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Biomedical subjects

T S Edgington

Publications and source records attributed to T S Edgington.

At least 181 records · Page 10Linked to original sources
PubMed1979

Differential sensitivity of lymphocyte subpopulations to suppression by low density lipoprotein inhibitor, an immunoregulatory human serum low density lipoprotein.

Reports by a number of investigators have described the thymus-derived (T)-cell dependence of immunoglobulin synthesis by pokeweed mitogen (PWM) stimulated human peripheral blood bone marrow-derived (B) cells. Because of the cooperative nature of this in vitro system, it was chosen for examination of the differential effects of low density lipoprotein inhibitor (LDL-In) on B- and T-cell functions. Supernates from 7-d cultures that contained either peripheral blood mononuclear cells (PBM) or combinations of isolated lymphocyte populations were assayed for immunoglobulin (Ig)G by competitive inhibition radio-immunoassay. LDL-In suppression of whole PBM IgG synthesis occurred at 5-20 mug protein/ml and was independent of PWM concentration. Maximal suppression required preincubation of cells with LDL-In before stimulation. Suppression was also observed when B cells alone were exposed for 24 h to LDL-In before PWM stimulation; these suppressed B cells were not rescued by normal T cells. Exposure of T cells alone to low doses of LDL-In for 24 h augmented, but high doses suppressed, IgG synthesis, suggesting a differential effect on T-helper vs T-suppressor cell populations. Independent LDL-In exposure of T-helper or T-suppressor cell enriched populations, separated by rosetting with IgG- or IgM-coated ox erythrocytes, identified the T-suppressor cell populations as the most sensitive of the lymphocyte populations tested. The sensitivities of lymphocyte subpopulations to LDL-In, relative to PBM, were 2.8, 1.2, and 0.3 for the T-suppressor cells, B cells and T-helper cells, respectively. Thus, both B and T lymphocytes are sensitive to and can be regulated by LDL-In. In addition, the biologic activity observed when unseparated PBM are exposed to LDL-In appears to represent a composite of the sensitivity of each of the lymphocyte subpopulations.

B-Lymphocytes↗
PubMed1979

Combined functional and immunochemical analysis of normal and abnormal human factor X.

Human Factor X was isolated from Cohn fraction III and characterized by polyacrylamide gel electrophoresis, amino acid composition, and isoelectric focusing. Two molecular forms with biological activity were observed at isoelectric points of 4.8 and 5.0. Antisera generated to Factor X was monospecific and used to establish an equilibrium competitive inhibition radioimmunoassay. This assay was specific for human Factor X and did not cross-react with human prothrombin or bovine Factor X within the sensitivity range of 6-300 ng Factor X antigen/ml. The mean concentration of Factor X based on the antigen was 11.9 mug/ml, whereas concentration values based on coagulant activity was 7.8 mug/ml. This 30% difference in measurement appears to result from the presence of a subpopulation of Factor X molecules devoid of coagulant activity. The radioimmunoassay was used to qualitatively and quantitatively compare purified Factor X to plasmic Factor X obtained from normal, warfarintreated, acquired Factor X-deficient, and congenitaldeficient patients. In all but one case, the Factor X present in these plasmas was immunochemically identical to the purified Factor X and permitted precise quantitation of these abnormal Factor X molecules. Factor X procoagulant activity was analyzed relative to Factor X antigen and the specific activities were used to characterize normal and abnormal Factor X molecules. Reduced Factor X activity in plasmas from warfarin-treated and acquired Factor X-deficient patients was attributed to both decreases in Factor X antigen and decreased function of the Factor X molecules. Congenitally deficient patients, in general, showed a reduction in Factor X antigen in parallel with Factor X procoagulant activities resulting from comparable decreases in specific biological activity of the molecules.

Amino Acids↗
PubMed1979

Carbohydrate of the factor VIII/von Willebrand factor in von Willebrand's disease.

We have examined the plasma Factor VIII/von Willebrand factor (FVIII/vWF) molecule from 16 patients with von Willebrand's disease, and have found no evidence of a significant decrease of carbohydrate content in 15 of these patients. FVIII/vWF was isolated by preparative counter immunoelectrophoresis directly from plasma using antibody to Factor VIII-related antigen, reduced in sodium dodecyl sulfate in the presence of urea, and electrophoresed in 5% polyacrylamide gels to separate the FVIII/vWF subunit from other proteins. Duplicate gels were stained by either the periodic acid-Schiff (PAS) reaction or by Coomassie Brilliant Blue G250. The ratio of Coomassie: PAS was determined by spectrophotometric scanning of the gels. Transferrin was used as an internal reference standard. The ratio for 23 normal individuals was 2.4+/-0.38 and the observed range was 1.8-3.8. 15 patients with von Willebrand's disease fell within this range. One patient independently reported as having decreased FVIII/vWF carbohydrate was also studied by this technique. A ratio of 6.8 was found, indicative of decreased, though not absent, carbohydrate. Cold insoluble globulin did not represent a significant contaminant in these analyses. 11 of the von Willebrand's disease patients with normal FVIII/vWF carbohydrate had abnormal crossed immunoelectrophoretic patterns characterized by absence of the less anodic forms of Factor VIII-related antigen. Four patients had normal patterns. These studies indicate that an absence or decrease of PAS reactive FVIII/vWF carbohydrate is not a consistent abnormality in von Willebrand's disease.

Blood Coagulation Factors↗
PubMed1978

Identification of a lymphocyte surface receptor for low density lipoprotein inhibitor, an immunoregulatory species of normal human serum low density lipoprotein.

The present study demonstrates the existence on human peripheral blood lymphocytes of a saturable cell surface receptor for low density lipoprotein inhibitor (LDL-In), a subset of normal human serum low density lipoprotein (LDL) that has been previously demonstrated to suppress selected lymphocyte functions in vivo and in vitro. The binding of radioiodinated LDL-In of demonstrable biological activity occurs rapidly and is quantitatively augmented by prior cultivation of the lymphocytes in lipoprotein-depleted serum, suggesting regulation of receptor density by lipoproteins in vivo. Binding is temperature dependent, facilitated by calcium ions, saturable at 4 degrees C within 40-60 min, and blocked by prior exposure to unlabeled LDL-In. The lymphocyte receptor is trypsin sensitive and regenerates in vitro with a t1/2 of 3.6 h. LDL-In receptors are calculated to have a maximum density of 4,860 +/- 460 per cell if uniformly distributed on all lymphocyte subsets. These receptors have an estimated average association constant of 1.47 X 10(7) liters/mol. When considered in context of the estimated concentration of LDL-In in blood, the receptors should be partially occupied in vivo by endogenous plasma LDL-In. Prior site occupancy inhibition experiments designed to analyze the specificity of LDL-In binding demonstrate that (a) LDL-In is 13.7-fold more effective than whole LDL in blocking the subsequent binding of 125I-LDL-In to cells; and that (b) LDL is 11-fold more effective than LDL-In in blocking the binding of 125I-LKL. This is consistent with the degree of contamination of each lipoprotein with the other lipoprotein. An independent identity of the LDL-In receptor is also supported by observations that in contrast to the previously described LDL receptor, synthesis and expression of the LDL-In receptor on lymphocytes are not suppressed by cultivation of the cells in the presence of 25-hydroxycholesterol and cholesterol. These findings suggest the existence of a previously undescribed and discrete receptor on lymphocytes for LDL-In, and that the modulation of lymphocyte function by LDL-In may be mediated by a specific cell surface receptor pathway.

Cholesterol↗
PubMed1978

Delineation of spontaneous erythrocyte autoantibody responses of NZB and other strains of mice.

Four anti-erythrocyte autoantibody responses (anti-X, anti-HB, anti-HOL, and anti-I) that occur spontaneously in mice have been characterized with regard to antigenic specificities, predominant immunoglobulin class, and pathogenetic importance. Each autoantibody response exhibits specificity for an independent erythrocyte membrane autoantigen (X, HB, HOL, or I) or a soluble analogue (SEA-X or SEA-HB) present in the plasma. The anti-X response, unique to NZB mice, is directed to a normally exposed murine erythrocyte autoantigen, whereas the anti-HB response is directed to a cryptic erythrocyte autoantigen exposed by limited enzymatic cleavage of the membrane. The anti-I response also is directed to a cryptic but distinct autoantigen, and anti-HOL autoantibodies react with an erythrocyte autoantigen located at the cytoplasmic surface of the membrane. Analysis of the predominant immunoglobulin class of each of the autoantibodies has demonstrated that anti-HB and anti-I antibodies are predominantly of IgM class, whereas anti-X and anti-HOL antibodies are IgG immunoblobulins. Only anti-X and anti-HB autoantibodies are recovered from Coombs' positive erythrocytes from NZB mice and erythrocytes with surface C3 are detected only in NZB mice greater than 9 months of age. These data suggest that only the anti-X and anti-HB responses are pathogenetically implicated in the autoimmune hemolytic anemia of NZB mice.

Animals↗
PubMed1977

Extrinsic modulation of human T-lymphocyte E rosette function associated with prolonged hepatocellular injury after viral hepatitis.

Defective T-lymphocyte E rosette (ER) function associated with viral hepatitis A and B may be due to mechanisms extrinsic or intrinsic to the target lymphocyte. The extrinsic defect is induced by an immunoregulatory plasma lipoprotein (RIF) and has the capacity to regenerate ER function in vitro. The intrinsic defect is refractory to regeneration and is not associated with RIF. Although both mechanisms occur with high frequency during the acute phase of viral hepatitis they tend to segregate in accordance with progression of hepatocellular injury at later stages of the disease. The extrinsic defect was observed in 7 out of 8 patients with longstanding chronic active hepatitis and in 10 out of 10 patients with unresolved hepatitis 12 wk after the onset of jaundice. In contrast, none of nine patients with resolved hepatitis had extrinsically defective ER function 12 wk after the onset of jaundice whereas eight of them displayed an intrinsic defect of ER function at that time. Among the various viral and liver diseases studied RIF appeared to be specific for hepatitis A and B viral infections. None of 64 sera from a variety of viral infections including Epstein-Barr virus cytomegalovirus mononucleosis with associated hepatitis nor 15 sera from patients with several chronic nonviral liver diseases were positive for RIF. RIF and its associated extrinsic defect in ER function therefore appear to correlate with a particular type of hepatocellular injury initiated by the hepatitis A and B viruses that may have a propensity for persistence and(or) progression to an aggressive form of chronic hepatitis.

Acute Disease↗
PubMed1977

Interaction of factor VIII antigen in hemophilic plasmas with human antibodies to factor VIII.

By utilizing a simple modification of previous immunological assays, we have demonstrated that most, if not all, hemophilic plasmas contain antigen reactive with human antibodies directed against Factor VIII procoagulant activity (VIIIc). Antibodies developing in a nonhemophiliac patient and in a hemophiliac patient gave similar results. The VIIIc antigen so identified was removed from hemophilic plasmas with immobilized rabbit antibody which reacted with normal VIIIc and von Willebrand's disease antigen. These data suggest that there are greater antigenic similarities between normal and hemophilic Factor VIII than previously thought.

Antigen-Antibody Reactions↗
PubMed1977

In vivo suppression of the primary immune response by a species of low density serum lipoprotein.

An apparent subspecies of normal human serum low density lipoprotein (LDL-In) has been identified with suppressive activity for early or facilitating events of human lymphocyte mitogen and allogenic cells stimulation in vitro. This report describes the effects of in vivo administration of LDL-In on the mouse anti-SRBC immune response. Human LDL-In is not species specific and was capable of suppressing the in vivo mouse anti-sheep erythrocyte (SRBC) hemagglutination response by 88% after the administration of 500 to 600 mug LDL-In IV, whereas human serum high density lipoproteins and fibrinogen had no effect. Maximal suppression occurred only when LDL-In was injected 24 to 48 hr before antigen administration. Simultaneous or subsequent injection of LDL-In had no effect. The activity of LDL-In was influenced by antigen dose and maximal at low antigen doses. The number of splenic plaque-forming cells was also reduced indicating a suppression of the clonal expansion of primary B cells to antibody-secreting cells rather than only suppression of antibody synthesis by differentiated B cells and their progeny. These observations suggest the hypothesis that endogenous LDL-In could play an important immunoregulatory role in the maintenance of immune homeostasis and the "natural" suppression of non-productive lymphocyte proliferation.

Animals↗
PubMed1977

Effect of LDL-In, a normal immunoregulatory human serum low density lipoprotein, on the interaction of macrophages with lymphocytes proliferating in response to mitogen and allogeneic stimulation.

The immunoregulatory properties of LDL-In, a normal species of human serum low density lipoprotein which suppresses indictive events involved in triggering of lymphoid cells by lectins and antigens, were analyzed in order to distinguish between a primary effect on macrophages and lymphocytes. LDL-In was found to be equally effective in suppression of the response of human lymphocytes to tpha at concentrations of lectin demonstrated to impart apparent macrophage-independence or macrophage-dependence to the culture system. Exposure of only the macrophages to LDL-In was shown to be without effect on subsequent in vitro lymphocyte responses to either PHA or allogeneic cells, whereas exposure of only the lymphocytes to LDL-In was fully effective. The cellular locus was further identified by demonstrating that the responder lymphocytes, but not the stimulator lymphocytes, were the target of the suppressive activity in mixed lymphocyte reactions. These data considered in conjunction with previous studies suggest that the primary untriggered lymphocyte is the most probable cellular target for the bioregulatory effects of LDL-In.

Cell Adhesion↗
PubMed1977

Recovery of soluble sheep erythrocyte receptor from the T lymphocyte surface by proteolytic cleavage.

Proteolytic digestion of the human T lymphoblastoid cell line (Molt-4) and of peripheral blood lymphocytes by trypsin, chymotrypsin, and pronase results in a progressive, time-and dose-dependent diminution of T lymphocyte-sheep red bloock cell (SRBC) rosette formation, whereas thrombin, plasmin, collagenase, DNAse, and phospholipase have not effect. Complete abrogation of SRBC binding is achieved when lymphocytes (1 x 108/ml) are incubated with either trypsin or chymotrypsin at 10 mug/ml for 30 min, and greater than 50% abrogation is observed between 3 to 10 min. Preincubation of SRBC with the 10 min and 20 min lymphocyte digest supernatants inhibited their subsequent binding by normal T lymphocytes by as much as 64%. Thirty-minute digests were less inhibitory. Equivalent digests from several human B lumphoblastoid cell lines and from a non-rosetting clone of Molt-4 cells were not inhibitory. Polyacrylamide gel electrophoresis followed by elution of serial gel slices revealed four distinct inhibitory bands (I-IV) in the 20-min digest supernatant whereas only bands I-III and band IV were present in the 10-min and 30-min digest supernatants, respectively, suggesting progressive proteolysis of a distinct receptor. These experiments indicate that the binding of SRBC by human T lymphocytes represents a receptor-ligand interaction rather than a nonspecific electrical charge phe nomenon and that the receptor is a discrete molecular species which can be isolated from the surface of T but not B lymphocytes by limited enzymatic proteolysis.

Binding Sites↗