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AID-induced remodeling of immunoglobulin genes and B cell fate.

Laffleur B, Denis-Lagache N, Péron S, Sirac C, Moreau J, Cogné M - Oncotarget (2014)

Bottom Line: In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID).AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR).In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.

View Article: PubMed Central - PubMed

ABSTRACT
Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.

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AID-modulation of B cell fate in the context of lymphoid tissuesAfter V(D)J recombination and IgM expression, recently emerged B cells circulate as transitional cells and can be committed to various compartments depending upon BCR signalling (Notch2 expression and weak BCR tonic signaling commit B cells to a marginal zone fate). After maturation into IgM+, IgD+ cells, naïve B cells encounter T-dependent Ag and undergo cognate interactions with pre-TFH cells. B cells then initially activate in extra-follicular foci and differentiate into short-lived plasma cells, or participate with TFH in the formation of GCs where their BCRs will be deeply remodeled by SHM (mostly in the proliferating dark zone) or CSR (mostly in the GC light zone), or eventually LSR. The GC reaction will yield both memory cells and plasma cells, some being long-lived and surviving after their migration to several protective niches (spleen red pulp, bone marrow, MALT…).
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Figure 3: AID-modulation of B cell fate in the context of lymphoid tissuesAfter V(D)J recombination and IgM expression, recently emerged B cells circulate as transitional cells and can be committed to various compartments depending upon BCR signalling (Notch2 expression and weak BCR tonic signaling commit B cells to a marginal zone fate). After maturation into IgM+, IgD+ cells, naïve B cells encounter T-dependent Ag and undergo cognate interactions with pre-TFH cells. B cells then initially activate in extra-follicular foci and differentiate into short-lived plasma cells, or participate with TFH in the formation of GCs where their BCRs will be deeply remodeled by SHM (mostly in the proliferating dark zone) or CSR (mostly in the GC light zone), or eventually LSR. The GC reaction will yield both memory cells and plasma cells, some being long-lived and surviving after their migration to several protective niches (spleen red pulp, bone marrow, MALT…).

Mentions: During AID-mediated competition that occurs among B cells within germinal centers, a few with high affinity are selected (Figure 3). Besides these winners, many cells are losers or undesired responders deserving elimination. Although some unfavorable mutations of V regions can promote apoptosis [69], abundant survival signals from the GC microenvironment might also activate or maintain bystander cells with useless or eventually harmful BCRs (the latter having, for example, acquired specificity for self or environmental antigens after random remodeling of V sequences). Since class-switched antibodies are potent actors of auto-immunity and/or hypersensitivity, means for restricting CSR and reentry of class-switched cells into SHM would help ensure the specificity of immune responses. Yet, how the post-GC repertoire is controlled remains poorly understood.


AID-induced remodeling of immunoglobulin genes and B cell fate.

Laffleur B, Denis-Lagache N, Péron S, Sirac C, Moreau J, Cogné M - Oncotarget (2014)

AID-modulation of B cell fate in the context of lymphoid tissuesAfter V(D)J recombination and IgM expression, recently emerged B cells circulate as transitional cells and can be committed to various compartments depending upon BCR signalling (Notch2 expression and weak BCR tonic signaling commit B cells to a marginal zone fate). After maturation into IgM+, IgD+ cells, naïve B cells encounter T-dependent Ag and undergo cognate interactions with pre-TFH cells. B cells then initially activate in extra-follicular foci and differentiate into short-lived plasma cells, or participate with TFH in the formation of GCs where their BCRs will be deeply remodeled by SHM (mostly in the proliferating dark zone) or CSR (mostly in the GC light zone), or eventually LSR. The GC reaction will yield both memory cells and plasma cells, some being long-lived and surviving after their migration to several protective niches (spleen red pulp, bone marrow, MALT…).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4012742&req=5

Figure 3: AID-modulation of B cell fate in the context of lymphoid tissuesAfter V(D)J recombination and IgM expression, recently emerged B cells circulate as transitional cells and can be committed to various compartments depending upon BCR signalling (Notch2 expression and weak BCR tonic signaling commit B cells to a marginal zone fate). After maturation into IgM+, IgD+ cells, naïve B cells encounter T-dependent Ag and undergo cognate interactions with pre-TFH cells. B cells then initially activate in extra-follicular foci and differentiate into short-lived plasma cells, or participate with TFH in the formation of GCs where their BCRs will be deeply remodeled by SHM (mostly in the proliferating dark zone) or CSR (mostly in the GC light zone), or eventually LSR. The GC reaction will yield both memory cells and plasma cells, some being long-lived and surviving after their migration to several protective niches (spleen red pulp, bone marrow, MALT…).
Mentions: During AID-mediated competition that occurs among B cells within germinal centers, a few with high affinity are selected (Figure 3). Besides these winners, many cells are losers or undesired responders deserving elimination. Although some unfavorable mutations of V regions can promote apoptosis [69], abundant survival signals from the GC microenvironment might also activate or maintain bystander cells with useless or eventually harmful BCRs (the latter having, for example, acquired specificity for self or environmental antigens after random remodeling of V sequences). Since class-switched antibodies are potent actors of auto-immunity and/or hypersensitivity, means for restricting CSR and reentry of class-switched cells into SHM would help ensure the specificity of immune responses. Yet, how the post-GC repertoire is controlled remains poorly understood.

Bottom Line: In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID).AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR).In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.

View Article: PubMed Central - PubMed

ABSTRACT
Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.

Show MeSH
Related in: MedlinePlus