Fas-Mediated Apoptosis Eliminates B Cells That Acquire Self-Reactivity during the Germinal Center Response to NP

Hoch, Susan; Boyd, Mark T.; Malone, Barbara; Gonye, Gregory E.; Schwaber, James S.; Schwaber, Jerrold

doi:10.1006/cimm.2000.1681

Cited by 13 publications

(10 citation statements)

References 41 publications

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“…GC B cells express elevated levels of Fas, and cultured GC B cells are highly susceptible to Fasmediated apoptosis, which can be blocked by inhibiting caspase 8 (6)(7)(8). Fas deficiency results in impaired selection of high-affinity clones (9) and the emergence of self-reactive GC B cell clones (10). Alternatively, the intrinsic apoptotic pathway can be triggered by DNA damage that leads to the activation of caspase 9 (11,12).…”

mentioning

confidence: 99%

AID and Caspase 8 Shape the Germinal Center Response through Apoptosis

Boulianne

Rojas

Haddad

et al. 2013

The Journal of Immunology

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Germinal centers (GCs) are clusters of activated B cells that form in secondary lymphoid organs during a T-dependent immune response. B cells enter GCs and become rapidly proliferating centroblasts that express the enzyme activation-induced deaminase (AID) to undergo somatic hypermutation and class-switch recombination. Centroblasts then mature into centrocytes to undergo clonal selection. Within the GC, the highest affinity B cell clones are selected to mature into memory or plasma cells while lower affinity clones undergo apoptosis. We reported previously that murine Aicda−/− GC B cells have enhanced viability and accumulate in GCs. We now show that murine Aicda−/− GC B cells accumulate as centrocytes and inefficiently generate plasma cells. The reduced rate of plasma cell formation was not due to an absence of AID-induced DNA lesions. In addition, we show that the deletion of caspase 8 specifically in murine GC-B cells results in larger GCs and a delay in affinity maturation, demonstrating the importance of apoptosis in GC homeostasis and clonal selection.

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confidence: 99%

AID and Caspase 8 Shape the Germinal Center Response through Apoptosis

Boulianne

Rojas

Haddad

et al. 2013

The Journal of Immunology

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“…Additionally, the germinal centers of Fas-deficient mice harbor an elevated number of highly mutated B cells. These may represent B cells with lowered affinity for the immunogen and increased reactivity for self (17,18).…”

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confidence: 99%

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Mongini

Jackson

Tolani

et al. 2003

The Journal of Immunology

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Defective expression of Fas leads to B cell autoimmunity, indicating the importance of this apoptotic pathway in eliminating autoreactive B cells. However, B cells with anti-self specificities occasionally escape such regulation in individuals with intact Fas, suggesting ways of precluding this apoptosis. Here, we examine whether coligation of the B cell Ag receptor (BCR) with the complement (C3)-binding CD21/CD19/CD81 costimulatory complex can enhance the escape of human B cells from Fas-induced death. This was warranted given that BCR-initiated signals induce resistance to Fas apoptosis, some (albeit not all) BCR-triggered events are amplified by coligation of BCR and the co-stimulatory complex, and several self Ags targeted in autoimmune diseases effectively activate complement. Using a set of affinity-diverse surrogate Ags (receptor-specific mAb:dextran conjugates) with varying capacity to engage CD21, it was established that BCR:CD21 coligation lowers the BCR engagement necessary for inducing protection from Fas apoptosis. Enhanced protection was associated with altered expression of several molecules known to regulate Fas apoptosis, suggesting a unique molecular model for how BCR:CD21 coligation augments protection. BCR:CD21 coligation impairs the generation of active fragments of caspase-8 via dampened expression of membrane Fas and augmented expression of FLIPL. This, in turn, diminishes the generation of cells that would be directly triggered to apoptosis via caspase-8 cleavage of caspase 3 (type I cells). Any attempt to use the mitochondrial apoptotic protease-activating factor 1 (Apaf-1)-dependent pathway for apoptosis (as type II cells) is further blocked because BCR:CD21 coligation promotes up-regulation of the mitochondrial antiapoptotic molecule, Bcl-2.

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“…Self-reactive B cells arising from somatic hypermutation in the germinal centre die by apoptosis, making apoptosis a critical mechanism for inducing tolerance [16]. However, the signals that determine the faith of B cells have not yet been characterized fully.…”

Section: Discussionmentioning

confidence: 99%

“…An experimental model for these events is the suicide experiment (injection of a high dose of antigen during an established immune response against the antigen [18][19][20]). The importance of other apoptosis-inducing mechanisms, such as stimulation via a death-receptor (Fas/ CD95), remains a matter of controversy [16,27]. The present study was designed to define the role of complement C4 in antigen-induced apoptosis, and its effects on primary and secondary immune responses.…”

Section: Discussionmentioning

confidence: 99%

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Antigen-induced B cell apoptosis is independent of complement C4

Faust¹,

Finke²,

Klempt-Giessing³

et al. 2007

Clinical and Experimental Immunology

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SummaryDeficiencies in early complement components are associated with the development of systemic lupus erythematosus (SLE) and therefore early complement components have been proposed to influence B lymphocyte activation and tolerance induction. A defect in apoptosis is a potential mechanism for breaking of peripheral B cell tolerance, and we hypothesized that the lack of the early complement component C4 could initiate autoimmunity through a defect in peripheral B lymphocyte apoptosis. Previous studies have shown that injection of a high dose of soluble antigen, during an established primary immune response, induces massive apoptotic death in germinal centre B cells. Here, we tested if the antigen-induced apoptosis within germinal centres is influenced by early complement components by comparing complement C4-deficient mice with C57BL/6 wild-type mice. We demonstrate that after the application of a high dose of soluble antigen in wild-type mice, antibody levels declined temporarily but were restored almost completely after a week. However, after antigen-induced apoptosis, B cell memory was severely limited. Interestingly, no difference was observed between wild-type and complement C4-deficient animals in the number of apoptotic cells, restoration of antibody levels and memory response.

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Fas-Mediated Apoptosis Eliminates B Cells That Acquire Self-Reactivity during the Germinal Center Response to NP

Cited by 13 publications

References 41 publications

AID and Caspase 8 Shape the Germinal Center Response through Apoptosis

AID and Caspase 8 Shape the Germinal Center Response through Apoptosis

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Antigen-induced B cell apoptosis is independent of complement C4

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