Biomedical subjects
Publications and source records attributed to E Merler.
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High concentrations of adenosine are known to be toxic to fibroblasts and lymphocytes under conditions of in vitro culture (1,2). Normally, accumulation of adenosine nucleotides in all mammalian cells is prevented by the presence of adenosine deaminase, an aminohydrolase which converts adenosine to inosine (3). A genetically determined deficiency of adenosine deaminase has been associated with the autosomal recessive form of severe combined immunodeficiency, a syndrome in which precursor lymphocytes fail to mature into T cells and B cells (4-7). Erythrocytes of affected infants convert exogenous adenosine to AMP and ATP at an abnormally increased rate as a consequence of the enzyme defect, and ATP at an abnormally increased rate as a consequence of the enzyme defect, and fail to form inosine from the exogenous adenosine (8). These metabolic disturbances can be mimicked in normal erythrocytes by coformycin (8), a potent competitive inhibitor of adenosine deaminase (9, 10). In this study, the effects of coformycin were examined on the in vitro function of normal lymphocytes.
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Four patients with common, variable agammaglobulinemia were preveiously reported to have normal numbers of circulating B lymphocytes which synthesized normal amounts of IgG in tissue culture but failed to secrete the newly synthesized IgG. The B lymphocytes of these patients fail to incorporate [3H]mannose and/or [3H]glucosamine into newly synthesized IgG, whereas such incorporation appears to occur just before IgG secretion in cultures of normal B lymphocytes.
Purified subpopulations of lymphocytes were obtained from discontinuous bovine serum albumin (BSA) gradients and by rosetting sheep erythrocytes (E) or EAC1-3. Cells from layers 1 to 3 of the BSA gradient which failed to rosette with E were highly reactive with EAC1-3 and with anti-human IgM. Demonstrating a high spontaneous rate of DNA synthesis and primitive morphology, these cells responded to pokeweed mitogen, concanavalin A and alloantigens, but not to phytohemagglutinin or soluble antigens. Constituting from 0.5% to 3.0% of all lymphocytes from each of the tissues studied, these lymphocytes appear to represent an earlier stage in human lymphocyte development distinct from both T and B cells.
Precursor lymphocytes, obtained from human tissue on bovine serum albumin (BSA) gradients followed by removal of sheep erythrocyte (E)-reactive thymocytes on Ficoll, are the predominant lymphoid subpopulation found in young fetal thymuses. This subpopulation shows a progressive decline in relative numbers during fetal life, accompanied by a rise in both the relative and absolute numbers of E-reactive thymocytes. Precursor thymocytes differentiate in vitro to E-reactive cells resembling T cells in their morphology, sedimentation on BSA gradients, and response to phytohemagglutinin. Agents tending to increase intracellular concentrations of cyclic-AMP accelerate the rate of differentiation of precursor cells to lymphocytes which closely resemble T cells.
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A peptide consisting of 10 amino acids derived from the CH3 region of human IgG was shown to bind to monocytes and to inhibit rosette formation of antibody-coated erythrocytes with human monocytes. Two myeloma proteins of the IgG1 and IgG3 subclass, both with known deletions in the CH2 region of the gamma chain, showed unimpaired ability to bind to monocytes. These experiments suggest that the isolated peptide represents the primary site of attachment of IgG to monocytes.
Human T lymphocytes from patients with ragweed hay fever, when exposed to ragweed antigen E (AgE) in vitro, produced an activity that, in the presence of antigen, induced B cells from AgE-sensitive donors to synthesize and secrete IgE and IgG antibodies to AgE. Anti-AgE specificity was assessed both in vitro and in vivo. B lymphocytes from ragweed-sensitive individuals exposed in vitro to AgE alone failed to transform or to secrete antibody to AgE. The T cells activity had no effect on B cells of individuals not sensitive to AgE. The results of this study suggest that the human reaginic antibody response requires T and B cell cooperation. The experimental approach used may be a useful model for the investigation of the antibody responses of allergic individuals.
The population of B lymphocytes was assessed in the blood of 16 patients with agammaglobulinemia using immunofluorescence and EAC1423 reactivity as B-cell markers. Lymphocytes were fractionated on gradients of bovine serum albumin which are capable of separating lymphocytes into B-cell-rich and T-cell-rich populations. There was complete absence of B lymphocytes in the majority of patients with X-linked agammaglobulinemia. Normal or increased numbers of B lymphocytes were found in all patients with common variable agammaglobulinemia.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
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Relatively pure populations of human T and B lymphocytes were obtained from blood and tonsils using density gradient centrifugation in bovine serum albumin. Antigen alone was incapable of triggering the B lymphocyte into blast transformation or to secrete antibody. However, supernatants from tetanus toxoid-stimulated T cells obtained from immune donors contained a factor mitogenic for B lymphocytes. 50-60% of B cells responded to this lymphocyte mitogenic factor (LMF) by proliferation, loss of C3 reactivity, and change to a secretory state. LMF-stimulated B cells exhibited a three- to fivefold increase in protein secretion and a six- to eightfold increase in gamma G globulin secretion. De novo secreted IgG had specificity directed to the tetanus toxoid present in the LMF containing T-cell supernatants. This was confirmed by an increase in the number of indirect plaque-forming cells to tetanus toxoid-coated sheep red blood cells after stimulation of B cells with LMF. It is proposed that in the course of the response to a previously encountered protein antigen, sensitized human T cells emit a signal in the form of a soluble product that, together with antigen, triggers B cells into division and antibody secretion. The experimental model utilized can be adapted to study human T-B cell cooperation under various conditions in normal individuals and in individuals with immunodeficiency diseases.