B-cell tolerance. IV. Differential role of surface IgM and IgD in determining tolerance susceptibility of murine B cells (original) (raw)
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Journal of Experimental Medicine, 1976
The relative susceptibility of neonatal and adult murine splenocytes to induction of B-cell tolerance was studied in vitro. Adult cells required approximately 1,000-fold more trinitrophenyl-human gamma globulin to be rendered tolerant than did cells from 9- to 12-day-old neonates. The potential effects of suppressor T cells were excluded by pretreating the cultured B cells with anti-Thy-1 and C' and the helper T cells with anti-Ly-2.2 and C'. The possible role of cell surface immunoglobulin isotypes in contributing to this observed difference is discussed.
Ontogeny of susceptibility of mouse splenic B cells to tolerance induction in vitro by TNP‐D‐GL
European Journal of Immunology, 1979
The susceptibility of mouse spleen cells to hapten‐specific tolerance induction of a primary in vitro thymus‐independent antibody response was examined. Both the induction of tolerance by 2,4,6‐trinitrophenyl‐D‐glutamic acid‐D‐lysine (TNP96D‐GL) and of antibody formation (elicited by TNP‐Brucella abortus) in neonatal spleen cell cultures were unaffected by anti‐Thy‐1.2 plus complement treatment. Spleen cells from neonatal mice were only slightly more sensitive to TNP96D‐GL tolerance induction than were cells from adult mice. The difference in susceptibility to tolerance induction was not nearly as great as that predicted by “clonal abortion”‐type theories of B cell tolerogenesis.
Journal of Experimental Medicine, 1977
The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from...
A role for immunoglobulin D: interference with tolerance induction
European Journal of Immunology, 1993
A role for immunoglobulin D: interference with tolerance induction Max-Planck-Institute for Immunobiology, Freiburg We have studied the induction and maintenance of tolerance in the B lymphocyte compartment. Neonatal and adult transgenic mice which expressed either surface IgM (sIgM) o r sIgM and sIgD anti-2,4,6-trinitrophenyl (TNF') were treated with soluble mono-and multivalent forms of TNP-modified carriers. We compared the B cell compartment of mice treated with antigen and of littermates injected with phosphate-buffered saline. Antigen-mcdiatcd cross-linking of membrane-bound IgM (sIgM) caused deletion of B cells both in neonatal and adult mice with p and x transgenes. Deletion was the result of apoptosis. In mice that carried an additional b transgene sIgD interfered with tolerance induction. The stage in which the cells were sensitive to deletion was characterized as a transitional stage between immature (sIgMdU", heat-stable antigenbrlght, B220dU", sIgD-) and more mature (IgMhrlght, heat-stable antigendu", B22Ohripht, sIgD-) B cells. Surviving cells were functional as measured by receptor-mediated changes in the intracel-M a r free Ca2+ concentration. We propose that when the immature B cells have reached the final stages of maturation IgM always transmits negative signals in the absence of T cell help.When B cells need to be screened against self reactivity IgM is the only antigen receptor expressed. Thc presence of sTgD protects resting Bcells from deletion and allows them t o initiate an effective immune response.
The Journal of experimental medicine, 1975
Purified goat antibodies against mouse mu-chains and rabbit antibodies against mouse Ig determinants, and their Fab fragments, inhibited the development of IgM-bearing B cells in explant cultures of 14-day mouse fetal liver, and caused the disappearance of cell surface IgM in explant and dissociated cell cultures of more developed lymphoid tissues. While treatment of cultures of fetal or newborn liver, or adult bone marrow, with low concentrations (less than or equal to 10 mug/ml) of anti-Ig for less than or equal to 24 h caused the complete, but reversible, disappearance (modulation) of cell surface IgM, treatment for greater than or less than 48 h produced irreversible IgM suppression. In contrast, anti-Ig-induced suppression of cell surface IgM in cultures of adult spleen or lymph nodes required much higher concentrations of antibody (greater than or equal to 100 mug/ml) and was always reversible. These differences between immature and mature IgM-bearing cells could not be relate...
B lymphocytes may escape tolerance by revising their antigen receptors
Journal of Experimental Medicine, 1993
To explore mechanisms that prevent autoreactivity in nonautoimmune mice, endogenous immunoglobulin (Ig) light (L) chains that associate with a transgenic anti-DNA heavy chain were analyzed. The antibodies from splenic B cell hybridomas of such mice did not bind double-stranded DNA (dsDNA) and their L chain sequences showed a biased use of V kappa and J kappa gene segments. The 44 L chains in this survey were coded for by just 18 germline genes. Six of the genes, each belonging to a different V kappa group, were used more than once and accounted for three fourths of all sequences. Based on the distribution of V kappa genes, the L chain repertoire in this line of transgenic mice was estimated at 37 V kappa genes. The most frequently observed gene, a member of the V kappa 12/13 group, was identified in 16 hybrids. In addition, the majority of V kappa genes used J kappa 5. We interpret the skewed representation of V kappa and J kappa gene segments to result from negative selection. Based on the data, we suggest that V kappa rearrangements giving rise to anti-dsDNA reactivity are removed from the repertoire by a corrective mechanism capable of editing self-reactive Ig.
Tolerogenicity of resting and activated B cells
Journal of Experimental Medicine, 1994
Antigen presentation by resting splenic B cells has been shown previously to induce T helper 1 cell (Th1) anergy. In contrast to expectations, it was found here that B cells treated with F(ab')2 goat anti-mouse immunoglobulin (IgM) for 24 or 48 h also presented antigen (Ag) to Th1 cells in a manner that induced dramatic Ag-specific proliferative inactivation. The tolerogenicity of the anti-Ig-treated B cells was consistent with the observation that these B cells were only slightly more efficient than resting B cells in stimulating human gamma globulin (HGG)-induced proliferation of HGG-specific Th1 cells in primary cultures. The activated B cells were, however, more efficient than resting B cells in stimulating a primary mixed leukocyte reaction, and exhibited increased expression of major histocompatibility complex class II molecules, RL388 Ag and transferrin receptor. In addition, unlike resting B cells, which expressed little detectable B7, anti-Ig-treated B cells expressed h...
A polyclonal model for B-cell tolerance
Cellular Immunology, 1991
Overnight exposure of adult splenic B cells to anti-Ig, a surrogate for antigen/tolerogen, can result in a hyporesponsive state in terms of antibody synthesis. Since B cells treated with either intact of F(ab'), fragments of anti-Ig will exit the Go phase of the cell cycle and enter G, or S, respectively, we examined which steps in B-cell activation were required for this form of hyporesponsiveness. We found that B-cell hyporesponsiveness could be induced under conditions leading to either abortive or productive B-cell cycle progression, depending on the immunogenic challenge employed. Thus, PMA + ionomycin, concanavalin A, PMA alone, or ionomycin alone induced hyporesponsiveness. Each of these reagents is able to drive B-cell exit from Go into Gi and cause class II hyperexpression. We next examined the effect of cyclosporin A (CSA), a reagent that blocks anti-Ig but not by PMA-induced class II hyperexpression. Interestingly, CSA only interfered with the induction of B-cell hyporesponsiveness with anti-Ig. These results suggest that upregulation of MHC class II may be coincident with a CSA-sensitive tolerance pathway in B cells stimulated by anti-Ig. Finally, IL-4 pretreatment was found to ablate hyporesponsiveness induced by either intact anti-Ig or PMA. These results parallel the Fc-dependent induction of hyporesponsiveness reported earlier (G. Warner and D. W. Scott, J. Immunol. 146,2 185, 199 1). We propose that crosslinking of surface Ig, leading to cell cycle progression out of Go as well as class II hyperexpression, in the absence of a cognate T cell signal, leads to B-cell hyporesponsiveness.