Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The autoimmune hemolytic anemia of NZB mice is pathogenetically mediated by a genetically prescribed anti-erythrocyte autoantibody response directed to the X erythrocyte autoantigen. The cellular locus of the immunoregulatory defect underlying the anti-X response was explored by adoptively transferring bone marrow cells (BMC) from NZB mice to lethally irradiated histocompatible recipients. Before adoptive transfer, BMC from donor mice were assayed for antigen-binding lymphocytes with receptors for the X autoantigen (X-ABL) by immunocytoadherence assays and for anti-X autoantibody-secreting cells (X-PFC) by plaque-forming cell assays. Twelve weeks after adoptive transfer, splenic lymphocytes from recipient mice were assayed for X-PFC and humoral anti-X autoantibody by Coombs' tests. Transfer of 15 to 30 x 10(6) BMC containing 6 to 12 x 10(3) X-ABL but no X-PFC from 6- to 8-week-old NZB mice to lethally irradiated BALB/c, B10.D2, C57BL/Ks, and DBA/2 mice produced X-PFC in 70% of the recipients. Development of X-PFC was not simply dependent upon available X-ABL since transfer of 15-30 x 10(6) BMC, containing comparable numbers of X-ABL, from BALB/c, B10.D2, C57BL/Ks, or DBA/2 mice to NZB or syngeneic recipients did not produce X-PFC. Transfer of BMC from NZB mice to BALB/c, B10.D2, and DBA/2 mice with weekly administrations of AKR anti-theta antiserum had no effect on the development of X-PFC; Tlymphocyte ablation was evidenced by the absence of theta+ spleen cells. These results suggest that the pathogenetic anti-X response is not genetically prescribed at the level of macrophages, humoral factors, or T cells, but rather appears to be a phenotypic expression of a primary B lymphocyte defect permitting or promoting differentiation of NZB X-ABL.
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PMID:Evidence for a B lymphocyte defect underlying the anti-X anti-erythrocyte autoantibody response of NZB mice. 32 60

The B-cell mitogens LPS and lipoprotein stimulate 20-35 percent of all B cells in the spleen of 6- to 8-wk old C3H/Tif mice, as determined by limiting dilution analysis of precursors. Each reactive cell grows to a clone of IgM-secreting PFC, enumerated in a hemolytic plaque assay detecting all IgM secreting cells, regardless of v-region specificity. We have used these mitogens to reveal the total repertoire of Ig specificities produced by these mitogen-reactive B cells. We have determined in plaque assays with six different target erythrocytes the number of spleen cells limiting to one the number of mitogen-reactive B cells detected as specific IgM-secreting clones in each of these plaque assays. By this method, the absolute frequencies of precursor B cells with defined v-gene specificities could be calculated, for at least, one third of all B cells. The frequencies of specific IgM-plaque-forming B-cell clones within the total pool of mitogen-reactive B cells was 1 in 10 for NIP(12),-SRC, 1 in 50 for TNP(12)- SRC, 1 in 100 for NIP(1)-SRC, 1 in 160 for TNP(3)- SRC, 1 in 500 for HRC, and 1 in 1,000 for SRC. These frequencies were the same in the LPS- and in the lipoprotein-reactive B-cell population for TNP(30)- SRC and SRC.
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PMID:Frequencies of mitogen-reactive B cells in the mouse. II. Frequencies of B cells producing antibodies which lyse sheep or horse erythrocytes, and trinitrophenylated or nitroiodophenylated sheep erythrocytes. 32 69

While rheumatoid-factor-producing haemolytic plaque-forming cells (RF--PFC) of the human peripheral blood were easily inhibited by cycloheximide, mouse spleen cells immune to sheep red cells (anti-SRC PFC) were inhibited only after prolonged preincubation in the drug. The RF--PFC were easily inhibited by propranolol, while the anti-SRC PFC were not at all inhibited. Vinblastine inhibited both systems equally. These differences are taken to suggest that the RF--PFC have very little preformed antibody in them and therefore depend upon active protein synthesis for their demonstration. In contrast, anti-SRC PFC, which may be predominantly mature plasma cells, generally need no new protein synthesis for their demonstration because of increased quantities of preformed antibody. A possible mechanism is that RF--PFC may represent primarily RF-specific B cells, the RF of which is released by surface immunoglobulin shedding and therefore susceptible to membrane stabilising agents such as propranolol.
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PMID:Metabolic inhibition of plaque-forming cells: comparison of human rheumatoid-factor-producing cells with mouse anti-sheep erythrocyte-producing cells. 38 30

Mice of 1.5, 9, 22, and 31 to 32 months of age were injected with the thymus-dependent antigen, TNP-SRC, or the thymus-independent antigen, TNP-SRC, TNP-MRC. The anti-SRC and TNP immune responses to TNP-SRC were markedly reduced in older mice, whereas the anti-TNP response to the TNP-MRC showed no substantial decline. Young mice produced higher anti-TNP plaque-forming cell responses after injection of TNP-SRC than after TNP-MRC, whereas in older mice the reverse obtained. Old mice but not young mice displayed a high anti-SRC cross-reactive response after injection of TNP-MRC. The avidity of anti-TNP antibody of young mice immunized with TNP-SRC was higher than that following immunization with TNP-MRC, whereas the avidities of anti-TNP antibodies from old mice injected with these two reagents were the same. Those individual mice which showed a poorly regulated immune response also displayed an autologous anti-MRC plaque-forming cell response after injection of either TNP-SRC or TNP-MRC. It is suggested that mechanisms mediated by suppressor T cells may be responsible for regulating the autoimmune response to modified self antigens, and that these are severely impaired in age individuals.
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PMID:Autoimmunity and aging: the age-related response of mice of a long-lived strain to trinitrophenylated syngeneic mouse red blood cells. 79 42

This study concerns the antigenic competition among heterologous red cells, a T suppressor-dependent phenomenon, in three cases, when the two antigens are administered by various routes, in (a) splenectomized mice or in Nude mice reconstituted with (b) lymph node cells, or spleen cells. Competition occurs whatever the routes of antigenic introduction, except when the two antigens are injected subcutaneously in the same leg and the anti-SRC plaque-forming cells are counted in the draining lymph nodes. In that case, the first antigen plays the role of adjuvant to the second. An adjuvant effect is also observed in splenectomized mice when the antigens are introduced intraperitoneally. However, competition does not occur in Nude mice but is present when those animals have been reconstituted either with lymphnode cells or with spleen cells. Those results play in favor of the presence of T suppressors, both in lymph nodes and in spleen; however, in lymph nodes, the immunosuppressive action induced by the first antigen is exceeded by an concomitant adjuvant effect.
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PMID:Antigenic competition between two sequentially acting antigens. Immunosuppressive effect of T cells in spleen and lymph nodes of mouse. 109 23

Simultaneous immunization of mice with sheep (SRBC) and horse (HRBC) erythrocytes regularly resulted in the appearance of hemolytic plaque-forming cells (PFC) specific for each type of erythrocyte and also of PFC lysing both types of erythrocytes. After primary stimulation the highest number of bispecific cells (42/10(6) cells) was found among PFC as revealed by the direct procedure (IgM producers). Among PFC enhanced with anti-mouse Fab serum (IgG producers), bispecific cells were less numerous (8/10(6) cells). In preparations enhanced by anti-mouse-gammaFc serum which reveals IgG producers without inhibiting IgM antibody, the number of bispecific PFC equalled the sum of bispecific cells revealed by direct and anti-Fab enhanced procedures. The number of direct bispecific PFC during primary and secondary response was approximately the same, whereas the number of IgG-producing, bispecific PFC increased considerably during the secondary response. Another difference was the time limitation of the appearance of bispecific cells: after primary immunization direct bispecific PFC were detected only on days 3, 4 and 5, but enhanced bispecific PFC were present from day 4 up to day 12. However, during the secondary reaction, bispecific PFC were detected by all three procedures only between days 3 and 6. Studies on the cross-reactivity between SRC and HRBC gave negative results at the humoral level, even when the mice were primed with a minimal amount of both erythrocytes and then two months later, boosted with one of them. Studies at the cellular level showed that after immunization with one antigen, only 0.4 to 0.7 direct or enhanced PFC/10(6) cells could simultaneously lyse both erythrocyte types. Thus, a hundred times more bispecific PFC were constantly found after double immunization of the animals. Moreover, sudden disappearance of all bispecific PFC on the 7th day after secondary stimulation makes it unlikely that all bispecific PFC are simply cross-reacting cells.
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PMID:Bispecific cells among IgM and IgG producers during the early phase of primary and secondary responses. 124 45

Two distinct mechanisms by which bladder carcinoma cells of the NBT-II cell line dissociate and migrate away from an in vitro reconstituted epithelial sheet were examined as regards intercellular adhesion and cell locomotion. Scattering of NBT-II bladder carcinoma cell line was promoted by 2 distinct culture protocols: (i) deposition of some components of the extracellular matrix onto the culture substratum (glass or plastic) induced cell dispersion of the epithelial sheet of carcinoma cells, and (ii) addition of Ultroser G, a serum substitute, to the culture medium induced scattering and acquisition of motility of NBT-II cells. Under both culture conditions, NBT-II cells dissociated, lost their epithelial morphology, acquired fibroblastic shape and migrated actively. We show that, among different extracellular matrix proteins, only collagens were able to promote the transition towards fibroblastic phenotype (referred as epithelium-to-mesenchyme transition or EMT). Furthermore, the native 3-dimensional helical structure of collagens was required for their function. During induction of EMT of NBT-II cells with Ultroser G, the junctions between epithelial cells were split, polarized epithelial cell organization was lost, and the resulting individual cells became motile and assumed a spindle-like fibroblastoid appearance. Using immunofluorescence microscopy techniques, we demonstrate that this change is accompanied by redistribution of desmosomal plaque proteins (desmoplakins, desmoglein, plakoglobin) and by reorganization of the cytokeratin and the actin-fodrin filament systems. Intermediate-sized filaments of the vimentin type were formed de novo in the fibroblastoid cell form. The observed transition towards fibroblastic phenotype (epithelium-to-mesenchyme transition or EMT) was fully reversed by removing the inducing factors from the culture medium, as shown by the disappearance of vimentin filaments and the reappearance of desmosomes in the newly formed epithelial cells.
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PMID:Reversible transition towards a fibroblastic phenotype in a rat carcinoma cell line. 250 87

Biochemical analysis of the kinetics of assembly of two cytoplasmic plaque proteins of the desmosome, desmoplakins I (250,000 Mr) and II (215,000 Mr), in Madin-Darby canine kidney (MDCK) epithelial cells, demonstrated that these proteins exist in a soluble and insoluble pool, as defined by their extract ability in a Triton X-100 high salt buffer (CSK buffer). Upon cell-cell contact, there is a rapid increase in the capacity of the insoluble pool at the expense of the soluble pool; subsequently, the insoluble pool is stabilized, while proteins remaining in the soluble pool continue to be degraded rapidly (Pasdar, M., and W. J. Nelson. 1988. J. Cell Biol. 106:677-685). In this paper, we have sought to determine the spatial distribution of the soluble and insoluble pools of desmoplakins I and II, and their organization in the absence and presence of cell-cell contact by using differential extraction procedures and indirect immunofluorescence microscopy. In the absence of cell-cell contact, two morphologically and spatially distinct patterns of staining of desmoplakins I and II were observed: a pattern of discrete spots in the cytoplasm and perinuclear region, which is insoluble in CSK buffer; and a pattern of diffuse perinuclear staining, which is soluble in CSK buffer, but which is preserved when cells are fixed in 100% methanol at -20 degrees C. Upon cell-cell contact, in the absence or presence of protein synthesis, the punctate staining pattern of desmoplakins I and II is cleared rapidly and efficiently from the cytoplasm to the plasma membrane in areas of cell-cell contact (less than 180 min). The distribution of the diffuse perinuclear staining pattern remains relatively unchanged and becomes the principal form of desmoplakins I and II in the cytoplasm 180 min after induction of cell-cell contact. Thereafter, the relative intensity of staining of the diffuse pattern gradually diminishes and is completely absent 2-3 d after induction of cell-cell contact. Significantly, double immunofluorescence shows that during desmosome assembly on the plasma membrane both staining patterns coincide with a subpopulation of cytokeratin intermediate filaments. Taken together with the preceding biochemical analysis, we suggest that the assembly of desmoplakins I and II in MDCK epithelial cells is regulated at three discrete stages during the formation of desmosomes.
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PMID:Kinetics of desmosome assembly in Madin-Darby canine kidney epithelial cells: temporal and spatial regulation of desmoplakin organization and stabilization upon cell-cell contact. II. Morphological analysis. 327 50

Novantrone mitoxantrone, an antineoplastic agent with antiproliferative properties, is under investigation as an immunomodulating agent. The impact of mitoxantrone treatment on B lymphocyte reactivity is presented here. Administered i.p. in H2O at a dose of 0.5 mg/kg, daily for 14 days, mitoxantrone abrogated both the in vivo antibody response (to ovalbumin) and the in vitro plaque-forming cell (PFC) response (to SRC). In addition to the effects on thymus-dependent reactivity, PFC responses to the thymus-independent antigens TNP-LPS and TNP-Ficoll were also inhibited when tested in vivo or in vitro. B cells were identified as a target for the suppressive activity of mitoxantrone by using T cell-replacing factor to reconstitute the in vitro anti-SRC PFC response of a T lymphocyte-depleted spleen cell preparation. LPS-induced B cell mitogenesis was largely inhibited by mitoxantrone treatment. However, depletion of Sephadex G-10-adherent cells significantly restored the proliferative response. Flow cytometric analysis revealed a dramatic decrease in splenic B lymphocyte content. Therefore, mitoxantrone exerted a potent suppressive influence on the humoral immune system through a direct reduction in B cell number augmented by macrophage-mediated inhibition of B cell proliferation.
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PMID:Selective immunomodulation by the antineoplastic agent mitoxantrone. I. Suppression of B lymphocyte function. 348 80

The effect of high specific activity thymidme-(3)H on proliferation and antibody production, using the hemolytic plaque-forming technique, by spleen cell suspensions in vitro from rabbits killed after a boost of SRC's has been studied. High specific activity thymidine-(3)H inhibited the proliferative ay well as the antibody response to antigen, and it was conduded that this was the result of the incorporation of radioactive (3)H into the nuclei of dividing cells which were synthesizing antibody in these cultures. The stimulation of the rate of DNA synthesis by specific antigen could be correlated with the ability of antigen to maintain antibody production, as measured by the specific hemolytic plaque-forming technique, above levels found in control cultures, incubated without antigen. Radioautographic studies of PFC's in vitro showed that the majority of the cells arose from the DNA-synthesizing population of cells in these cultures, confirming the conclusions from the results of the inhibitory effects of high specific-activity thymidine-(3)H on PFC's. It was found that these PFC's, labeling with thymidine-(14)C, formed only a small proportion of all the cells labeled in this way in these cultures. The postulation was made that antigen, in vitro, provided a stimulation for cell proliferation in the responsive population of rabbit spleen cells, but that only a small proportion of this population could be induced by antigen to synthesize antibody.
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PMID:Antibody production in vitro. I. Single cell studies of the secondary response to sheep erythrocytes. 564 63


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