FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen.

Smith, Kenneth G. C.; Nossal, G. J. V.; Tarlinton, David M.

doi:10.1073/pnas.92.25.11628

Cited by 122 publications

(93 citation statements)

References 22 publications

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“…5A). In addition, consistent with the observations that expression of PNA and Fas is up-regulated on germinal center B cells (34,35), the staining shows that CD40 ϩ cells are exclusively represented among the PNA high and Fas high cells (Fig. 5, B and C …”

Section: Cd40 ϩ B Cells Are Selectively Activated To Become Germinal supporting

confidence: 75%

Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells

Kim

Flaño

Woodland

et al. 2003

The Journal of Immunology

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It has been proposed that the γ-herpesviruses maintain lifelong latency in B cells by gaining entry into the memory B cell pool and taking advantage of host mechanisms for maintaining these cells. We directly tested this hypothesis by kinetically monitoring viral latency in CD40+ and CD40− B cells from CD40+CD40− mixed bone marrow chimera mice after infection with a murine γ-herpesvirus, MHV-68. CD40+ B cells selectively entered germinal centers and differentiated into memory B cells. Importantly, latency was progressively lost in the CD40− B cells and preferentially maintained in the long-lived, isotype-switched CD40+ B cells. These data directly demonstrate viral exploitation of the normal B cell differentiation pathway to maintain latency.

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Section: Cd40 ϩ B Cells Are Selectively Activated To Become Germinal supporting

confidence: 75%

Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells

Kim

Flaño

Woodland

et al. 2003

The Journal of Immunology

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“…High doses of soluble Ags have been shown to induce apoptosis of germinal center B cells (22,23), and introduction of a Bcl-2 transgene allowed B cells with dual specificity for a foreign and self-Ag to be recovered from germinal center B cells (24,25). If B cells develop an increased sensitivity to apoptosis as they enter the germinal center pathway (as suggested by elevated levels of Fas expression) (42)(43)(44), the ubiquitous expression of PR8 HA could induce apoptosis of PR8 HA-specific B cells more rapidly than T3 HA-specific B cells and T3 HA-specific B cells may then be at a competitive advantage for niches that can be filled by cells receiving positively selecting or survival signals from CD4 ϩ T cells. The defining characteristic of somatic hypermutation in B cells is the reproducible selection of rare cells that have enhanced reactivity toward an immunizing agent, implying that their selection is based on competition for niches that provide survival signals based on goodness of fit (2)(3)(4).…”

Section: Discussionmentioning

confidence: 99%

Specificity-Based Negative Selection of Autoreactive B Cells during Memory Formation

Guay

Panarey

Reed

et al. 2004

The Journal of Immunology

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Autoreactive B cells are not completely purged from the primary B cell repertoire, and whether they can be prevented from maturation into memory B cells has been uncertain. We show here that a population of B cells that dominates primary immune responses of BALB/c mice to influenza virus A/PR/8/34 hemagglutinin (HA) are negatively selected in transgenic mice expressing PR8 HA as an abundant membrane-bound Ag (HACII mice). However, a separate population of B cells that contains precursors of memory B cells is activated by PR8 virus immunization and is subsequently negatively selected during the formation of the memory response. Negative selection of PR8 HA-specific B cells altered the specificity of the memory B cell response to a mutant virus containing a single amino acid substitution in a B cell epitope. Strikingly, this skewed reactivity resulted from an increase in the formation of memory B cells directed to non-self-epitopes on the mutant virus, which increased 8-fold in HACII mice relative to nontransgenic mice and precisely compensated for the absence of autoreactive PR8 HA-specific memory B cells. Negative selection of PR8 HA-specific B cells was a dominant process, since B cells from HACII mice could induce negative selection of PR8 HA-specific B cells from BALB/c mice. Lastly, HA-specific memory responses were unaffected by self-tolerance in another lineage of HA-transgenic mice (HA104 mice), indicating that the amount and/or cell type in which self-Ags are expressed can determine their ability to prevent autoreactive memory B cell formation.

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“…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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FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen.

Abstract: In establishing the memory B-cell population and maintaining self-tolerance

Cited by 122 publications

References 22 publications

Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells

Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells

Specificity-Based Negative Selection of Autoreactive B Cells during Memory Formation

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

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