39 research outputs found
Pemphigus autoimmunity: Hypotheses and realities
The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients
Therapy of recurrent high grade gliomas with surgery, and autologous mitogen activated IL-2 stimulated killer (MAK) lymphocytes: I. Enhancement of MAK lytic activity and cytokine production by PHA and clinical use of PHA.
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Relationship of cloning inhibition factor, "lymphotoxin" factor, and proliferation inhibition factor release in vitro by mitogen-activated human lymphoctes.
Human lymphocytes were stimulated in vitro with mitogens, phytohemagglutinin and concanavalin A to secrete proliferation inhibitory factor (PIF), cloning inhibitory factor (CIF), and lymphotoxin (LT). These three activities were demonstrable in the same supernatant, moreover, the particular effect observed was shown to depend on the concentration of the medium and the type of target cell employed. In general, the medium effects on target cells were: a) cytotoxic at high concentrations, b) growth inhibitory at intermediate concentrations, and c) only temporarily growth inhibitory at low concentrations. The absolute concentration producing a certain effect varied, depending on the target cell type employed. In addition, the sensitivity of the target cells to LT parallels the sensitivity of the cell to each of the other activities, PIF and CIF, and no species specificity was observed
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Relationship of CIF, LT, and PIF released in vitro by activated human lymphocytes. II. A further functional comparison of LT and PIF activities on HeLa and L-929 target cells.
Lymphotoxin (LT), and proliferation inhibition factor (PIF) activities found in 5-day supernatants of mitogen-activated human lymphocytes (SAL) were further compared. In agreement with previous results, the activities could not be distinguished functionally. Quantitative differences in the amount of activity detected in the SAL could be accounted for on the basis of target cell differences, concentration of the lymphocyte effector molecules in the supernatant, and the parameter employed to assess cell function. Growth inhibitory activity detected at high supernatant dilutions was completely reversible, whereas the cytotoxic activity detected at low supernatant dilutions was irreversible. When the active medium was fractionated on DEAE, two peaks of inhibitory activity were detected. Depending upon the amount of activity and target cell, both peaks of activity were growth inhibitory or cytotoxic. Since both peaks of material affected HeLa and L-929 cells, the materials were not species specific. Thus, it appears that cloning inhibitor factor, LT, and PIF activities may actually be measures of the same stable materials found in 5-day activated lymphocyte supernatants
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Relationship of cloning inhibition factor, "lymphotoxin" factor, and proliferation inhibition factor release in vitro by mitogen-activated human lymphoctes.
Human lymphocytes were stimulated in vitro with mitogens, phytohemagglutinin and concanavalin A to secrete proliferation inhibitory factor (PIF), cloning inhibitory factor (CIF), and lymphotoxin (LT). These three activities were demonstrable in the same supernatant, moreover, the particular effect observed was shown to depend on the concentration of the medium and the type of target cell employed. In general, the medium effects on target cells were: a) cytotoxic at high concentrations, b) growth inhibitory at intermediate concentrations, and c) only temporarily growth inhibitory at low concentrations. The absolute concentration producing a certain effect varied, depending on the target cell type employed. In addition, the sensitivity of the target cells to LT parallels the sensitivity of the cell to each of the other activities, PIF and CIF, and no species specificity was observed
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Relationship of CIF, LT, and PIF released in vitro by activated human lymphocytes. II. A further functional comparison of LT and PIF activities on HeLa and L-929 target cells.
Lymphotoxin (LT), and proliferation inhibition factor (PIF) activities found in 5-day supernatants of mitogen-activated human lymphocytes (SAL) were further compared. In agreement with previous results, the activities could not be distinguished functionally. Quantitative differences in the amount of activity detected in the SAL could be accounted for on the basis of target cell differences, concentration of the lymphocyte effector molecules in the supernatant, and the parameter employed to assess cell function. Growth inhibitory activity detected at high supernatant dilutions was completely reversible, whereas the cytotoxic activity detected at low supernatant dilutions was irreversible. When the active medium was fractionated on DEAE, two peaks of inhibitory activity were detected. Depending upon the amount of activity and target cell, both peaks of activity were growth inhibitory or cytotoxic. Since both peaks of material affected HeLa and L-929 cells, the materials were not species specific. Thus, it appears that cloning inhibitor factor, LT, and PIF activities may actually be measures of the same stable materials found in 5-day activated lymphocyte supernatants
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Release of LT molecules with restricted physical heterogeneity by a continuous human lymphoid cell line in vitro.
Lymphotoxins released by lectin activated human lymphoid cells in vitro are complex and can be resolved by molecular sieving techniques into multiple classes of activity, termed complex, Ī±,Ī² and Ī³. The classes can be further resolved into sub-classes on the basis of their charge by ion-exchange chromatography and electrophoresis. We found the lytic activity spontaneously released by the continuous human B lymphoid cell line, PGLC-33H, to be of limited physical heterogeneity, and essentially identical to the Ī± mol. wt class of human LTā molecules. This was determined by functional, physcial-chemical and immunologic means. We found that most of the Ī±-LT charge sub-classes present in supernatants from mitogen stimulated normal lymphocyte cultures were also detected in these supernatants. These studies suggest: (a) this cell line provides a source of human LT for study with restricted heterogeneity; (b) different lymphoid cells (T and B) may be capable of releasing different LT molecules; and (c) use of selected human lymphoid cell lines may be useful to examine the biokinetics of LT synthesis and release. Ā© 1979
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Release of LT molecules with restricted physical heterogeneity by a continuous human lymphoid cell line in vitro.
Lymphotoxins released by lectin activated human lymphoid cells in vitro are complex and can be resolved by molecular sieving techniques into multiple classes of activity, termed complex, Ī±,Ī² and Ī³. The classes can be further resolved into sub-classes on the basis of their charge by ion-exchange chromatography and electrophoresis. We found the lytic activity spontaneously released by the continuous human B lymphoid cell line, PGLC-33H, to be of limited physical heterogeneity, and essentially identical to the Ī± mol. wt class of human LTā molecules. This was determined by functional, physcial-chemical and immunologic means. We found that most of the Ī±-LT charge sub-classes present in supernatants from mitogen stimulated normal lymphocyte cultures were also detected in these supernatants. These studies suggest: (a) this cell line provides a source of human LT for study with restricted heterogeneity; (b) different lymphoid cells (T and B) may be capable of releasing different LT molecules; and (c) use of selected human lymphoid cell lines may be useful to examine the biokinetics of LT synthesis and release. Ā© 1979
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Lymphotoxin detected in the blister fluid of bullous pemphigoid patients.
The role of lymphocytes in the pathogenesis of bullous pemphigoid was examined by assaying the blister fluid obtained from bullous pemphigoid patients for the presence of the lymphokine, lymphotoxin. Blister fluids from six bullous pemphigoid were assayed on L-929 target cells for the presence of cytolytic molecules in the standard lymphotoxin assay. Three of six blister fluids obtained from bullous pemphigoid patients and one linear IgA bullous dermatosis patient contained significant levels of cytolytic activity. Control blister fluids from suction blisters, herpes, pemphigus, and toxic epidermal necrolysis patients did not contain cytolytic activity. Serum from five bullous pemphigoid patients also had no cytolytic activity. Neutralization studies using rabbit anti-alpha-lymphotoxin demonstrated that 54 to 88% of the cytolytic activity found in bullous pemphigoid blister fluid was due to alpha-lymphotoxin. These results indicate that lymphotoxin is locally released in the skin of bullous pemphigoid lesions and is detectable in blister fluids