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Biomedical subjects

T S Edgington

Publications and source records attributed to T S Edgington.

At least 199 records · Page 11Linked to original sources
PubMed1977

Evidence for a B lymphocyte defect underlying the anti-X anti-erythrocyte autoantibody response of NZB mice.

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.

Anemia, Hemolytic, Autoimmune↗
PubMed1976

Mechanisms responsible for defective human T-lymphocyte sheep erythrocyte rosette function associated with hepatitis B virus infections.

The expression of selected lymphocyte surface-membrane markers was evaluated in 37 patients with acute viral hepatitis B, 10 of whom were studied serially through the resolving and convalescent phases of disease. Bone marrow-derived (B) lymphocytes were identified by reference to surface immunoglobulin, whereas normal thymus-derived (T) lymphocytes were assayed by their capacity to form spontaneous nonimmune rosettes with sheep erythrocytes (E rosettes, ER). During the acute and resolving phases of viral hepatitis B, the relative and absolute number of ER-positive lymphocytes was significantly reduced, whereas the number of surface immunoglobulin-positive lymphocytes and the absolute lymphocyte count remained normal. This resulted in the appearance of a third population of cells, deficient in respect to both surface immunoglobulin and ER markers. Such cells accounted for nearly 25% of peripheral blood lymphocytes, approximately 5 x 105ml blood. Depression of the number of ER-positive lymphocytes occurred at least once during the course of disease in every patient studied serially, and was observed in 55 of 67 individual assays of the 37 cases of acute viral hepatitis B. Lymphocytes from some patients reacquired ER function when cultured in fetal calf serum but not in the presence of autologous serum. Such autologous serum was capable of suppressing ER function of lymphocytes from normal donors. The extrinsic suppression of er function by a serum factor (designated as the Rosette Inhibitory Factor), was found to be time dependent, characterized by a 4-h latent period and requiring approximately 18 h for maximum attenuation of ER function. The Serum Rosette Inhibitory Factor was: (a) heat and freeze-thaw stable, (b) nondialyzable, (c) physically separable from hepatitis B surface antigen, (d) not a lymphocytotoxic antibody, and (e) had the buoyant density of a lipoprotein. This extrinsic mechanism was observed in 41.8% of patients with reduced numbers of ER-positive lymphocytes. The Rosette Inhibitory Factor was not detectable in the serum of the remaining 58.2% of the cases of acute and resolving viral hepatitis B despite the presence of reduced numbers of ER-positive lymphocytes. The lymphocytes from these cases did not reacquire ER function when cultured in the absence of autologous serum. The mechanisms responsible for the suppression of normal ER function in these cases appears to be intrinsic to the lymphocytes and not the result of a humoral factor. The T lymphocyte lineage of cells deficient in respect to ER function, whether of intrinsic or extrinsic type, was demonstrated by their capacity to form spontaneous rosettes with neuraminidase-treated sheep erythrocytes. Both intrinsic and extrinsic suppression of T lymphocyte ER function commonly occurred during the first 4 wk of acute viral hepatitis B.9 of the 10 patients followed serially continued to manifest defective ER function at 12 wk...

Adult↗
PubMed1976

Specific antigen-binding and antibody-secreting lymphocytes associated with the erythrocyte autoantibody responses of NZB and genetically unrelated mice.

The receptor characteristics as well as incidence of antigen-binding lymphocytes (ABL) or B and T cell classes with membrane receptors specific for the exposed (X) and cryptic (HB) murine erythrocyte autoantigens were examined in NZB and nine control strains of mice. Whereas only NZB and NZB hybrid mice synthesize anti-X autoantibody pathogenetically implicated in the genetically determined autoimmune hemolytic anemia, the NZB as well as control strains synthesize the ubiquitous anti-HB anti-erythrocyte autoantibody. By utilizing immunocytoadherence assays, maximum numbers of specific ABL of both B and T lymphocyte classes were optimally demonstrated at erythrocyte:lymphocyte ratios of 20:1 and after lymphocyte fixation at 56 degrees C for 20 min. Surface membrane receptor specificity was established by inhibition with semi-purified soluble X or HB autoantigen. Inhibition of immunocyto-adherence with class specific antisera to mouse immuno-globulins demonstrated that the receptors on both B and T cells were of IgM class. Specific receptors regenerated in vitro after trypsinization which excluded the role of cytophilic antibody in the immunocytoadherence reactions. B lymphocyte ABL reactive with the X autoantigen were demonstrable in NZB, NZB hybrid, and control mice. Only in NZB and NZB hybrid mice, strains that uniformly synthesize anti-X autoantibody, were X ABL of T lymphocyte class demonstrated. The presence and incidence of T lymphocyte X ABL is compatible with the expression of a single dominant gene carried by the NAB strain. The incidence of B lymphocyte X ABL increased with age, suggesting proliferation of this cell population. HB ABL of both B and T lymphocyte classes were observed in all strains, concordant with the ubiquitous presence of humoral anti-HB autoantibodies. Differentiation of precursor B cells are evaluated by PFC assay of cells secreting specific autoantibodies. Anti-X PFC were observed only in NZB and NZB hybrid mice; and the observed frequency suggested that less than 3.5% of the specific ABL were differentiated for the secretion of anti-X autoantibody. Anti-HB PFC were observed in all strains and represented as high as 11.8% of specific ABL. Genetic determination of the anti-X anti-erythrocyte autoantibody response does not prescribe the presence of precursors of the antibody-forming cell, but rather appears to influence regulation of the differentiation of these cells. These data suggest that circumvention of immunologic tolerance to this specific erythrocyte autoantigen may occur at the level of the T lymphocyte; or alternatively, that T lymphocytes as well as B lymphocytes, are induced to proliferate and differentiate in the NZB strain.

Animals↗
PubMed1976

Regulatory serum lipoproteins: regulation of lymphocyte stimulation by a species of low density lipoprotein.

Low density lipoproteins (LDL) containing apolipoprotein B were separated from 15 fresh normal human serum pools by three independent isolation methods including sequential ultracentrifugal flotation, affinity chromatography, and polyanion precipitation. A discrete subpopulation of LDL (LDL-In) was isolated which possessed comparable inhibitory activity for PHA, PWM, and allogenic cell stimulated human lymphocytes in vitro at concentrations of 1 to 10 mug protein/1 x 10(5) lymphocytes/0.25 ml culture. LDL-In was characterized by a mean buoyant density of 1.055 g/ml in KBr, a m.w. of 2 to 3 x 10(6) daltons and a composition of 20 to 25% protein and 75 to 80% lipid with beta electrophoretic mobility. The biologic activity of LDL-In was non-cytotoxic, independent of mitogen concentration, and dependent upon the concentration of serum in the culture assay. The effect was temporally dependent requiring approximately 24 hr for induction of a stable suppressed state. Suppression was reversible with shorter periods of exposure to LDL-In. LDL-In did not inhibit lymphocytes at periods greater than 19 hr after stimulation, suggesting that LDL-In may influence metabolis events associated with the inductive phase of lymphocyte activation by lectins and allogeneic cells. LDL-In was clearly distinguishable from T lymphocyte E rosette inhibitory factor since it did not influence E rosette function of lymphocytes. The physicochemical and biologic properties of LDL-In clearly distinguish this reguloratory lipoprotein from previously described immunoregulatory factors.

Centrifugation, Density Gradient↗
PubMed1975

Lymphocyte E rosette inhibitory factor: a regulatory serum lipoprotein.

Rosette inhibitory factor, RIF, previously described in serum from patients with hepatitis B virus infection, has been isolated and identified as a minor species of beta-lipoprotein of the low-density (LDL) class. It is unrelated to hepatitis B virus proteins or particles. Although discrete by reference to charge and density (1.050 +/- 0.004 g/cm3), RIF appears to be a complex macromolecular structure containing apolipoproteins A, B, and C. Greater than 400% recovery is achieved upon 300,000-fold purification from RIF+ sera suggesting activation of a precursor form that is not present in normal serum. RIF inhibits E rosette function of T lymphocytes in vitro with a lag period of approximately 4 h and maximal effect at 24 h consistent with a metabolically-induced event. RIF is functionally active at concentrations of 1 X 10(-12) M or greater, rapidly binds to lymphocytes, and has a functionally effective half-life of approximately 1.5 h. Approximately 2,900 receptors for RIF appear to be present per cell and a high mutual affinity is apparent (k approximately to 9 X 10(10) liters/mol). RIF has no detectable effect on mitogen (PHA) responsiveness of lymphocytes, but inhibits the capacity of lymphocytes to respond to histoincompatible cells in vitro at concentrations greater than 10(-8) M. Equivalent RIF- lipoprotein fractions from normal serum are equally inhibitory in the mixed lymphocyte reaction suggesting that this effect is not directly attributable to RIF activity. These data indicate that RIF is a unique and functionally specific species of LDL that represents either an association complex of lipoproteins or a hybrid molecule of unusual composition. The association of this factor with viral-induced hepatocellular injury underscores the need to elucidate its structure and function in greater detail.

Adult↗
PubMed1975

Association of an isomeric species of carcinoembryonic antigen with neoplasia of the gastrointestinal tract.

We studied the association between serum levels of an isomeric species of carcinoembryonic antigen and neoplasia of the gastrointestinal tract in 993 patients. With use of an empirically determined threshold, the antigen was found to be elevated in 80.4 per cent of 138 patients with neof other tumors, predominantly lung and breast tumors. Serum levels were elevated in 0.23 per cent of random patients and 0.41 per cent of 725 patients without neoplasia, including those with liver diseases, inflammatory bowel disease and chronic renal disease. The results of this study suggest that this species of carcinoembryonic antigen, and that assay for it offers an improved approach to the diagnosis and management of neoplasia of the gastroinetestinal tract.

Adenocarcinoma↗
PubMed1975

Isolation and characterization of a homogeneous isomeric species of carcinoembryonic antigen: cea-s.

A single homogeneous isomeric species of carcinoembryonic antigen was isolated by reference to solubility in 0.9 M perchloric acid, isoelectric focusing, molecular exclusion chromatography, ion exchange chromatography, passage through immuno-absorbants, and isopyknic density gradient ultracentrifugation. The final product, representing approximately 1.8% of the perchloric acid soluble glycoprotein of the tumor, is homogeneous and devoid of other proteins by polyacrylamide gel electrophoresis. This single species of carcinoembryonic antigen, CEA-S, has a sedimentation velocity of 6.6, a diffusion constant of 3.05 times 10-minus 7 cm-2/sec, a mean Stokes radius of 65 A, a density of 1.41 ml/g in cesium chloride and an estimated molecular weight of 181,000, and it is devoid of detectable A or B blood-group antigens. Immunochemical studies demonstrate qualitative similarities between CEA-S and conventional carcinoembryonic antigens; however, competitive inhibition analyses demonstrate significant quantitative immunochemical differences between CEA-S and preparations of carcinoembryonic antigen. These results are consistent with the concept that CEA-S is an immunochemical isomer of carcinoembryonic antigen.

Adenocarcinoma↗
PubMed1975

A cleavage-associated neoantigenic marker for a gamma chain site in the NH2-terminal aspect of the fibrinogen molecule.

The E fragment, derived from the NH2-terminal aspect of fibrinogen by plasmin cleavage (fg-E), possesses two generically distinct sets of antigenic expressions. The major set of antigens is expressed by the parent molecule as indicated by the capacity of a major subpopulation of antibodies present in antiserum to fg-E and reactive with fg-E to: (a) react with fibrinogen, and (b) be specifically absorbed by fibrinogen but appears following proteolysis with plasmin. These cleavage associated neoantigens (fg-E-neo) specifically react with a minor subpopulation of antibodies present in antiserum to fg-E.E fragments isolated after varying exposures to plasmin all expressed fg-E-neo, but early E fragments exhibited quantitatively less neoantigenic expression than more extensively degraded E fragments. The entire fg-E-neo expression is recovered on a single isolated constituent chain of the E fragment, and immunochemical analysis with antiserum to the isolated constituent chain-bearing fg-E-neo identifies it as a derivative of the gamma chain constituent, exhibits marked stability to physicochemical denaturation and enzymatic degradation. These properties suggest that the neoantigen may be associated with a specific amino acid sequence which is exposed by the cleavage process. The identification and localization of fg-E-neo provides a specific molecular marker site for the characterization of structural and conformational changes associated with catabolism and function of fibrinogen.

Animals↗
PubMed1975

Conformational and structural modulation of the NH2-terminal regions of fibrinogen and fibrin associated with plasmin cleavage.

Conformational and structural modulations of the NH2-terminal region of fibrinogen and fibrin associated with plasmin cleavage have been examined utilizing specific antibody probes. The E region derived from the NH2-terminal aspects of fibrinogen undergoes complex structural and conformational changes throughout the cleavage process as indicated by differences in the quantitative and qualitative expression of antigenic determinants by the E region of each isolated cleavage fragment. When the range of antigenic determinants recognized by the antibody probe is limited to a specific molecular marker on the gamma chain within the E region, fg-E-neo, evidence for a systematic and progressive modulation of this site during plasmin cleavage is observed. Fg-E-neo undergoes progressive exposure as the cleavage of fibrinogen proceeds from X to Y to D:E complex. Separation of the D:E complex into its constituent, D and E fragments, is associated with further exposure of fg-E-neo determinants. The sequential cleavage of fibrin by plasmin also leads to progressive exposure of the fg-E-neo site; however, comparison of corresponding fragments derived from fibrinogen and fibrin reveals significant differences in the character of fg-E-neo expression. Immunochemical differences between fibrin and fibrinogen E fragments are not abolished by further exposure of the fragments to plasmin, are apparently not due to the presence or absence of fibrinopeptides, and are maintained following denaturation and renaturation of the fragments. These results suggest that the differential expression of fg-E-neo by the E fragments may be primarily dependent upon differences in amino acid compositions of the fragments.

Antigen-Antibody Reactions↗
PubMed1975

Factor-VIII-related antigen: multiple molecular forms in human plasma.

Analysis of Factor-VIII-related antigen (vWAg) in normal plasma by crossed immunoelectrophoresis reveals an asymmetric pattern indicative of molecular heterogeneity. This asymmetric pattern apparently results from the presence of multiple molecular forms of VWAg with distinct, though partially overlapping, mobilities on crossed immunoelectrophoresis. Evidence for this conclusion has been obtained by separating these forms, one from another, utilizing cryoprecipitation, agarose gel chromatography, and ion-exchange chromatography. Variation in the relative destribution of VWAg forms in liver disease and disseminated intravascular coagulation suggests that the processes which govern generation and/or breakdown of these forms can be altered by disease.

Antigens↗
PubMed1975

An alternative pathway for fibrinolysis. I. The cleavage of fibrinogen by leukocyte proteases at physiologic pH.

An alternative fibrinolytic system, active at physiological pH, is present in peripheral blood leukocytes. The fibrinolytic proteases localized predominantly in the leukocyte granules are capable of degrading both fibrinogen and fibrin, and plasmin activity does not contribute significantly to this proteolytic event. The specificity of the alternative fibrinolytic proteases for fibrinogen and the characteristics of the derivative cleavage fragments are clearly distinguishable from the classical plasmin system. The high molecular weight derivatives of fibrinogen, generated by the alternative system, under physiological conditions, are larger than the plasmin-generated X fragment, exhibit immunoelectrophoretic mobility comparable to native fibrinogen, and are not coagulable by thrombin. Analysis of the constituent polypeptide chains of the fragments reveals cleavage of the Aalpha, Bbeta, and gamma chains of fibrinogen. The lower molecular weight derivatives of fibrinogen, generated by the alternative system, are structurally distinct from previously described fibrinogen degradation products and exhibit potent anticoagulant activity. This anticoagulant activity can be attributed to interference with normal fibrin polymerization. The proteases of the alternative fibrinolytic systems are actively secreted by leukocytes when stimulated to undergo a nonlytic release reaction. These results provide direct evidence for a fibrinolytic system resident in leukocyte granules that is associated with the leukocyte release reaction and is capable of generating unique fibrinogen cleavage fragments.

Electrophoresis, Polyacrylamide Gel↗
PubMed1975

Immune responses to the cleavage-associated neoantigens of fibrinogen in man. Identification and characterization of humoral antibodies specific for cleavage fragments.

Cleavage of human fibrinogen and fibrin by plasmin is associated with modification of native antigenic expression and the exposure of cleavage-associated neoantigenic sites on the derivative molecular fragments. In this study, the presence of humoral antibodies in man to cleavage-associated neoantigens has been demonstrated by primary antigen binding radioimmunochemical assays. Specific binding of radioiodinated human fibrinogen D fragment by serum immunoglobulins was demonstrated in 52 of 59 random normal human sera and was independent of immunoglobulin concentration. Binding was mediated by F (ab)2 fragments of IgG, and specificity for neoantigens was indicated by the capacity of the D fragment but not native fibrinogen to competitively inhibit the antibody. The population distribution of antibody to these cleavage-associated neoantigens indicated the presence of a major group of individuals (77%) with a mean antigen binding capacity of 11.8 pmol/ml serum. Two minor populations with : (a) low or undetectable binding capacities (less than 6.0 pmol/ml serum) and (b) exhibiting markedly elevated binding capacities (less 18.0 pmol/ml serum) were delineated. Independent of these features, sera could also be readily separated into two groups that differed with respect to relative antibody affinity. The antibodies in most sera exhibited marked heterogeneity of binding affinity, whereas a small group of sera contained antibodies exhibiting relative homogeneity of binding affinity. Specific antibody was rather equally distributed between the major immunoglobulin classes, and in no serum was the antibody restricted to a single immunoglobulin class. Antibodies capable of binding fibrinogen fragments X, Y, and D and fibrin D fragment were detected in most sera. The quantity of antibody differed for different fragments with X greater than Y congruent to D greater than fibrin D. The presence of antibody capable of binding any single fragment was statistically correlated with the presence of antibody capable of binding other cleavage fragments. No antibody to the E fragment was detected. Antibody to cleavage fragments was not demonstrable in sera containing fibrinogen or fibrin cleavage fragments. Demonstration of this humoral immune response to the products of the fibrinolytic systems provides a new interface between the coagulation and immune system.

Antibodies↗