Signal Transduction by the Antigen Receptor of B Lymphocytes

DeFranco, A L; Page, Dawne M.; Blum, John D.; Gold, Michael R.

doi:10.1101/sqb.1989.054.01.086

Cited by 10 publications

(8 citation statements)

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“…Using allotype-specific antibodies, they can be distinguished from the endogenous IgM b molecules that are found in the C57BL/6 and/516 strains. The tolerization of B lymphocytes requires the surface expression of autoreactive Igs in order to ensure signal transduction via the Ig antigen receptor complex (27,28). Since the B cells of the #19 ~m mice express the anti-CD8.2 # heavy chain in combination with endogenous light chains on their surface ( Fig.…”

Section: Resultsmentioning

confidence: 99%

B cell tolerance in mice transgenic for anti-CD8 immunoglobulin mu chain.

Brombacher

Köhler

Eibel

1991

The Journal of Experimental Medicine

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Snrrll'nary To analyze in vivo the induction of B cell tolerance against a T cell surface antigen, we generated transgenic mice expressing an anti-CD8.2/~ heavy chain gene. We show that self-specific B cells are efficiently tolerized if they express the membrane-bound form of the transgenic/~ chain on their surface but that they can escape tolerization if they express only the secreted form. In the latter, we find an enhanced expression of anti-CD8.2 antibodies after polyclonal B cell activation. As a result, transgenic anti-CD8.2 antibodies bind to the CD8 § T cells but they did not induce their elimination. Furthermore, we observed the preferential expression of a limited subset of endogenous light chains with the transgenic/~ chain. This suggests a positive or negative selection for particular heavy and light chain combinations in B lymphocytes.T olerance to self is one of the key properties of the immune system. To. explain the generation and the expansion of self-reactive B lymphocytes, several regulatory mechanisms have been either postulated (1-3) or documented. Self-reactive clones were shown to be clonally deleted (4-6), to be functionally inactivated by clonal anergy (7-12), to be suppressed (13,14), and to be controlled by virtue of antiidiotypic network interactions (3).The low frequency of self-reactive clones in healthy animals with a wide range of autoantibody affinities hampered the in vivo analysis of the origin and fate of autoreactive B lymphocytes. These restrictions were overcome by creating transgenic mice whose B cells express autoreactive antibodies of defined affinity (5,6,(8)(9)(10)(11)(12). In the absence of the autoantigen, the transgenic receptors are expressed by nearly all B lymphocytes of these mice. Their fate in the autoreactive situation was analyzed by introducing the autoantigen in matings to appropriate mouse strains. Several recent investigations have been carried out analyzing the reaction of self-reactive B cells to either soluble (6,(8)(9)(10)(11)(12) or membrane-bound (5, 6) autoantigens. In these studies, the B cell repertoire of the autoreactive transgenic mice was either nearly monospecific due to the presence of transgenic heavy and light chains (5,6,(8)(9)(10)(11)(12) or showed a high degree of permissiveness in the light chain usage in mice transgenic for the autoreactive heavy chain (12).We chose as autoantigenic determinant an epitope present on the CD8 oe chain expressed on the surface of T cells. Two alleles, CD8.1 and CD8.2, of the CD8 ol chain are found in mice. They differ by the exchange of a single amino acid: a methionine residue located in the V-like domain of the CD8.2 ol chain is replaced by valine in the CD8.1 a chain (15). Only the CD8.2 allelic form is recognized by a mAb produced by the hybridoma line 19/178 (16) from which we cloned the antibody genes. To allow a certain degree of variability within the B cell repertoire, we introduced only the functionally rearranged anti-CD8/z heavy chain into the germline of mice (17). The selection of the ant...

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Section: Resultsmentioning

confidence: 99%

B cell tolerance in mice transgenic for anti-CD8 immunoglobulin mu chain.

Brombacher

Köhler

Eibel

1991

The Journal of Experimental Medicine

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“…Further progression signals are provided by soluble factors derived from T cells [13,17], These interactions induce a wide range of changes such as increase in intracellular calcium. activation of protein kinase C (PKC) [6,11], and expression of new molecules on the cell membrane [9]. Two molecules that appear to be functionally involved in the activation process are CD40 (Bp50.…”

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confidence: 99%

Expression of CD40 and CD43 during Activation of Human B Lymphocytes

1991

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CD40 and CD43 are two cell-surface glycoproteins that appear to be functionally involved in the growth stimulation of human B cells. Whereas CD40 is structurally similar to the NGF receptor and is present on all resting B cells, CD43 displays no homology to other known proteins and is expressed only on a subpopulation of these cells. To further understand the extra- and intracellular signals regulating these molecules and in which stage of activation they may play a role, we used various activation strategies and studied their expression on tonsillar B cells. As expected, activation of protein kinase C by TPA increased both CD40 and CD43. In contrast, a rise in intracellular Ca2+, e.g. by ionomycin, did not influence the expression of these antigens. However, in the presence of TPA, ionomycin further up-regulated CD43 but not CD40. Anti-IgM behaved similarly to ionomycin suggesting that the effect of this reagent was due primarily to its ability to increase intracellular Ca2+. Of three interleukins (IL-2, IL-4 and IL-6) only IL-4 had a significant effect when used alone in that it up-regulated CD40 but not CD43. However, in the presence of anti-IgM, both IL-2 and IL-4 synergistically up-regulated the two antigens. Complementation of antigen receptor stimulation with TPA or IL-4 increased CD40 during the first 24 h, whereas up-regulation of CD43 did not occur until 24 to 48 h after stimulation. With regard both to up-regulation in response to different stimuli and to kinetics, CD40 expression paralleled that of the early activation antigen CD23, whereas CD43 was induced in parallel with the transferrin receptor (CD71). Taken together, our results suggests that the expression of CD40 and CD43 is regulated by different intracellular signals and that CD40 may be important during early activation, whereas CD43 may have its major function during later stages of B-cell differentiation. These assumptions are in line with the observations that CD40 antibodies can directly activate resting B cells and that CD43 are retained on plasma cells.

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“…Several groups have used the transgenic mouse model to look at the regulation of IgM autoantibodies and have observed anergy or deletion depending, in part, upon whether the autoantigen is soluble or membrane bound (3,4,7,8). Tolerance induction is dependent on antigen-receptor-mediated crosslinking and subsequent signal transduction (11,12). IgM antibodies can be expressed on the membrane only in association with an a/p heterodimer.…”

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Induction of tolerance to an IgG autoantibody.

Offen

Spatz

Escowitz

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Nonautoimmune mice transgenic for the heavy chain of an IgG2b anti-double-stranded-DNA antibody express the transgene in lymphoid organs and display partial allelic exclusion of this y2b transgene. The spleens ofthese mice are characterized by marked B-cell depletion. Although there are B cells in these mice that express the transgene and recognize double-stranded DNA, they are anergic in vivo. Recovery from the state of anergy occurs in vitro after lipopolysaccharide stimulation. Thus this transgenic model demonstrates the induction ofselftolerance to an IgG autoantibody.

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Signal Transduction by the Antigen Receptor of B Lymphocytes

Cited by 10 publications

References 0 publications

B cell tolerance in mice transgenic for anti-CD8 immunoglobulin mu chain.

B cell tolerance in mice transgenic for anti-CD8 immunoglobulin mu chain.

Expression of CD40 and CD43 during Activation of Human B Lymphocytes

Induction of tolerance to an IgG autoantibody.

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