Biomedical subjects
Publications and source records attributed to R F Ashman.
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The redistribution of lymphocyte surface immunoglobulin (Ig) induced by anti-Ig antibody or bound sheep erythrocyte antigen (capping) was inhibited reversibly by hydrocortisone succinate (2 x 10(-4) M). Capping inhibition was also effected by cholesterol and progesterone, favoring the hypothesis that the effect was mediated through changes in the physical properties of the cell membrane rather than hormonal action. Capping was also inhibited by propranolol at concentrations where it may exert a local anesthetic as well as a beta-adrenergic blocking effect (2 x 10(-4) M). Since a fourfold excess of the beta agonist isoproterenol failed to restore capping in the presence of propranolol, the local anesthetic mode of action is most likely. Nitroprusside, an inhibitor of contraction in vascular smooth muscle and platelets, failed to inhibit capping.
Capping provides a rapid assay for the transduction of 1 type of membrane signal generated by the cross-linking of cell surface receptors. The order of the steps comprising this signal was determined by employing reversible inhibitors of lymphocyte surface Ig capping in a sequential incubation protocol. The results demonstrated that surface Ig cross-linking leads to capping by a linear series of discrete events. Although the steps inhibited by the calcium ionophore A23187 and the tranquilizer chlorpromazine could not be distinguished, other agents also thought to influence calcium distribution in the cell acted at different steps. The order of inhibited steps was shown to be: 1) hydrocortisone; 2) calcium ionophore or chlorpromazine; 3) cytochalasins; 4) dibucaine; 5) propranolol; 6) fluoride; 7) azide. These results suggest a model wherein cross-linked membrane Ig aggregates engage the preassembled microfilament system by means of a calcium-dependent linkage. Further calcium redistribution within the cell then leads to an energy-consuming contractile event.
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Immunoregulatory defects in patients can be assigned to B cells, T helper cells, or T suppressor cells by means of a modification of the in vitro PWM-stimulated Ig biosynthesis assay. When lymphocyte subpopulations from patient and normal are recombined, multiple internal comparisons within a single experiment reveal the functional activity of each subpopulation. By this technique we studied nine adult patients with acquired panhypogammaglobulinemia and one with isolated IgG deficiency. Low total Ig production by the B cell fraction was demonstrated in seven of the nine panhypogammaglobulinemic patients. In four of these seven, IgG and IgA secretion was markedly reduced compared with IgM. In the two patients with normal total Ig production, elevated IgM compensated for lower IgA and IgG. The one patient with no surface Ig+ cells had a B cell defect, but no T cell defect. Reduced T help and excessive T suppression characterized two of the four patients with the most severe B cell defects. Three patients were anergic by delayed hypersensitivity skin testing and failed to sensitize to DNCB, but the patient with the most severe T cell defects in vitro was not among them. One of these three patients showed a mild T cell help defect and suppressor excess and the other two had pure B cell defects. Thus, anergy and T regulator function were not correlated. In three instances where hypersuppression was more evident by adding patient unfractionated cells than by adding patient T cells, suppression by the T depleted fraction could be demonstrated. No cases of radiation-resistant T suppression were revealed among the seven patients tested. Subnormal total protein synthesis, noted in six of seven patients with low Ig production, was invariably less marked than the Ig defect and often affected both T and B cells. One additional patient with pure IgG deficiency of 2 yr duration was essentially normal in her in vitro lymphocyte function. The general applicability of this experimental design for analysis of positive or negative immunoregulatory abnormalities is emphasized.
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Staphylococcal protein A is a bacterial cell wall product that binds human immunoglobulin G and thereby interferes with opsonization and phagocytosis of Staphylococcus aureus by neutrophils. Phagocytic cells are also responsive to various non-immunoglobulin lymphocyte mediators. We utilized the detection of a newly recognized mediator, a neutrophil migration inhibition factor from T-lymphocytes (NIF-T), to show that aggregates of staphylococcal protein A and immunoglobulins G could inhibit the responsiveness of neutrophils to NIF-T. That such aggregates may alter the responsiveness of neutrophils to lymphocyte mediators that amplify or modulate phagocytic functions may have important pathogenetic implications in staphylococcal infection.
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A biochemical parameter of lymphocyte activation, lipid synthesis, has been measured in a purified specific antigen-binding cell population (ABC). ABC isolated form immune and nonimmune animals by sequential centrifugation on buoyant density and sedimentation velocity gradients have a 2- to 7-fold higher rate of 14-C choline incorporation into phospholipid than either unfractionated spleen cells or cells depleted of ABC. Aslo ABC from immune animals were shown to have a 4- to 7-fold higher rate of 14C-acetate incorporation into their neutral lipids than nonbinding controls. The elevated lipid synthesis seen in both nonimmune SRBC-ABC and TNP-SRBC ABC indicates that antigenic contact via the B cell immunoglobulin receptor results in signal transduction and activation of the specific receptor-bearing lymphocyte population. Binding of the same particle (SRBC) to B cells via their Fc receptors did not regularly result in activation of lipid synthesis. The magnitude of the increased lipid synthesis in ABC populations approached that seen in LPS-stimulated spleen cells. We propose that the measurement of early activation events in purified ABC may be a more appropriate criterion for antigen-induced signals that later events such as thymidine incorporation or antibody secretion.
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