition, but produce TGF-, with various amounts of IL-4 and IL-10. Because Th3 regulatory cells are triggered in an antigen-specific fashion but suppress in an antigen-non-specific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. In vivo induction of Th3 cells and low dose oral tolerance is enhanced by oral administration of IL-4. Anti-CD86 but not anti-CD80 blocks the induction of Th3 cells associated with low dose oral tolerance. Th3 regulatory cells have been described in other systems (e.g. recovery from experimental allergic encephalomyelitis) but may be preferentially generated following oral antigen administration due to the gut immunologic milieu that is rich in TGF-, and has a unique class of dendritic cells. CD4+CD25+ regulatory T-cell function also appears related to TGF-,. [source]

    Activating and inhibitory nature of the murine paired immunoglobulin-like receptor family

    Toshiyuki Takai
    Summary: Clones for murine paired immunoglobulin-like receptors (PIR) were first isolated as those coding for type I transmembrane glycoproteins with six immunoglobulin-like domains homologous to human Fc,R, bovine Fc,2R, and other related receptors. However, they turned out to bind neither IgA nor other immunoglobulins in the case of the ectopic expression on COS-1 fibroblastic cells. PIR-A and B are expressed on a wide variety of cells in the murine immune system, such as in B cells, mast cells, macrophages, and dendritic cells, mostly in a pairwise fashion. PIR-A requires homodimeric Fc receptor common , chain, which harbors an immunoreceptor tyrosine-based activation motif, for its efficient cell surface expression and for the delivery of activation signaling. In contrast, PIR-B contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic portion and inhibits receptor-mediated activation signaling in vitro upon engagement with other activating-type receptors such as the antigen receptor on B cells and the high affinity Fc receptor for IgE on mast cells. ITIMs of PIR-B on macrophages and B cells have been shown to be constitutively phosphorylated in their tyrosine residues. Although the ligand for PIR still remains unknown, the transgenics and the gene-targeted mice will provide us with valuable information on their physiological roles in the immune regulation. We thank Hiromi Kubagawa for discussion. This work is supported by CREST Program of JST, Virtual Research Institute of Aging funded by Boehringer Ingelheim, and by research grants from the Ministry of Education, Science, Sports and Culture of Japan to T. Takai. [source]

    The riddle of the dual expression of IgM and IgD

    IMMUNOLOGY, Issue 4 2006
    Roland Geisberger
    Summary Signalling through the B cell antigen receptor (BCR) is required for peripheral B lymphocyte maturation, maintenance, activation and silencing. In mature B cells, the antigen receptor normally consists of two isotypes, membrane IgM and IgD (mIgM, mIgD). Although the signals initiated from both isotypes differ in kinetics and intensity, in vivo, the BCR of either isotype seems to be able to compensate for the loss of the other, reflected by the mild phenotypes of mice deficient for mIgM or mIgD. Thus, it is still unclear why mature B cells need expression of mIgD in addition to mIgM. In the current review we suggest that the view that IgD has a simpIy definable function centred around the basic signalling function should be replaced by the assumption that IgD fine tunes humoral responses, modulates B cell selection and homeostasis and thus shapes the B cell repertoire, defining IgD to be a key modulator of the humoral immune response. [source]

    Regulation of T-cell receptor signalling by membrane microdomains

    IMMUNOLOGY, Issue 4 2004
    Tahir M. Razzaq
    Summary There is now considerable evidence suggesting that the plasma membrane of mammalian cells is compartmentalized by functional lipid raft microdomains. These structures are assemblies of specialized lipids and proteins and have been implicated in diverse biological functions. Analysis of their protein content using proteomics and other methods revealed enrichment of signalling proteins, suggesting a role for these domains in intracellular signalling. In T lymphocytes, structure/function experiments and complementary pharmacological studies have shown that raft microdomains control the localization and function of proteins which are components of signalling pathways regulated by the T-cell antigen receptor (TCR). Based on these studies, a model for TCR phosphorylation in lipid rafts is presented. However, despite substantial progress in the field, critical questions remain. For example, it is unclear if membrane rafts represent a homogeneous population and if their structure is modified upon TCR stimulation. In the future, proteomics and the parallel development of complementary analytical methods will undoubtedly contribute in further delineating the role of lipid rafts in signal transduction mechanisms. [source]

    Models of signal transduction through the B-cell antigen receptor

    IMMUNOLOGY, Issue 4 2003
    Roland Geisberger
    No abstract is available for this article. [source]

    B-cell antigen-receptor signalling in lymphocyte development

    IMMUNOLOGY, Issue 4 2003
    Leo D. Wang
    Summary Signalling through the B-cell antigen receptor (BCR) is required throughout B-cell development and peripheral maturation. Targeted disruption of BCR components or downstream effectors indicates that specific signalling mechanisms are preferentially required for central B-cell development, peripheral maturation and repertoire selection. Additionally, the avidity and the context in which antigen is encountered determine both cell fate and differentiation in the periphery. Although the signalling and receptor components required at each stage have been largely elucidated, the molecular mechanisms through which specific signalling are evoked at each stage are still obscure. In particular, it is not known how the pre-BCR initiates the signals required for normal development or how immature B cells regulate the signalling pathways that determine cell fate. In this review, we will summarize the recent studies that have defined the molecules required for B-cell development and maturation as well as the theories on how signals may be regulated at each stage. [source]

    Molecular abnormalities of T-cells in systemic lupus erythematosus

    Tsutomu TAKEUCHI
    Abstract Substantial evidence supports that T-cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE). To explore the molecular basis of the defective function of SLE T-cells, we focused on the signal transduction system via T-cell antigen receptor (TCR) in peripheral blood T-cells from SLE patients. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR , chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR , chain, including spliced variants lacking exon 7 and with a short 3,-UTR, were detected in SLE T-cells. Although attenuated expression of the TCR , chain is also observed in patients with cancers, infections, and other autoimmune diseases, sustained attenuation of TCR , expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR , defects in SLE. [source]

    Lower antibody response to Porphyromonas gingivalis associated with immunoglobulin G Fc, receptor IIB polymorphism

    Y. Honma
    Background and Objective:, Human Fc,RIIB is one of the receptors for immunoglobulin G (IgG) and suppresses the activation of B lymphocytes through cross-linking with the B cell receptor via immune complexes. This function of Fc,RIIB is essential for the negative regulation of antibody production. Our previous study has demonstrated the gene polymorphism Fc,RIIB-I232T to be associated with periodontitis. The polymorphism Fc,RIIB-232T has been reported to inhibit B-cell antigen receptor signaling more effectively compared to Fc,RIIB-232I, while other groups concluded that Fc,RIIB-232T had no ability to inhibit activatory receptors. In this study, we examined whether Fc,RIIB-I232T polymorphism would change the IgG antibody response to the periodontopathic bacteria Porphyromonas gingivalis. Material and Methods:, Forty-seven patients with periodontitis were genotyped with the direct sequencing of genome DNA. Serum IgG and specific IgG subclass levels for the sonicate of P. gingivalis and the recombinant 40 kDa outer membrane protein (OMP) were determined. Results:, No significant difference in the total IgG level and IgG response to P. gingivalis sonicate were observed between sera from Fc,RIIB-232T carriers and non-carriers. The Fc,RIIB-232T carriers revealed a significantly lower IgG2 response to P. gingivalis 40 kDa OMP compared to non-carriers (p = 0.04, Mann,Whitney U -test). Lower responses of Fc,RIIB-232T carriers were also observed in specific IgG and IgG1 levels. The Fc,RIIB-232T carriers revealed a low level of IgG2 response to P. gingivalis 40 kDa OMP, even with a high average probing pocket depth. Conclusion:, These results suggest that association of the Fc,RIIB-232T allele with periodontitis might be related to the lower levels of antibody response to P. gingivalis. [source]

    Getting down to malarial nuts and bolts: the interaction between Plasmodium vivax merozoites and their host erythrocytes

    Julian Rayner
    Summary Of the four Plasmodium species that routinely cause malaria in humans, Plasmodium falciparum is responsible for the majority of malaria mortality and consequently gets most of the headlines. Outside Africa, however, more malaria cases are caused by its distant cousin Plasmodium vivax, resulting in a daunting morbidity and economic burden for countries across Asia and the Americas. Plasmodium life cycles are complex, but the symptoms and pathology of malaria occur during the blood phase, when merozoites recognize and invade erythrocytes, initiating a developmental programme that culminates in lysis of the erythrocyte and release of multiple daughter merozoites. P. vivax merozoites are dependent on a single host cell receptor for erythrocyte invasion, the Duffy antigen receptor for chemokines, and humans that do not express this receptor on the surface of their erythrocytes are immune to P. vivax infection. This essential receptor,ligand interaction is addressed from both the host and parasite side in two papers in this issue of Molecular Microbiology, with important implications for plans to develop a P. vivax vaccine. [source]

    ,, T-cell large granular lymphocyte (LGL) leukemia with spontaneous remission

    Tsutomu Shichishima
    Abstract T-cell large granular lymphocyte (LGL) leukemia is a clonal disorder with an indolent clinical course. In July 1995, a 46-year-old Japanese man was admitted to our hospital because his anemia had progressed. He had a white blood cell count of 3.9 × 109/L with 75% lymphocytes, which were intermediate to large and had almost round nuclei and azurophilic granules, and anemia with a red blood cell count (RBC) of 2.69 × 1012/L, hemoglobin (Hb) of 9.5 g/dL, and hematocrit (Hct) of 28.3%. Electron microscopic examination showed that most of the lymphocytes had a parallel tubular array and dense core granules in their cytoplasm. Flow cytometry and Southern blotting of the T-cell antigen receptor (TCR) genes using the peripheral blood species showed monoclonal proliferation of LGLs with a CD3+, TCR,,+, CD4,, CD8,, CD16+, CD56,, CD57,, HLA-DR+ phenotype, and a TCR , gene rearrangement, respectively, suggesting that the patient was diagnosed as having ,, T-cell LGL leukemia. He had no symptoms, organomegaly, or skin lesions. About 1.5 years after diagnosis, the anemia gradually improved with disappearance and appearance of a rearranged band in the TCR-, gene and TCR-, gene, respectively. About 7 years after diagnosis, the anemia improved completely with a RBC of 5.01 × 1012/L, Hb of 14.8 g/dL, and Hct of 44.3%, and he was in complete remission without TCR-, and -, gene rearrangements. He had received no therapy. This is the first report of spontaneous remission of ,, T-cell LGL leukemia. Am. J. Hematol. 75:168,172, 2004. © 2004 Wiley-Liss, Inc. [source]

    Limited humoral immunoglobulin E memory influences serum immunoglobulin E levels in blood

    G. Achatz-Straussberger
    Summary The switch of B cells expressing membrane-bound Igs, which serve as antigen receptors, to antibody-secreting plasmablasts and finally to non-dividing, long-lived plasma cells (PCs) lacking an antigen receptor, marks the terminal differentiation of a B cell. Antibody-secreting PCs represent the key cell type for the maintenance of a proactive humoral immunological memory. Although some populations of long-lived PCs persist in the spleen, most of them return to their ,place of birth' and travel to the bone marrow or invade inflamed tissues, where they survive up to several months in survival niches as resident, immobile cells. Existing data strongly support the notion that isotype-specific receptor signalling influences the migration behaviour of plasmablasts to the bone marrow. The recent observation in the murine sytem that the immigration of plasmablasts and the final differentiation to long-lived PCs in the bone marrow is dependent on the expressed B-cell isotype and the related expression of chemokine receptors leads to the conclusion that during a T-helper type 2 (Th2)-mediated immune response in wild type mice, IgE plasmablasts do not have the same chance to contribute to long-lived PC memory as IgG1 plasmablasts. The overall limited humoral IgE memory additionally restricts the quantity of IgE Igs in the serum. [source]

    TLR7 and CD40 cooperate in IL-6 production via enhanced JNK and AP-1 activation

    Vanden Bush
    Abstract During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells. [source]

    Deletion of the LIME adaptor protein minimally affects T and B cell development and function

    Claude Grégoire
    Abstract LIME (Lck-interacting membrane protein) is a transmembrane adaptor that associates with the Lck and Fyn protein tyrosine kinases and with the C-terminal Src kinase (Csk). To delineate the role of LIME in vivo, LIME-deficient mice were generated. Although Lime transcripts were expressed in immature and mature B and T cells, the absence of LIME impeded neither the development nor the function of B and T cells. TCR transgenic mice deprived of LIME showed, however, a 1.8-fold enhancement in positive selection. Since B cells and activated T cells express LIME and the related adaptor NTAL, mice lacking both adaptors were generated. Double-deficient mice showed no defect in the development and function of B and T cells, and the lack of LIME had no effect on the autoimmune syndrome that develops in aged NTAL-deficient mice. In contrast to a previous report, we further showed that this autoimmune syndrome develops in the absence of T cells. Therefore, our in vivo results refute all the previous roles postulated for LIME on the basis of studies of transformed B and T cells and demonstrate that LIME has no seminal role in the signaling cassette operated by antigen receptors and coreceptors. [source]

    Regulation of the immune response by stress-activated protein kinases

    Mercedes Rincón
    Summary:, Activation of immune cells to mediate an immune response is often triggered by potential ,danger' or ,stress' stimuli that the organism receives. Within the mitogen-activated protein kinases (MAPKs) family, the stress-activated protein kinase (SAPK) group was defined as group of kinases that activated by stimuli that cause cell stress. In the immune cells, SAPKs are activated by antigen receptors (B- or T-cell receptors), Toll-like receptors, cytokine receptors, and physical,chemical changes in the environment among other stimuli. The SAPKs are established to be important mediators of intracellular signaling during adaptive and innate immune responses. Here we summarize what is currently known about the role of two sub-groups of SAPKs , c-Jun NH2 -terminal kinase and p38 MAPK-in the function of specific components of the immune system and the overall contribution to the immune response. [source]

    The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms

    John P. Cannon
    Summary:, The adaptive immune system arose in ancestors of the jawed vertebrates approximately 500 million years ago. Homologs of immunoglobulins (Igs), T-cell antigen receptors (TCRs), major histocompatibility complex I (MHC I) and MHC II, and the recombination-activating genes (RAGs) have been identified in all extant classes of jawed vertebrates; however, no definitive homolog of any of these genes has been identified in jawless vertebrates or invertebrates. RAG-mediated recombination and associated junctional diversification of both Ig and TCR genes occurs in all jawed vertebrates. In the case of Igs, somatic variation is expanded further through class switching, gene conversion, and somatic hypermutation. Although the identity of the ,primordial' receptor that was interrupted by the recombination mechanism in jawed vertebrates may never be established, many different families of genes that exhibit predicted characteristics of such a receptor have been described both within and outside the jawed vertebrates. Recent data from various model systems point toward a continuum of immune receptor diversity, encompassing many different families of recognition molecules whose functions are integrated in an organism's response to pathogenic invasion. Various approaches, including both genomic and protein-functional analyses, currently are being applied in jawless vertebrates, protochordates, and other invertebrate deuterostome systems and may yield definitive evidence regarding the presence or absence of adaptive immune homologs in species lacking adaptive immune systems. Such studies have the potential for uncovering previously unknown mechanisms of generating receptor diversity. [source]

    Sibling rivalry: competition between Pol X family members in V(D)J recombination and general double strand break repair

    Stephanie A. Nick McElhinny
    Summary:, The nonhomologous end-joining pathway is a major means for repairing double-strand breaks (DSBs) in all mitotic cell types. This repair pathway is also the only efficient means for resolving DSB intermediates in V(D)J recombination, a lymphocyte-specific genome rearrangement required for assembly of antigen receptors. A role for polymerases in end-joining has been well established. They are a major factor in determining the character of repair junctions but, in contrast to ,core' end-joining factors, typically appear to have a subtle impact on the efficiency of end-joining. Recent work implicates several members of the Pol X family in end-joining and suggests surprising complexity in the control of how these different polymerases are employed in this pathway. [source]

    The role of the preBCR, the interleukin-7 receptor, and homotypic interactions during B-cell development

    Angela Stoddart
    Summary: Considerable progress has been made in defining intermediate stages in the process leading from stem cells to mature B cells. Cell-bound and secreted molecules direct the progression through these stages and regulate the selection of clones from which the immune repertoire emerges. In fact, a myriad of signals derived from B-cell progenitors themselves and the microenvironment in which they develop direct the differentiation process. These signals are provided by B-cell antigen receptors (BCR) and their surrogates, and by adhesion and cytokine receptors. The co-operation of these receptors to control survival, expansion, and differentiation of early B-cell progenitors is the topic of this review. Specifically, we will summarize recent findings from our laboratory demonstrating that preBCR expression lowers the threshold for interleukin (IL)-7 responsiveness. How signals initiated by these receptors may intersect at this critical point of B-cell selection will be discussed. At the stage following IL-7 responsiveness we have shown that interactions between B-cell progenitors themselves promote their differentiation to immunoglobulin-secreting B cells. We propose that one function of stromal cells, known to be central to B lymphopoiesis, is to promote critical preB,preB homotypic interactions and ensuing signals. [source]