Murine Models of Tolerance Induction in Developing and Mature B Cells

Metcalf, Eleanor S.; Schrater, A F; Klinman, Norman R.

doi:10.1111/j.1600-065x.1979.tb00421.x

Cited by 74 publications

(44 citation statements)

References 95 publications

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“…Several studies have suggested that exposure to Ag deletes newly generated B cells more readily than mature B cells (37)(38)(39)(40); however, previous studies with Ig Tgn and HEL-Ig mice and with mice injected with anti-IgD mAb have demonstrated that mIg crosslinking in the absence of T cell help also deletes mature B cells (12,32,41). Our studies with IL-4 suggest that the difference between the behavior of immature and mature B cells is quantitative rather than qualitative.…”

Section: Relationship Between B Cell Survival and Maturitymentioning

confidence: 49%

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

Morris

Dragula

Finkelman

2002

The Journal of Immunology

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Persistent cross-linking of hen egg lysozyme (HEL)-specific B cell membrane Ig (mIg) in double transgenic mice that express soluble HEL as a self Ag (HEL-Ig mice) decreases B cell mIgM expression, responsiveness, and life span. Because in vitro treatment with IL-4 inhibits T cell apoptosis through a Stat6-independent mechanism, increases mIg expression, and suppresses activation-induced B cell death, we studied IL-4 effects on B cell mIg expression, survival, and Ab secretion in Stat6-sufficient and deficient HEL-Ig mice. IL-4 treatment nearly normalized B cell number and greatly increased the percentage of mature B cells in HEL-Ig mice, but failed to normalize mIgM expression or spontaneous LPS-induced IgM secretion. IL-4 effects on B cell survival and maturation were CD4+ T cell independent, but Stat6 dependent, and did not involve receptor editing. IL-4 had to be present while B cells were generated to have a detectable effect on autoreactive B cell survival; however, the survival of B cells generated in the presence of IL-4 was substantially increased even after IL-4 was withdrawn. These observations suggest that: 1) activation-induced B cell death and anergy are independent processes; 2) B cells that survive to maturity develop increased resistance to Ag-induced deletion; and 3) IL-4 promotes B and T cell survival through different mechanisms.

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Section: Relationship Between B Cell Survival and Maturitymentioning

confidence: 49%

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

Morris

Dragula

Finkelman

2002

The Journal of Immunology

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“…(a) 2,4-dinitrophenyl (DNP)-and PC-reactive splenic B cells are tolerizable only for the first few days after their initial expression in the murine neonate (12,13). (b) Neonatal bone marrow B cells can be rendered unresponsive to antigen longer in development than neonatal splenic B cells (13,14). (c) Whereas adult splenic B cells are not susceptible to in vitro tolerance induction, 25% of adult bone marrow B cells are tolerizable (13,14).…”

mentioning

confidence: 99%

“…This conclusion is based primarily on the following observations. (a) 2,4-dinitrophenyl (DNP)-and PC-reactive splenic B cells are tolerizable only for the first few days after their initial expression in the murine neonate (12,13). (b) Neonatal bone marrow B cells can be rendered unresponsive to antigen longer in development than neonatal splenic B cells (13,14).…”

mentioning

confidence: 99%

“…(b) Neonatal bone marrow B cells can be rendered unresponsive to antigen longer in development than neonatal splenic B cells (13,14). (c) Whereas adult splenic B cells are not susceptible to in vitro tolerance induction, 25% of adult bone marrow B cells are tolerizable (13,14). …”

mentioning

confidence: 99%

“…Previous studies, which used a modification of the in vitro splenic focus technique (12), have suggested that susceptibility to in vitro tolerance induction m a y serve as a functional marker for developing (immature) B cells and B-cell m a t u r a t i o n (12)(13)(14). This conclusion is based primarily on the following observations.…”

mentioning

confidence: 99%

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Susceptibility to in vitro tolerance induction of adult B cells from mice with an X-linked B-cell defect.

Metcalf¹,

Scher²

1980

The Journal of Experimental Medicine

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C B A / N mice, a m u t a n t subline of the C B A / C a strain, have an X-linked B l y m p h o c y t e -i m m u n e defect. These mice and F1 male progeny derived from C B A / N females fail to produce specific a n t i b o d y after i m m u n i z a t i o n with certain thymicindependent (TI) antigens (1-4). In addition, these mice fail to produce I g M or IgG responses to either the T I or T -d e p e n d e n t derivatives of the hapten phosphorylcholine (PC) (5, 6). Moreover, analysis of surface m e m b r a n e characteristics indicates that B cells derived from i m m u n e defective mice fail to express determinants that are present on a population of B lymphocytes that appears late in ontogeny. These include minor lymphocyte-stimulating determinants (7), Lyb5 (8), and Lyb3 (9). Furthermore, the B cells of C B A / N mice have unusually high amounts of surface I g M (sIgM) and exhibit a low ratio of surface 8:/~ heavy chains when c o m p a r e d with the B cells of normal mice (10, 11). These surface characteristics are similar to those that are exhibited by neonatal B cells (10). T a k e n together, these findings are consistent with the hypothesis that the i m m u n e defect(s) in C B A / N mice arise from a m a t u r a t i o n a l arrest either in the development of C B A / N B cells or of a subpopulation of these B cells.Previous studies, which used a modification of the in vitro splenic focus technique (12), have suggested that susceptibility to in vitro tolerance induction m a y serve as a functional marker for developing (immature) B cells and B-cell m a t u r a t i o n (12-14). This conclusion is based primarily on the following observations. (a) 2,4-dinitrophenyl (DNP)-and PC-reactive splenic B cells are tolerizable only for the first few days after their initial expression in the murine neonate (12, 13). (b) Neonatal bone marrow B cells can be rendered unresponsive to antigen longer in development than neonatal splenic B cells (13,14). (c) Whereas adult splenic B cells are not susceptible to in vitro tolerance induction, 25% of adult bone marrow B cells are tolerizable (13,14).

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Clonal anergy: Inhibition of antigen‐driven proliferation among single B lymphocytes from tolerant animals, and partial breakage of anergy by mitogens

Pike¹,

Abrams²,

Nossal³

1983

Eur J Immunol

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Mice were injected with fluoresceinated human gamma globulin (FLU-HGG) either at 2-3 days of age or as pregnant females. At 2 weeks of age, the spleen cells of the injected suckling mice or offspring were fractionated on FLU-gelatin dishes to yield FLU-binding B cells. These B cells were then cloned in microcultures using one of two recently described systems in which single B cells grow in the absence of feeder or filler cells, namely following stimulation with FLU-polymerized flagellin (FLU-POL) and conditioned media containing B cell growth and differentiation factor(s); or mitogenic activation by a mixture of E. coli lipopolysaccharide (LPS) and dextran sulfate (DxS). As such cultures permit visualization of clonal proliferation as well as ultimate harvesting of cultures for assay of hemolytic plaque-forming cells, it was possible to ask whether the lesion in the tolerant state affected the B cell's capacity to divide, to differentiate to antibody secretion, or both. The results indicated that, when stimulated with antigen, the anergic cells could neither divide nor differentiate. However, when the strong mitogen mixture was used, clonal anergy was partially broken. The cells proliferated, and a small proportion of them differentiated into anti-FLU antibody-forming cells. A marked variation in antigen-binding avidity of the FLU-binding cells made it difficult to quantitate the degree of uncoupling of proliferation and differentiation among tolerant, LPS plus DxS-stimulated cells. Nevertheless, a partial reversibility of clonal anergy must affect views on mechanisms of self-tolerance.

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Murine Models of Tolerance Induction in Developing and Mature B Cells

Cited by 74 publications

References 95 publications

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

Susceptibility to in vitro tolerance induction of adult B cells from mice with an X-linked B-cell defect.

Clonal anergy: Inhibition of antigen‐driven proliferation among single B lymphocytes from tolerant animals, and partial breakage of anergy by mitogens

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