Through a glass less darkly: apoptosis and the germinal center response to antigen

Abstract

Summary: The regulation of cell death is crucial for normal immune responses. Apoptosis is required for appropriate affinity‐based recruitment of B cells into an immune response, for the normal expansion, contraction – and thereby selection – of B cells within germinal centers, and also for the normal expansion, contraction, and persistence of plasma cells, both extrafollicular and germinal center‐derived. In this review, we focus on the intrinsic pathway of apoptosis, which is mediated by the interaction of pro‐ and anti‐apoptotic members of the Bcl‐2 family of proteins. Early, relatively crude studies using transgene‐mediated over‐expression of pro‐survival proteins or germline‐encoded loss of pro‐apoptotic proteins demonstrated clearly the consequences of dysregulation of this apoptosis pathway on immunity. More recent studies have both been more targeted and extensive, meaning that a large number of Bcl‐2 family members have been assessed for roles in immune regulation in a relatively precise manner. These studies are revealing a level of specialization in the use of the pro‐survival proteins during immune responses, with several showing what appear to be stage‐specific contributions. Lastly, we consider the involvement of Bcl‐2 family proteins in the transformation of B cells at distinct stages of the response to antigen, comparing this involvement with that in the normal processes.

Human t(14;18)positive germinal center B cells: a new step in follicular lymphoma pathogenesis?

“…17 This approach revealed variable amounts of isolated PAX-5 pos BCL2 pos B cells within the GC in t (14;18) hi RLNs, whereas such cells were essentially undetectable in the GC from t (14;18) neg samples (supplemental Figure 1) pos memory B cells previously described in peripheral blood. 9,18 However, the number of t (14;18) pos cells outside the GC was higher in t(14;18) hi than in negative RLNs and probably included post-GC FLLCs.…”

Transcription factors regulating B cell fate in the germinal centre

“…Apoptosis induced by the loss of 'environmental cues' such as growth factor withdrawal or loss of BCR signalling is initiated by pro-apoptotic members of the BCL2 family of proteins (including BIM, BAD, BIK and BAX), while it is prevented by the anti-apoptotic BCL2 factors [BCL2, BCLXL and myeloid cell leukaemia 1 (MCL1)]. Thus, a B cell's apoptotic potential is determined by the balance between pro-apoptotic and anti-apoptotic signalling (reviewed in Peperzak et al [70]). Although apoptosis, or rather its inhibition, impinges upon many aspects of B cell biology, it appears to be most critical to the regulation of PC differentiation.…”

“…In the GC, B cells undergo rapid clonal expansion (proliferation) and express the genome mutator enzyme V C 2015 British Society for Immunology, Clinical and Experimental Immunology, 183: [65][66][67][68][69][70][71][72][73][74][75] activation-induced cytidine deaminase (AID). AID is indispensible for two key GC processes, somatic hypermutation (SHM) and class-switch recombination (CSR).…”

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

“…9). In the germinal center, in which Bach2 is important ), many proliferating cells eventually undergo apoptosis (Peperzak et al 2012). What happens to the heme they contain?…”