Biomedical subjects
Publications and source records attributed to R S Geha.
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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.
Normal human peripheral blood lymphocytes were separated on discontinuous gradients of 17-35% bovine serum albumin (BSA) into nine fractions. Three subpopulations of lymphocytes were obtained. One occupies the top third of the gradient (fractions 1-3, 17-23% BSA) and is rich in cells characterized by a high spontaneous rate of DNA synthesis and by the ability to give rise to colony-forming units. The middle portion of the gradient (fractions 4 and 5, 23-27% BSA) is rich in thymus-derived (T) lymphocytes identified by their vigorous response to mitogens and by their ability to form rosettes with sheep erythrocytes (E). The third subpopulation at the bottom of the gradient (fractions 6-9, 27-35% BSA) is rich in bone marrow-derived (B) lymphocytes capable of staining with fluorescent antiimmunoglobulin antisera and of forming rosettes with EAC1423. The peripheral blood lymphocytes of five boys with proved X-linked agammaglobulinemia and two with probable X-linked agammaglobulinemia were found to be totally deficient in B lymphocytes (fractions 6-9) and lacked the subpopulation identified by immunofluorescent staining or rosette formation with EAC1423. One boy with proved X-linked agammaglobulinemia and two with probable X-linked agammaglobulinemia possessed a normal amount of circulating B lymphocytes.
Anti-idiotypic (anti-Id) antibodies are directed against antigenic determinants expressed by the antigen-binding region of the immunoglobulin molecules. Their interaction with antigen receptors on immune cells modulates the immune response. In man auto-anti-Id antibodies have been demonstrated. These antibodies not only participate in the regulation of the immune response, but can result in disease as in the case of acquired angioedema with B cell malignancy and possibly in autoimmune diseases. Anti-Id antibodies may be useful tools in cancer immunotherapy and in the production of vaccines.
The Prausnitz-Küstner (P-K) reaction is a sensitive test for the presence and activity in the skin of immunoglobulin E, an important class of immunoglobulin mediating allergic reactions. A fragment of the human myeloma ND epsilon-chain gene, encoding the second, third and fourth domains of the IgE constant region (C epsilon 2-4) was assessed here for its ability to inhibit the P-K reaction in vivo. Injection of the fragment in skin sites of healthy human adults prevented subsequent sensitization with serum containing IgE antibody to ragweed antigen. Inhibition of the P-K reaction required a 200-fold molar excess of the C epsilon fragment over the IgE present in the sensitizing serum. The efficacy of the C epsilon fragment in inhibiting the P-K reaction compared favourably with that of natural myeloma IgE (PS) in terms of both blocking concentrations and duration of the blocking effect. The inhibition of the P-K reaction by C epsilon 2-4 fragments was specific and probably caused by the saturation of IgE receptors on mast cells by the recombinant gene product.
Kawasaki disease (KD) is an acute vasculitis of infancy and early childhood characterized by high fever, rash, mucositis, lymphadenopathy and coronary artery damage. Large epidemics have been described in Japan and the United States and the number of cases reported annually is steadily increasing. The aetiology of KD is unknown. During the acute phase of the disease marked immunologic alterations occur including generalized T-cell lymphocytopenia, activation of circulating T4+ helper T cells, decreased numbers of T8+ suppressor T cells and marked B-cell activation. We postulated that a lymphotropic virus with affinity for endothelial and lymphoid cells might explain the vasculitis and immunological abnormalities in KD. We report here our study of the particulate fraction from culture supernatants of peripheral blood mononuclear cells (PBMC) for evidence of retrovirus-associated reverse transcriptase (RT) activity. Activity was found in the supernatants from KD patients but not control cultures. This RT activity was transmitted to an established T-cell line (HUT-78) and thus may be due to an exogenous agent infecting KD lymphocytes.
CD40 is a surface antigen expressed on B cells. The CD40 ligand (CD40L) is expressed on activated T cells. Interaction between CD40 and CD40L is critical for proliferation and isotype switching in the context of a response to a T-cell-dependent antigen. Patients with X-linked hyper-IgM syndrome (HIGMX-1) in their CD40L gene are unable to switch from IgM to IgG, IgA and IgE. Mice with a disrupted CD40 gene fail to undergo isotype switching to T-cell-dependent antigens but respond normally to T-independent antigens.
CD40 ligand (CD40L) delivers a contact-dependent signal to B cells which, in the presence of interleukin (IL)-4, drives immunoglobulin isotype switching to IgE. CD40L expression in T cells is transient, requires activation of protein kinase C and a rise in intracellular calcium concentration ([Ca2+]i), and is inhibited by cyclosporin A (CsA). CsA also inhibited T-cell-dependent IL-4-driven IgE synthesis. We have found that expression of CD40L is developmentally regulated. Expression of CD40L was restricted to mature single-positive thymocytes which, in the presence of IL-4, were capable of inducing B cells to undergo IgE isotype switching. CD40L expression was severely decreased in cord blood lymphocytes and was associated with a severely decreased ability to undergo T-cell-dependent IgE isotype switching.
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The reagenic antibody in the sera of atopic individuals, first described by Prausnitz and Kustner and later determined to be Immunoglobulin (Ig) E by the Ishizakas, plays a critical role in the pathogenesis of allergic disease. Investigation into the cellular basis of IgE regulation has provided important insights into a disease process that affects up to 30% of the population world-wide. Over the last decade, the molecular events regulating IgE synthesis have been actively investigated. In this review, we will discuss the various components of this system including the cells, cytokines, signal transduction events, and molecular mechanisms that participate in human IgE synthesis and explore rational therapeutic approaches directed at the modulation of these systems.
We report the clinical and pathologic features of primary intestinal malakoplakia in a 14-year-old boy. The transmural involvement of small bowel, chronicity of the disease, and development of fistulas simulated chronic inflammatory bowel disease, specifically Crohn's disease. The diagnosis of malakoplakia was only possible by tissue biopsy. The clinical and pathologic differential diagnosis is briefly reviewed.