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H Yakura

Publications and source records attributed to H Yakura.

At least 37 records · Page 2Linked to original sources
PubMed1996

Antigen receptor-mediated B cell death is blocked by signaling via CD72 or treatment with dextran sulfate and is defective in autoimmunity-prone mice.

Mature B cells undergo programmed cell death when surface (s) Ig is extensively multimerized. A signal that blocks death of B cells is thus required for activation of B cells in response to antigen stimulation. Here we show that only a few diverse transmembrane signals capable of inducing activation and proliferation of B cells blocked sig-mediated death of normal mature B cells, and that there is no correlation between mitogenic activity and the ability to rescue B cells from death. The results suggest that a specific signal is required for abrogating B cell death induced by sig cross-linking. Signaling via IL-4 receptor and CD40, both of which are derived from activated T cells, blocked sig-mediated death, as described previously. Signaling through a B cell antigen CD72, a counter-receptor of the pan-T antigen CD5, also blocked death of anti-Ig-treated mouse spleen B cells. CD72 signal may play a role in survival of B cells at the initial step of T-B interaction, where resting T cells recognize antigens presented by B cells. Moreover, B cell death by anti-Ig was blocked by T cell-independent antigens such as lipopolysaccharide and dextran sulfate, and spleen B cells from New Zealand mice, which are prone to autoantibody-dependent autoimmune diseases, were resistant to sig-mediated death. Mechanisms for blocking sig-mediated death may therefore be required in antibody response to foreign antigens regardless of T independence or T dependence and in autoantibody production.

Animals↗
PubMed1995

Selective regulation of Lyn tyrosine kinase by CD45 in immature B cells.

It has been well established that protein-tyrosine phosphatase CD45 is critically involved in the regulation of initial tyrosine phosphorylation and effector functions of T and B cells. However, the signaling pathway governed by CD45 is not completely understood. In B cells, it has not been unequivocally resolved as to which protein-tyrosine kinases (PTKs) associated with B cell antigen receptor are regulated by CD45 in intact cells. As a first step toward the elucidation of CD45-initiated signaling events, we have tried to identify physiological substrates for CD45 by analyzing PTK activity in CD45-deficient clones recently generated from the immature B cell line WEHI-231. The results clearly demonstrated that among PTKs examined (Lyn, Lck, and Syk), only Lyn kinase is dysregulated in the absence of CD45 such that without B cell antigen receptor ligation, Lyn is hyperphosphorylated and activated in CD45-negative clones. Thus, Lyn seems to be a selective in vivo substrate for CD45 in immature B cells.

Animals↗
PubMed1995

Antigen receptor-initiated growth inhibition is blocked in CD45-loss variants of a mature B lymphoma, with limited effects on apoptosis.

Role of CD45 in B cell antigen receptor (BcR)-mediated signaling events in mature B cells was examined using BAL-17 and its CD45-negative clones. In the CD45-negative clones, BcR stimulation induced tyrosine phosphorylation almost identical to the parental cells, with a few exceptions of reduced phosphorylation, especially of a protein of about 60 kDa. BcR-induced calcium responses were reduced in the CD45-negative clones, but the kinetics were similar to the parent. BcR stimulation led to growth inhibition in the parental cells, but signals for growth inhibition were completely blocked in the CD45-negative clones. Interestingly, the same stimulation induced low, but significant levels of apoptosis both in the parent and in the CD45-negative clones. Thus, in mature BAL-17 cells, CD45 subtly mediate early signaling events (tyrosine phosphorylation and Ca2+ mobilization), and is absolutely required for the signaling pathway leading to growth regulation, but has limited effects on apoptosis.

Animals↗
PubMed1995

Assignment of the human protein tyrosine phosphatase, receptor-type, zeta (PTPRZ) gene to chromosome band 7q31.3.

Human protein tyrosine phosphatase, receptor-type, zeta (PTPRZ; also denoted HPTP zeta or RPTP beta) has a large extracellular region with the N-terminal carbonic anhydrase-like domain and a cytoplasmic region with two tandemly located protein tyrosine phosphatase domains. One of the characteristics of PTPRZ is its preferential expression in the central nervous system. We localized the human PTPRZ gene to chromosome band 7q31.3 by somatic cell hybrid mapping and fluorescence in situ hybridization.

Chromosome Mapping↗
PubMed1994

Developmental regulation of gene expression for the MPTP delta isoforms in the central nervous system and the immune system.

MPTP delta is a murine transmembrane protein tyrosine phosphatase which has three isoforms, types A-C, differing in the structure of the extracellular regions. In this study, we examined MPTP delta isoform expression in the brain and the immune system at discrete developmental or differentiation stages. RT-PCR analysis demonstrated that another isoform, type D, is transcribed from the MPTP delta gene. In the brain, only type D was expressed until postnatal day 7 (P7), but after P14, all four isoforms were detected. In contrast, the spleen, thymus and all the hematopoietic cell lines examined express only types B and C isoforms. An in situ hybridization study showed that MPTP delta mRNA is diffusely expressed throughout the spleen, but its expression in the thymus is restricted to the medullary region.

Animals↗
PubMed1994

Negative regulation of apoptotic death in immature B cells by CD45.

Cross-linking of membrane IgM receptor on B cells induces tyrosine phosphorylation within 1 min. This biochemical alteration triggers a cascade of signaling events which ultimately leads to activation in mature B cells but growth arrest and cell death by apoptosis in immature B cells. To study the mechanisms underlying the bifurcation of signals, we chose to examine the role of receptor-type protein tyrosine phosphatase (PTP) CD45 using CD45- clones isolated from an immature B cell line WEHI-231. Here we report that in CD45- clones, tyrosine phosphorylation was constitutively induced but not enhanced by anti-IgM stimulation and anti-IgM-induced Ca2+ flux was slightly delayed but evidently prolonged. Further, the degree of growth arrest and DNA fragmentation induced by anti-IgM antibody was more evident in CD45- clones than the parental cells. These results indicate that initial alterations in signaling are effectively transduced into effector signals and that IgM receptor-mediated growth arrest and apoptosis in immature B cells are negatively regulated by CD45.

Animals↗
PubMed1994

The role of protein tyrosine phosphatases in lymphocyte activation and differentiation.

Protein tyrosine phosphorylation is involved in the regulation of every facet of biological phenomena. Signal transduction mechanisms operative in lymphocyte development, activation, and differentiation have been studied intensively, and are also found to support this premise. In this review, I focus on the crucial problems surrounding CD45, a prototypic receptor-type protein tyrosine phosphatase (RPTP) of the immune system: (1) the role of CD45 for antigen receptor-initiated signaling in T and B cells, (2) the physiological relevance of CD45 isoforms, (3) potential regulatory mechanisms of CD45 PTP activity, and (4) the clinical significance of structural abnormalities in PTP. Furthermore, other PTPs that may be important to the exquisite functioning of the immune system are reviewed.

Animals↗
PubMed1993

Induction of CD45 isoform switch in murine B cells by antigen receptor stimulation and by phorbol myristate acetate and ionomycin.

In this study, we examined whether CD45 isoform can be switched in murine mature B cells and what signals are responsible for the process. Stimulation of murine splenic B cells with lipopolysaccharide did not reduce the expression of CD45RA-, B-, and C-exon-dependent epitopes or a CD45 common epitope, but rather enhanced the expression. Stimulation with goat antimouse IgM antibody did not significantly reduce CD45 expression but caused a partial reduction in the expression of CD45RA-, B-, and C-exon-dependent epitopes. Phorbol myristate acetate (PMA) alone did not significantly alter the expression of CD45 but the combination of PMA and ionomycin induced a strong reduction in the expression of CD45RA-, B-, and C-exon-dependent epitopes without affecting the level of CD45 common epitope expression. Reverse transcription and polymerase chain reaction analysis demonstrated that CD45 isoform switch induced by anti-IgM or PMA plus ionomycin is indeed mediated by alternative splicing of A-, B-, and C-exon-derived mRNA. These results suggest that CD45 isoform of murine mature B cells can be switched by antigen receptor-mediated signals, and the process seems to be regulated at least in part by protein kinase C activation and mobilization of calcium ions.

Alternative Splicing↗
PubMed1993

Chromosomal assignment of the gene for protein tyrosine phosphatase HPTP delta.

Protein tyrosine phosphatase (PTP) negatively regulates the effect of protein tyrosine kinases and is implicated in the regulation of a variety of biological phenomena such as cell activation, differentiation and neoplastic transformation. To gain insight into the role of PTPs, we cloned the human receptor-type PTP gene and assigned the chromosome harboring the gene for HPTP delta by using DNAs from human-mouse hybrid cell lines and by fluorescence in situ hybridization. The results clearly demonstrated that HPTP delta gene maps to human chromosome 9p24.

Animals↗
PubMed1993

MPTP delta, a putative murine homolog of HPTP delta, is expressed in specialized regions of the brain and in the B-cell lineage.

Protein tyrosine phosphatases (PTPs), together with protein tyrosine kinases (PTKs), are involved in the regulation of cell activation, growth, and differentiation. To further elucidate the fine tuning of cell growth and differentiation through tyrosine phosphorylation, we tried to isolate mouse receptor-type PTP (RPTP) cDNA clones by screening mouse brain cDNA libraries with mouse CD45 PTP domain probes under reduced-stringency conditions. Characterization of isolated cDNA clones for RPTP showed that the cytoplasmic region contains two tandem repeats of PTP domain of about 230 amino acids with intrinsic phosphatase activity. The extracellular region was composed of immunoglobulin (Ig)-like domains and fibronectin type III (FN-III)-like domains. The gene was highly homologous to human PTP delta (HPTP delta) and thus was named MPTP delta (murine counterpart of HPTP delta). The MPTP delta gene appeared to generate at least three species of mRNA, which differ in the composition of the extracellular domain: type A, one Ig-like and four FN-III-like domains; type B, one Ig-like and eight FN-III-like domains; and type C, three Ig-like and eight FN-III-like domains. Interestingly, the 5' untranslated region and the leader peptide of types A and B were completely different from those of type C. Northern (RNA) blot analysis demonstrated that brain, kidney, and heart cells express three mRNA species of about 7 kb. Antibody directed against part of the extracellular domain of type A MPTP delta recognized a 210-kDa protein in brain and kidney lysates. In situ hybridization of brain samples revealed that MPTP delta mRNA is present in the hippocampus, thalamic reticular nucleus, and piriform cortex, where some Src family PTKs have been also demonstrated to exist. Although MPTP delta mRNA was not detected in lymphoid tissues, all of the pre-B-cell lines tested and one of three B-cell lines tested expressed MPTP delta mRNA, whereas antibody-producing B-cell hybridomas and T-cell and macrophage lines did not. Finally, the MPTP delta locus was tightly linked to the brown (b) locus on mouse chromosome 4.

Amino Acid Sequence↗
PubMed1992

Regulation of lipopolysaccharide- and IL-4-induced immunoglobulin heavy chain gene activation: differential roles for CD45 and Lyb-2.

We have demonstrated that CD45, a receptor-type protein tyrosine phosphatase, selectively regulates IgG production at the generative phase of precursors of IgG producers whereas Lyb-2 regulates IgG1 production induced by IL-4 in lipopolysaccharide (LPS)-activated B cells by acting on the generation of IgG1 precursor cells. These results point to an interesting possibility that both CD45 and Lyb-2 mediate a critical regulatory step(s) in IgG class switching. The present study was conducted to examine this possibility by elucidating the molecular mechanisms whereby CD45 and Lyb-2 control IgG synthesis in B cells activated by LPS and IL-4. Northern blot analysis showed that steady-state levels of C gamma 3, C gamma 2b and C gamma 1, but not Cmu, mRNA in LPS-activated B cells were reduced approximately 3- to 5-fold by CD45 mAb, and that the C gamma 1 mRNA level in B cells activated by LPS and IL-4 was significantly decreased by Lyb-2 mAb and CD45 mAb. Further, CD45 mAb inhibited expression of germline gamma 2b and gamma 3 transcripts induced by LPS and germline gamma 1 transcript expression induced by IL-4 plus LPS, but caused no inhibition in IL-4-induced germline gamma 1 transcript expression. In contrast, Lyb-2 mAb did not exert any inhibitory effect on the generation of germline gamma 1 transcripts induced by IL-4 and LPS or by IL-4 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

A novel homodimeric molecule involved in human T cell activation.

A mAb, 10D1, was obtained by fusing spleen cells from BALB/c mice immunized with a CD3/TCR- human T cell line, P12/ichikawa, to mouse myeloma cells, P3X63-Ag8-653. 10D1 mAb is specific for T cells in that it reacted with all the T cell lines tested, but not with B or myeloid cell lines. A small fraction of normal peripheral blood T cells, preferentially CD4+, was also reactive with 10D1 mAb. Biochemical studies revealed that 10D1 mAb recognizes a disulfide-linked homodimeric molecule composed of 90-kDa polypeptide. 10D1 mAb induced a substantial proliferation of peripheral blood T cells when cross-linked with goat anti-mouse Ig antibody. The elimination of CD4+ cells totally abrogated the proliferative response induced by 10D1 mAb, whereas the elimination of CD8+ cells rather enhanced it. The proliferative response of peripheral blood T cells induced by 10D1 mAb was almost completely inhibited after modulation of the CD3/TCR complex with anti-CD3 mAb. In addition, a prompt increase in intracellular [Ca2+] was observed in a CD3+ T cell line, Jurkat but not in its surface CD3- mutant when 10D1 mAb was added. These results indicate that the 10D1 molecule is involved in a novel pathway of human CD4+ T cell activation, which is associated with the CD3/TCR-mediated pathway.

Antibodies, Monoclonal↗
PubMed1990

Signal transduction mechanisms of Ia induction in B cells by interleukin 4 and immunoglobulin receptors.

Molecular mechanisms of signal transduction through receptors for interleukin 4 (IL-4) are still largely unknown. To elucidate the second messenger(s) of IL-4 action in mature B cells, we performed blocking experiments with inhibitors of various aspects of cellular responses, using Ia-inducing activity of IL-4 as a readout system. In the event, only agents that are shown to inhibit calcium ion (Ca2+) release from intracellular stores, such as 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8) and ryanodine, could block the IL-4 action in a dose-dependent fashion. These results suggest that the process leading to the final expression of IL-4 action may be mediated, at some point, by the release of Ca2+ from intracellular stores. In the parallel experiments with antiimmunoglobulin (Ig) antibody, we found that amiloride, an inhibitor of Na+/H+ pump, blocks the Ia induction by anti-IgM antibody. Thus the Na+/H+ exchange system activated by anti-Ig antibody may be present in mature B cells.

Animals↗
PubMed1989

Alleviation of autoimmunity in BXSB mice by monoclonal alloantibody to Ly-5 (CD45).

One of the hallmarks of immunological abnormalities in mice that are prone to syndromes resembling systemic lupus erythematosus is polyclonal activation of B cells and a switch of serum immunoglobulins or autoantibodies from IgM to IgG that coincides with onset of autoimmune disease. Therefore, we investigated whether the development of autoimmunity can be alleviated in such mice by administration of monoclonal alloantibody directed against Ly-5, because this was known to reduce levels of polyclonal IgG antibody without affecting other immunoglobulin isotypes. Our results indicate that at least some forms of autoimmune disease may be effectively treated by thus reducing the concentration of IgG autoantibody in this manner.

Animals↗
PubMed1989

Intracranial malignant teratoma diagnosed in a fetus--case report.

The authors describe a case of intracranial malignant teratoma in a 28-week fetus, discovered on assessment of the mother's excessive abdominal enlargement. Alpha-fetoprotein levels in amniotic fluid and serum were high. Ultrasonography revealed a large, solid intracranial mass. The fetus was viable until completion of a cesarean delivery, at which time the heart stopped. At autopsy, the fetal brain was found to have been extensively replaced by a solid, cystic tumor, which proved to be a malignant teratoma comprising elements of all three germ cell layers. The authors' experience and review of the reported cases indicate that prenatal malignant intracranial teratoma can be safely and accurately diagnosed, and that immediate delivery or cranial decompression may be advisable when the diagnosis is established. The usefulness and limitations of ultrasonography are particularly emphasized.

Brain Neoplasms↗
PubMed1989

[Functional and structural analysis of the Lyb-2 system].

The Lyb-2 system of the mouse is a B cell-specific cell surface molecule encoded by a gene on chromosome 4. We have previously reported that Lyb-2 is involved in an early phase of B cell differentiation, specifically a process mediated by B cell stimulatory factor-1 (BSF-1) or-interleukin 4. It is thus very important to define the functional role and structural features of Lyb-2 molecule for the understanding of the regulatory mechanisms of B cell activation initiated by BSF-1. In our attempt to resolve these issues, we found that Lyb-2 antibody inhibits activation processes mediated by BSF-1 such as induction of Ia antigen on the B cell surface and of IgG1 production in lipopolysaccharide-activated B cells, suggesting that Lyb-2 molecule participates in a signaling event triggered by the binding of BSF-1 to its receptor. In the structural analysis, we found that in contrast to previous reports, Lyb-2 is not a monomer of 45 kilodaltons (kDa) but is composed of two components with molecular weight of 45 kDa and 105 kDa. Reduced and nonreduced two-dimensional electrophoresis analysis further revealed that Lyb-2 molecules are present on the B cell surface in two forms, a disulfide-bonded heterodimer of 45 kDa and 105 kDa chains and a 45 kDa homatrimer. How the structural uniqueness of Lyb-2 is related to its functional expression remains to be determined.

Animals↗
PubMed1988

Differential regulation by Ly-5 and Lyb-2 of IgG production induced by lipopolysaccharide and B cell stimulatory factor-1 (IL-4).

We have previously shown that mAb Ly-5 which on B cells recognizes a 220,000-Da (B220) molecule, inhibits LPS-induced IgG responses without affecting IgM or proliferative responses, whereas mAb Lyb-2 which modulates B cell activation processes induced by B cell stimulatory factor-1 (BSF-1) or IL-4, has no effect on LPS-induced B cell responses. In this report we further examined the cellular mechanisms of Ly-5 antibody action and the effect of Lyb-2 antibody in IgG responses induced by LPS and BSF-1. The results presented demonstrated that the inhibitory effect of Ly-5 antibody seems to be restricted to the IgG class and is observed in all IgG subclasses induced by LPS. Limiting dilution analysis showed that the Ly-5 antibody reduces primarily the precursor frequency of IgG-secreting cells and that the effect on the clone size is partial. Lyb-2 antibody, on the other hand, greatly inhibited IgG1 induction initiated by LPS and BSF-1 by the action on processes triggered by BSF-1, although it could not reverse the reduced IgG2b or IgG3 responses. Limiting dilution analysis revealed that Lyb-2 antibody reduces the precursor frequency but not the clone size of BSF-1-induced IgG1-producing cells, supporting our previous proposition that Lyb-2 plays a critical role in the B cell differentiation mediated by BSF-1. Taken together, these results indicate that both Ly-5 and Lyb-2 are important molecules in IgG subclass regulation, each acting on a distinct activation step.

Animals↗