The microanatomic segregation of selection by apoptosis in the germinal center

Mayer, Christian T.; Gazumyan, Anna; Kara, Elodie; Gitlin, Alexander D.; Golijanin, Jovana; Viant, Charlotte; Pai, Joy A.; Oliveira, Thiago Y.; Wang, Qiao; Escolano, Amelia; Medina-Ramírez, Max; Sanders, Rogier W.; Nussenzweig, Michel C.

doi:10.1126/science.aao2602

Cited by 204 publications

(234 citation statements)

References 52 publications

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“…GC B cells with high affinity BCR express high densities of pMHCII, which in turn, increase the quality of T FH proliferation signals that promote GC B-cell division (16, 17, 24, 25). It is unclear whether GC B cells with higher BCR affinity also gain fitness through increased survival; contrary to the conclusions of early studies (20, 21, 26), recent experiments suggest that GC apoptosis is linked weakly, if at all, to BCR affinity (27). Regardless, the current T-cell help model for affinity-driven selection in GCs posits that higher-affinity GC B cell populations outstrip lower-affinity competitors by positive – not negative – selection.…”

Section: Introductionmentioning

confidence: 84%

Germinal center responses to complex antigens

Finney

Yeh

Kelsoe

et al. 2018

Immunological Reviews

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Germinal centers (GCs) are the primary sites of antibody affinity maturation, sites where B-cell antigen-receptor (BCR) genes rapidly acquire mutations and are selected for increasing affinity for antigen. This process of hypermutation and affinity-driven selection results in the clonal expansion of B cells expressing mutated BCRs and acts to hone the antibody repertoire for greater avidity and specificity. Remarkably, whereas the process of affinity maturation has been confirmed in a number of laboratories, models for how affinity maturation in GCs operates are largely from studies of genetically restricted B-cell populations competing for a single hapten epitope. Much less is known about GC responses to complex antigens, which involve both inter- and intraclonal competition for many epitopes. In this review, we (i) compare current methods for analysis of the GC B-cell repertoire, (ii) describe recent studies of GC population dynamics in response to complex antigens, discussing how the observed repertoire changes support or depart from the standard model of clonal selection, and (iii) speculate on the nature and potential importance of the large fraction of GC B cells that do not appear to interact with native antigen.

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Section: Introductionmentioning

confidence: 84%

Germinal center responses to complex antigens

Finney

Yeh

Kelsoe

et al. 2018

Immunological Reviews

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“…Survival signals include those provided by the interaction between costimulatory molecules, CD28-B7, CD40-CD154 and ICOS-ICOSL, and by cytokines such as IL-21 and BAFF. In the absence of these signals, B cells undergo apoptosis, while positively selected B cells migrate into the dark zone to undergo cell proliferation and BCR diversification through Ig somatic hypermutation (SMH) mediated by activation-induced cytidine deaminase (AID) (23, 24), (25, 26). One consequence of AID activity is damage of BCR genes and apoptosis of these B cells, while those with intact BCR exit the dark zone and reenter the light zone where their newly generated BCR are tested for binding to antigen and access to T cell help (25).…”

Section: How Naïve B Cells Differentiate Into Antibody Secreting Cellmentioning

confidence: 99%

“…In the absence of these signals, B cells undergo apoptosis, while positively selected B cells migrate into the dark zone to undergo cell proliferation and BCR diversification through Ig somatic hypermutation (SMH) mediated by activation-induced cytidine deaminase (AID) (23, 24), (25, 26). One consequence of AID activity is damage of BCR genes and apoptosis of these B cells, while those with intact BCR exit the dark zone and reenter the light zone where their newly generated BCR are tested for binding to antigen and access to T cell help (25). Following repeated rounds of entry and exit from the dark zone (reviewed in (22)), post-GC B cells emerge as plasma cells (PC) that are ultimately responsible for persistent circulating antibodies, or as memB cells that are responsible for the recall antibody response upon antigen reencounter.…”

Section: How Naïve B Cells Differentiate Into Antibody Secreting Cellmentioning

confidence: 99%

Heterogeneity of memory B cells

Chong

Ansari

2018

American Journal of Transplantation

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Potential solid organ transplant recipients broadly sensitized to HLA have long wait times, low transplant rates and poor outcomes. The new kidney allocation system has improved access to the most highly sensitized recipients; however, their long-term outcomes are unknown. Emerging data suggest that memory B cell repertoire is broader than the plasma cell repertoire, therefore, despite refinements in anti-HLA antibody detection technology, donor-specific HLA- specific memory B cells may in fact be present in some, if not most, highly sensitized recipients with no detectable donor-specific antibodies. In addition, new findings have underscored the heterogeneity in memory B cell generation, and in the signals that determine memory versus plasma cell fate during primary antigen encounter, as well as memory B cell differentiation upon antigen reencounter into plasma cells or reentry into germinal centers to subsequently emerge as higher affinity and class-switched plasma cells. Thus, heterogeneity memory B cells generation may affect the efficacy of specific immunomodulation during the recall response. We propose that the ability to quantify donor-specific B cell in transplant recipients is urgently required to provide insights into the mechanisms of sensitization and recall, and for the early detection of acute and chronic AMR.

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“…Many repeated rounds of antibody diversification and affinity-based selection lead over time to dramatic improvements in antibody affinities and pathogen neutralizing abilities. GC B cells that do not receive T FH signals die by apoptosis and are rapidly phagocytosed by tingible body macrophages 31 . Cells exit the germinal center either as memory B cells, or as plasma blasts 32,33 .…”

Section: Introductionmentioning

confidence: 99%

New dimensions in intravital multi-photon imaging of immune reactions

Niesner¹

2017

J Immunological Sci

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In the last two decades intravital multi-photon imaging has become a central tool to investigate cellular and molecular dynamics of immune reactions in vivo. Currently, challenges in exploiting the full power of this technology include limitations on the number of simultaneously detectable parameters as well as in expanding the acquisition in time and space. Here we discuss technological advancements developed in order to overcome these challenges and focus on the example of germinal center reactions as multi-parametric immunological processes evolving over a time course of days and weeks.

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The microanatomic segregation of selection by apoptosis in the germinal center

Cited by 204 publications

References 52 publications

Germinal center responses to complex antigens

Germinal center responses to complex antigens

Heterogeneity of memory B cells

New dimensions in intravital multi-photon imaging of immune reactions

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