Differential Transmembrane Signaling in B Lymphocyte Activation (original) (raw)

Regulation of B-lymphocyte activation, proliferation, and immunoglobulin secretion

Cellular Immunology, 1986

Lymphocyte growth and differentiation are controlled by signals resulting from the interaction of antigen and cellular products, such as lymphokines, with specific cell membrane receptors. Resting B lymphocytes can be activated by low concentrations (l-5 &ml) of antibodies to membrane IgM, which is the B-lymphocyte receptor for antigen. The binding of anti-IgM to B cells causes a rapid increase in intracellular free calcium concentration ([Ca"]i), in inositol phosphate concentration, and in protein kinase activity. Moreover, the effects of anti-IgM on B cells are mimicked by the combined use of calcium ionophores and phorbol esters. Since phorbol esters activate protein kinase c, this suggests that the increase in [Ca*']i and in phosphatidylinositol metabolism stimulated by anti-&M are critical events in B-cell activation. The entry into S phase of B cells stimulated with anti-IgM depends on the action of a T-cell-derived factor designated B-cell stimulatory factor (BSF)-1. This is a 20,000-Da protein which is a powerful inducer of class II major histocompatibility complex molecules. Although an important cofactor for B-cell proliferative responses to anti-IgM, its major locus of action is on resting B cells. B cells stimulated with anti-IgM and BSF-1 do not synthesize secretory IgM. However, if two additional T-cellderived factors, B 15 I-TRF and interleukin-2, are added to cultures, a substantial proportion of stimulated B cells produce secretory IgM. BSF-1 has also been shown to participate in the "switch" in Ig class expression. Resting B cells cultured with lipopolysaccharide will switch to IgG, secretion in the presence of purified BSF-1.

Immunity Mediated by B Cells and Antibodies

The production of antibodies is the sole function of the B-cell arm of the immune system. Antibodies are useful in the defense against any pathogen that is present in the extracellular spaces of the body's tissues. Some human pathogens, such as many species of bacteria, live and reproduce entirely within the extracellular spaces, whereas others, such as viruses, replicate inside cells but are carried through the extracellular spaces as they spread from one cell to the next. Antibodies secreted by plasma cells in secondary lymphoid tissues and bone marrow find their way into the fluids filling the extracellular spaces. Figure 7.1 Cross-linking of antigen receptors is the first step in B-cell activation. The B-cell receptors (BCR) on B cells are physically cross-linked by the repetitive epitopes of antigens (Ag) on the surface of a bacterial cell. The B-cell receptor on a mature, naive B cell is composed of surface IgM, which binds antigen, and associated Iga and Igb chains, which provide the signaling capacity. B-cell receptors are activated by cross-linking with antigens Ag BCR IgM Igα, Igβ B cell signals bacterial cell 183 Antibody production by B lymphocytes

Regulation of B-Lymphocyte Activation, Proliferation, and Differentiation

Annals of the New York Academy of Sciences, 1987

Lymphocyte growth and differentiation are controlled by signals resulting from the interaction of antigen and cellular products, such as lymphokines, with specific cell membrane receptors. Resting B lymphocytes can be activated by low concentrations (l-5 &ml) of antibodies to membrane IgM, which is the B-lymphocyte receptor for antigen. The binding of anti-IgM to B cells causes a rapid increase in intracellular free calcium concentration ([Ca"]i), in inositol phosphate concentration, and in protein kinase activity. Moreover, the effects of anti-IgM on B cells are mimicked by the combined use of calcium ionophores and phorbol esters. Since phorbol esters activate protein kinase c, this suggests that the increase in [Ca*']i and in phosphatidylinositol metabolism stimulated by anti-&M are critical events in B-cell activation. The entry into S phase of B cells stimulated with anti-IgM depends on the action of a T-cell-derived factor designated B-cell stimulatory factor (BSF)-1. This is a 20,000-Da protein which is a powerful inducer of class II major histocompatibility complex molecules. Although an important cofactor for B-cell proliferative responses to anti-IgM, its major locus of action is on resting B cells. B cells stimulated with anti-IgM and BSF-1 do not synthesize secretory IgM. However, if two additional T-cellderived factors, B 15 I-TRF and interleukin-2, are added to cultures, a substantial proportion of stimulated B cells produce secretory IgM. BSF-1 has also been shown to participate in the "switch" in Ig class expression. Resting B cells cultured with lipopolysaccharide will switch to IgG, secretion in the presence of purified BSF-1.

The Immunoglobulin Receptors on B Cells Bind Antigen, Focus Activation Signals to Them and Initiate Antigen-Presentation

Scandinavian Journal of Immunology, 1991

We do not agree with the analysis of Langman and Cohn on the function of Ig receptors. We have reviewed the available literature regarding anti-Ig activation of B cells and found it contradictory and unconvincing. We have presented experimental evidence on the inability of Ig receptors on B cells to mediate activation or tolerogenic signals. We suggest that the Ig receptors serve to focus antigen to specific B cells so the B cells can be activated by TI antigens or helper T cells. The Ig molecules also bind foreign antigen and thereby initiate internalization and antigen processing. The processed peptides are exported to the membrane, where they associate with MHC class II antigens, thus transforming B cells into efficient antigen-presenting cells.

The Role of I-A/E Molecules in B-Lymphoeyte Activation

Scandinavian Journal of Immunology, 1987

We have previously demonstrated ihat monuclunal anii-I-A/E antibodies inhibil B-cell responses lolipupolysiiccharide (LPS). In the present report, the inhibitory effects were shown to be carried out directly on B cells. ;ind to be totally independent of the LPS concentration used, thereby showing that anlihodies do not mediate their effect through blocking of accessory cells or stcrie hindrance of LPS-receplors. Of Ihe three different phases in B-cel! activation/ induction, proliferation, and maturation, induction was shown to be ihe most sensitive to inhibition by anti-I-A/E antibodies. Thus, kinctie studies showed that anli-LA/E antibodies are only inhibitory for the first Id h of LPS aclivation. afler whieh B cells can no longer be inhibited by these antibodies. Class II MHC molecules appear, therefore, to be pan of a nietiibrane tnolecular complex whieh regulates delivery of activation signals lo resling B ceils. Since it was also shown ihai this lime period corresponds approximately to the time required for B cells to express I'uneiional reaciivtty lo growth factors, we suggest that anti-I-A/E antibodies act on resting B lymphocytes to inhibit mitogen-dependent induction of growth receptor expression.

Three classes of signalling molecules on B‐cell membranes

Journal of cellular …, 1985

The question of whether surface immunoglobulin and la molecules have a signalling function in helper T cell-dependent activation of B cells has been evaluated. Two sources of B cells have been used, one a purified population of haptenbinding B cells, the other a B-cell lymphoma, CH12, with known antigen specificity. Evidence is presented that both immunoglobulin and Ia molecules are receptors actively involved in the initial activation of resting B cells. Nevertheless, the requirements for ligand binding to either receptor can be bypassed under appropriate conditions, and the implications of this result for the function of these molecules is discussed. With respect to B-cell Ia, the authors present data that demonstrate two distinct functions of this molecule, one as a restricting element for T-cell activation, the second as a signalling receptor for B-cell excitation. On the CH12 surface, the LA molecule fulfills the former function, but T-cell interactions with I-A fail to result in B-cell stimulation, suggesting that B-cell Ia may limit helper T cell-B cell interactions. We suggest that the binding of antigen surface immunoglobulin and binding of helper T-cell receptors to the appropriate la molecule(s) results in the activation of genes that encode for a third class of membrane B-cell receptors, those that bind B-cell stimulating factors.