Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A morphological, immunophenotypic and ultrastructural study, cell cycle estimation, DNA and cytogenetic analysis were performed in ten cases of B-MALT lymphomas. Five had low grade lymphoma and five had high grade. Low and high grade cases showed the same cells but in different percentages: These included centrocyte-like cells with occasional monocytoid cytoplasmic changes, and centroblast-like cells. However, in high grade cases more dysplastic and large cells were present. All cellular types showed an important development of rough endoplasmic reticulum. In all cases a large panel of monoclonal antibodies was employed to study the B-cell immunophenotype. Ki-67 positivity ranged from 5% to 30% in low-grade cases and from 50% to 70% in high-grade cases. Gene rearrangement analysis showed rearrangement with Jh probe and half of the cases were also rearranged with the Kde probe (Kappa constant chain gene). A rearrangement banding pattern with TCR genes was not present in any of the cases. Cytogenetic study showed complex alterations in high grade cases and a normal karyotype in low grade lymphomas. Only one case had rearrangement for the bcl-2 probe.
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PMID:A multiparametric study of malignant lymphoma of mucosa associated lymphoid tissue (MALT). 149 75

DNA was isolated from 20 fine needle aspiration (FNA) biopsies from lymphomas, hyperplastic lymph nodes and nonlymphoid malignant tumors. Small aliquots (0.2 microgram to 2.0 micrograms) of DNA from each sample were digested to completion with restriction endonuclease Eco RI and/or Bam HI and electrophoresed in 0.8% agarose minigels. DNA was transferred to a nylon filter after brief treatment in HCl and subsequent denaturation and neutralization. Filters were hybridized to radiolabeled JH, C kappa, TCR beta or bcl-2 probes to determine if these genes were in germline or rearranged configurations in each of the samples. It was possible to demonstrate rearrangement of at least one immunoglobulin gene in each of the samples diagnosed as lymphoma, while all samples derived from hyperplastic lymph nodes and nonlymphoid malignant tumors exhibited a germline pattern for each probe tested. Thus, FNA biopsies can provide suitable and sufficient DNA for genotypic analysis using molecular probes that detect gene rearrangement.
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PMID:Genotypic analysis of DNA isolated from fine needle aspiration biopsies. 321 71

Minor thymus subpopulations representing possible intermediates in thymic positive selection were isolated by cell sorting from bcl-2 transgenic mice, and cultured 1 to 4 days in simple medium to assess their ability to spontaneously develop the surface phenotype of mature T cells. Recovery of cells was in the 60 to 80% range, and no cell proliferation occurred. Only cells originally expressing high, near mature T cell levels of CD3 developed further in culture by down-regulation of CD4 or CD8. The main mature cell product was CD4-8+, regardless of whether the starting phenotype of the CD3high intermediates was CD4+8+, CD4int8+, or CD4+8int; only an intermediate subpopulation expressing the highest levels of CD4 (CD4high8int) produced a dominance of CD4+8- mature progeny. Partial down-regulation of CD8 was therefore not a good indicator of CD4+ T lineage commitment. These and previous results indicate that maturation to the CD8+ T lineage involves a rapid up-regulation of the TCR-CD3 complex, but a relatively slow down-regulation of CD4; it may also involve a partial, transient reduction in surface CD8. In contrast, maturation to the CD4+ T lineage involves a relatively rapid down-regulation of CD8, with maintenance of high levels of CD4. There appears to be a marked asymmetry in the developmental steps leading from CD4+8+ thymocytes to the CD8+ or to the CD4+ T cell lineage.
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PMID:Intermediate steps in thymic positive selection. Generation of CD4-8+ T cells in culture from CD4+8+, CD4int8+, and CD4+8int thymocytes with up-regulated levels of TCR-CD3. 756 Oct 86

Extensive immunohistochemical analyses of the hyperplastic human palatine tonsil disclosed variegated B cell phenotypes on the lymphoid cells among the crypt epithelium. The reticular epithelial network was evident by cytokeratin immunostaining. The reticular epithelium near the crypt lumen was positive for lysozyme. Secretory component was negative, while HLA-DR was frequently expressed. Intramucosal small lymphocytes, densely distributed in the luminal side, consisted mainly of B cells expressing CD19, CD20, CD21, CD22, CD45R, CD74, DBB42, HLA-DR, HLA-DQ, bcl-2 protein and surface IgM. Some B cells revealed mantle zone phenotypes (surface IgD+, CD5+, CD24+, DBA44+, CD10-, DNA7-). Cells of germinocyte phenotype (CD10+, DNA7+) were sparsely seen. A good number of intramucosal lymphoid cells were further labeled for CD11b, a phenotype of so-called B-1 cells. Plasma cells were clustered within the basal half. IgG was their major immunoglobulin class, followed by IgA, IgM and IgD classes. A smaller number of T cells (CD2+, CD3+, CD5+, CD45RO+, TCR alpha beta+) were identified among the epithelium. CD4+ cells predominated over CD8+ cells. TCR gamma delta+ cells were rare. Macrophages (CD68+), dendritic histiocytes (S-100 protein+, CD1+), and natural killer cells (CD16+ or CD57+) were also dispersed. Another unique feature of this lymphoepithelial complex was the existence of HLA-DR- intramucosal intramucosal microvasculature, where lymphocyte recirculation was suggested. Proliferating cell nuclear antigen was detected commonly in the epithelial cells but rarely in the lymphoid cells. Possible lymphoepithelial interactions and morphologic similarities to the thymic medulla are discussed.
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PMID:Reticular crypt epithelium and intra-epithelial lymphoid cells in the hyperplastic human palatine tonsil: an immunohistochemical analysis. 770 42

Apoptosis plays a crucial role in shaping the T cell repertoire during T cell development in the thymus. The observed disappearance in the thymus of CD4+ CD8+ thymocytes with a specific TCR, and the lack of CD4+ or CD8+ single positive mature cells expressing the same TCR specificity in the periphery have led to the conclusion that deletion occurs at the CD4+ CD8+ double positive stage; however, there is no direct evidence demonstrating apoptotic CD4+ CD8+ cells in situ. Apoptosis of thymocytes in situ at other stages of T cell development has also not been reported. Using three-color immunofluorescence and flow cytometric assays on frozen human thymic tissue and freshly isolated human thymocytes respectively, we directly identify CD4+ CD8+ and CD4- CD8- thymocytes in newborn human thymus that contain intracellular fragmented DNA and are therefore apoptotic. We determine that 75% of the apoptotic thymocytes are CD4+ CD8+ double positive apoptotic thymocytes, and interestingly, that 13% are CD4- CD8- double negative thymocytes. The majority of apoptotic thymocytes in situ are detected at the cortical-medullary junction; however, apoptotic thymocytes are also found scattered throughout the cortex. Furthermore, we determine that within the apoptotic thymocyte population, 54% express the apoptotic regulatory protein bcl-2 in vivo, whereas 32% are bcl-2 negative. Thus, our in vivo data directly demonstrate that both CD4+ CD8+ and CD4- CD8- human thymocytes die in situ via an apoptotic process, and that expression of the bcl-2 protein in situ does not prevent immature thymocytes from apoptosis.
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PMID:In situ detection and characterization of apoptotic thymocytes in human thymus. Expression of bcl-2 in vivo does not prevent apoptosis. 772 94

Engagement of the TCR on immature CD4+CD8+ (DP) thymocytes by an appropriate peptide/MHC ligand evokes a complex program of maturation known as positive selection. As a result, DP thymocytes are rescued from programmed cell death, become committed to the CD4 or CD8 lineage, extinguish expression of V(D)J recombinase activity, and undergo further maturation. We describe here a panel of DP thymic lymphoma cell lines that, in response to in vitro TCR engagement, undergo many of the TCR-beta-induced maturation events that have been reported to accompany positive selection of DP thymocytes in vivo. These events include increased expression of CD5, CD69, CD45, TCR-alpha, and MHC class I, and decreased expression of Thy-1 and heat-stable Ag. In addition, we observed TCR-induced expression of the bcl-2 gene, a well described inhibitor of programmed cell death. Finally, TCR engagement decreased expression of recombinase-activating genes and terminal deoxynucleotidal transferase genes, as well as V(D)J recombinase activity. However, TCR engagement did not elicit demonstrable CD4/CD8 lineage commitment. These observations suggest that engagement of the TCR on these DP cell lines elicits multiple maturation events that are part of the positive selection developmental program, but not CD4/CD8 lineage commitment. Thus, these DP cell lines provide the opportunity to elucidate molecular mechanisms of maturation and CD4/CD8 lineage commitment in vitro.
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PMID:In vitro maturation of clonal CD4+CD8+ cell lines in response to TCR engagement. 773 Jun 8

Positive selection of T cells is a complex developmental process generating long-lived, functionally mature CD4+CD8- and CD4-CD8+ cells from short-lived, immature CD4+CD8+ precursors. The process is initiated in the thymus by interaction of the alpha beta TCR with molecules encoded by the MHC, occurs without cell division, and involves rescue from programmed cell death (PCD), as well as induction of differentiation and maturation of selected precursors. It is unclear whether development of small, positively selected CD4+CD8+ thymocytes (characterized by up-regulated levels of TCR and CD69 molecules) depends on further interactions with MHC molecules and, if so, whether such interactions are required for survival, for maturation, or for both. The involvement of the TCR and/or CD4/CD8 coreceptors in transmitting additional signals is also unknown. We have examined these questions by analyzing survival and differentiation of early (CD4+CD8+TCRhi) and later (CD4-CD8+TCRhi) postselection stages of thymocytes from normal and bcl-2 transgenic mice expressing transgenic, class I MHC-restricted TCR, upon intrathymic transfer into recipients that lacked ligands either for both the TCR and CD8 coreceptor, or for the TCR only. The results provide direct evidence that induction of differentiation of CD4+CD8+ thymocytes by recognition of MHC molecules does not rescue them from PCD and is insufficient to activate the entire maturation program. Both processes require continual engagement of the TCR by positively selecting MHC molecules that, at least in the case of class I MHC-restricted CD4-CD8+ T cells, cannot be substituted by the engagement of coreceptor alone.
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PMID:Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor. 775 93

The stimulation through TCR-CD3 complexes by immobilized anti-CD3 antibody induced the production of IL-2 and activation-induced cell death (ACD) in the majority of T cell hybridomas. However, some hybridomas produced IL-2 without showing any signs of ACD by the same stimulation, indicating that TCR-CD3-mediated signaling pathways of IL-2 production and of ACD are different. These pathways were discriminated from each other by protein kinase inhibitors and cAMP-elevating reagents such as forskolin. The pathway of IL-2 production but not of ACD was inhibited by protein kinase inhibitors. On the other hand, various cAMP-elevating reagents prevented the T cell hybridomas from TCR-mediated ACD with minimal inhibition of IL-2 production. The elevated cytoplasmic cAMP did not block dexamethasone-induced apoptosis. This indicates that apoptosis is regulated by multiple pathways. Furthermore, the inhibitory effect of cAMP is specific for the TCR-mediated signaling pathway of ACD. Messenger RNA for bcl-2 was detected after treatment with forskolin.
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PMID:Prevention of TCR-mediated apoptosis by the elevation of cAMP. 794 59

Two primary types of TCR-alpha/beta+ T cells are found in the peripheral lymphoid system; CD4+8- T cells, with MHC-class II restricted TCR, and CD4-8+ T cells, which are MHC-class I restricted. Both lineages develop in the thymus from a series of common precursors. However, the precise stage at which they diverge, and the combination of factors that regulates such divergence, are not well defined. The up-regulation of CD3/TCR to high mature levels is thought to be an early event associated with positive selection for self-MHC recognition. Using purified cells from bcl-2 transgenic mice in order to overcome the limitations imposed by cell death on normal thymocytes, we find that a minor subset of CD4+8+ thymocytes expressing high levels of CD3/TCR gives rise to both CD4+8- and CD4-8+ mature cells upon intrathymic transplantation, but only to CD4-8+ in culture. Thus, in addition to demonstrating the dual lineage potential of this subset, these findings show that additional post-selection processing events are required for the production of mature thymocytes, and that CD4+8- and CD4-8+ subsets differ in the types of processing required.
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PMID:CD4+8- and CD4-8+ mature thymocytes require different post-selection processing for final development. 810 40

To ensure that the mature T cell repertoire is MHC-restricted yet not autoreactive, cortical thymocytes that express low levels of the TCR/CD3 complex along with CD4 and CD8 (double positive cells) are subjected to positive and negative selection. Surviving cells lose either CD4 or CD8 (single positive cells) and are located primarily in the thymic medulla. bcl-2, a novel proto-oncogene that promotes cell survival by inhibiting programmed cell death (apoptosis), may be an important protein in regulating cell survival during thymocyte development. We have examined the expression of bcl-2 during T cell development by using human thymocytes. Consistent with previous studies, human thymic tissue sections stained for bcl-2 revealed occasional bcl-2+ cells within the thymic cortex and intense staining of virtually all medullary thymocytes. More quantitative western blot analysis and S1 nuclease protection assay revealed that single positive thymocytes contained approximately 2 to 3 times the level of bcl-2 protein and 3 to 4 times the level of bcl-2 mRNA as double positive thymocytes. Flow cytometric analysis of purified double positive thymocytes revealed that minimal amounts of bcl-2 protein was in fact detectable in most cells, although a small subpopulation (10-20%) contained higher levels. In contrast, brighter staining for bcl-2 was observed in virtually all single positive thymocytes. Surprisingly, CD4-CD8- thymocytes (both CD3- and CD3+) expressed the same amount of bcl-2 as did the single positive thymocytes. Because a large percentage of CD3-CD4-CD8- cells are cycling, we examined the effect of mitogenic stimulation on bcl-2 expression by double positive thymocytes by using western blot analysis. bcl-2 expression in double positive thymocytes could not be induced by cell cycle entry following stimulation with PMA and ionomycin. Our data demonstrate that bcl-2 expression is biphasic during T cell development. Both CD3-CD4-CD8- and CD3+CD4+ and CD3+CD8+ thymocytes express high levels of bcl-2. Therefore, diminished bcl-2 expression in double positive thymocytes seems to be the result of specific down-regulation in order to facilitate the selection CD4+CD8+ thymocytes.
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PMID:bcl-2 proto-oncogene expression during human T cell development. Evidence for biphasic regulation. 832 41


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