Relaxed Negative Selection in Germinal Centers and Impaired Affinity Maturation in <i>bcl-x</i>L Transgenic Mice

Takahashi, Yoshimasa; Cerasoli, Douglas M.; Porto, Joseph M. Dal; Shimoda, Michiko; Freund, Robert; Fang, Wei; Telander, David G.; Malvey, Erika Nell; Mueller, Daniel L.; Behrens, Timothy W.; Kelsoe, Garnett

doi:10.1084/jem.190.3.399

Cited by 104 publications

(87 citation statements)

References 49 publications

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“…They found decreases in somatic mutation as well as in affinity of Ab secreted by splenic memory B cells, whereas the BM AFC remained unaffected. A discriminatory effect of the bcl-x L transgene on the repertoire of GC B cells and BM AFC was reported also by Takahashi et al (25). Studies from our laboratory have shown that the late, NP-specific Ab response in BM and the anamnestic response to Ag boost may be dominated by different B cell clones (20).…”

Section: Repertoire Of Antibody Response Inmentioning

confidence: 61%

Repertoire of Antibody Response in Bone Marrow and the Memory Response Are Differentially Affected in Aging Mice

Černý

2002

The Journal of Immunology

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The primary burst of Ab and germinal center (GC) formation in response to T-dependent Ag is compromised in aging mice. Here we examine the effects of aging on the post-GC phase of memory B cell differentiation and the late Ab repertoire maturation in bone marrow (BM) in mice immunized with a hapten nitrophenyl coupled to chicken γ-globulin. Specific Ab-forming cells (AFC) with mutated VH genes accumulated preferentially in the BM of aged mice, although the AFC numbers and average number of mutations per VH were lower, and the D gene usage was less restricted compared with those in the young animals. However, the repertoire of AFC after an Ag boost demonstrated the hallmarks of Ag selection, including the recurrent mutations and canonical VD rearrangements, similar to the late primary response in young animals. It is postulated that the Ab repertoire maturation in aged mice is delayed and may be notably improved by repeated immunizations.

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Section: Repertoire Of Antibody Response Inmentioning

confidence: 61%

Repertoire of Antibody Response in Bone Marrow and the Memory Response Are Differentially Affected in Aging Mice

Černý

2002

The Journal of Immunology

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“…34,35 The importance of apoptosis as it pertains to affinity maturation has been shown previously through the genetic manipulation of apoptotic genes. Transgenic expression of prosurvival factors of the Bcl-2 family, such as Bcl-2 and Bcl-x L , 14,15,36 leads to a variety of abnormalities in GC formation and function, such as a reduction in apoptosis within the GC and a subsequent defect in affinity maturation. Studies using mice with either deleted or defective Fas receptors have implicated a similar role for this death receptor in clonal selection.…”

Section: Discussionmentioning

confidence: 99%

“…Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, [12][13][14][15][16][17] and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells.…”

Section: Introductionmentioning

confidence: 99%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

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“…Similarly, CD19 Ϫ/Ϫ mice have a block in GC response to T-dependent Ags, as discussed above, and a deficiency in B-1 cells (50). This stage of differentiation is also critical for up-regulation of survival factors, such as Bcl-2 and Bcl-xl, and overexpression of these survival genes leads to excess survival of low-affinity GC B cells (39,40). Thus, cross-linking of coreceptor enhances upregulation of Bcl-2 (51) and Bcl-xl (52) and would enhance continued B-cell differentiation within the GC.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, efficient CSR of the NP ϩ B cells required an intact CR CD19 coreceptor. This could be explained by a requirement for coreceptor signaling for efficient Ag presentation to cognate T cells (38) and/or for enhanced up-regulation of survival genes, such as Bcl-2, cFLIP, or Bcl-xl (39,40). Interestingly, CSR was more efficient in the Cr2 ⌬/⌬gfp than Cr2 Ϫ/Ϫ B cells, suggesting that binding of C3-coated Ag (or CRP activity) could also contribute to CSR and survival.…”

Section: Gc Responses In Cr Mutantmentioning

confidence: 99%

Uncoupling CD21 and CD19 of the B-cell coreceptor

Barrington

Schneider

Pitcher

et al. 2009

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

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Complement receptors (CRs) CD21 and CD35 form a coreceptor with CD19 and CD81 on murine B cells that when coligated with the B-cell receptor lowers the threshold of activation by several orders of magnitude. This intrinsic signaling role is thought to explain the impaired humoral immunity of mice bearing deficiency in CRs. However, CRs have additional roles on B cells independent of CD19, such as transport of C3-coated immune complexes and regulation of C4 and C3 convertase. To test whether association of CR with CD19 is necessary for their intrinsic activation-enhancing role, knockin mice expressing mutant receptors, Cr2 ⌬/⌬gfp , that bind C3 ligands but do not signal through CD19 were constructed. We found that uncoupling of CR and CD19 significantly diminishes survival of germinal center B cells and secondary antibody titers. However, B memory is less impaired relative to mice bearing a complete deficiency in CRs on B cells. These findings confirm the importance of interaction of CR and CD19 for coreceptor activity in humoral immunity but identify a role for CR in B-cell memory independent of CD19. In mice, complement receptors CD21 and CD35 (CRs) are encoded at the Cr2 locus by splicing of message, and they are coexpressed primarily on B cells and follicular dendritic cells (FDCs) (5, 6). CD35 and CD21 bind similar split products of C3, but in addition CD35 binds C3b and C4b. CD35 also interacts with CD19 to form a B-cell coreceptor (7). Systemic blocking of CR by antibody (8-10) or soluble receptor (11) results in impaired humoral immunity. Likewise, mice deficient in the receptors (Cr2 Ϫ/Ϫ ) bear impaired B-cell immunity to T-independent (12-14) and T-dependent Ags (15-17), infectious bacteria (18), and viruses (19,20). Studies using chimeric mice expressing CRs on either B cells (16) or FDCs (21, 22) indicate that overall humoral immunity is dependent on the presence of the receptors on both cell types. Thus, intrinsic B-cell signaling by the coreceptor and retention of Ags on FDCs are both important in B-cell immunity.Recent studies demonstrate that CR expression on B cells is important in the transport of immune complexes (ICs). Bloodborne complexes of complement-coated Ags are bound rapidly by marginal zone (MZ) B cells and are transported into the splenic follicles (12,13,23), and Ag is offloaded to FDCs (24). An analogous role for CRs on follicular B cells in peripheral lymph nodes (LNs) was identified. ICs draining via afferent lymph are trapped by subcapsular sinus (SCS) macrophages and ''transferred'' to noncognate B cells in the underlying follicular region in a CR-dependent manner (25,26). The complement-coated ICs are then transported to FDCs in a manner similar to that proposed for MZ B cells. Thus, CRs have at least two intrinsic roles on B cells: coreceptor on cognate B cells, and transport of ICs by noncognate B cells. A third, less studied role for CRs on B cells is complement regulatory activity. All mammalian cells express complement regulatory proteins (CRPs), such as Decay Activating F...

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Relaxed Negative Selection in Germinal Centers and Impaired Affinity Maturation in bcl-xL Transgenic Mice

Cited by 104 publications

References 49 publications

Repertoire of Antibody Response in Bone Marrow and the Memory Response Are Differentially Affected in Aging Mice

Repertoire of Antibody Response in Bone Marrow and the Memory Response Are Differentially Affected in Aging Mice

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Uncoupling CD21 and CD19 of the B-cell coreceptor

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