Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease

Abstract

T he development and maintenance of B lymphocytes is regulated at multiple checkpoints (1). Newly generated pro-B cells undergo B cell antigen-receptor (BCR) recombination in fetal liver and adult bone marrow (BM). B cells that fail to produce a functional BCR lack survival signals and thus undergo death by neglect (2). B cells that express surface BCRs that interact with self-antigens with too high affinity may be eliminated, at least in part, by apoptotic cell death, as well as anergy and receptor editing (3, 4). Immature B cells that successfully pass through developmental checkpoints in the BM migrate to the spleen as transitional B cells and undergo further maturation steps (5). The number of B lymphocytes in BM and secondary lymphoid organs is kept under tight control. Disruption of this homeostasis and accumulation of excess lymphocytes may give rise to the development of autoimmunity or malignancy.BCL-2 family member proteins are requisite for the maintenance of lymphocyte numbers by regulating an intrinsic apoptosis pathway (2, 6-8). The antiapoptotic members, including BCL-2, BCL-xL, and MCL-1, display sequence conservation in four BCL-2 homology domains (BH1-BH4). Multidomain proapoptotic members, including BAX and BAK, possess the BH1, BH2, and BH3 domains. The ''BH3-only'' proteins, including BID, BAD, BIM, NOXA, and PUMA, show homology only within this single amphipathic ␣-helical segment. BH3-only molecules function as upstream sentinels that sense cellular abnormalities, such as lack of survival signals or DNA damage. Activated BH3-only molecules trigger the oligomerization of multidomain proapoptotic BCL-2 members by sequestering antiapoptotics and͞or by direct activation of BAX or BAK (9-12). Oligomerization of BAX or BAK leads to the release of cytochrome c from mitochondria to the cytoplasm, causing the formation of the apoptosome and execution of cell death.The role of the BCL-2 family in B cell homeostasis has been analyzed intensively by using mouse models that either have overexpression or deletion of BCL-2 family molecules (2, 13-15). Overexpression of BCL-2 protects B cells from death by neglect and by negative selection, and causes the accumulation of B cells (13,16,17). In addition, lymphocytes from Bcl-2 transgenic mice show defects in cell cycle progression (18,19). In contrast, targeted deletion of the Bcl-2 gene in mice resulted in the massive loss of mature lymphocytes due to apoptosis, as well as increased turnover of thymocytes (15,20). Deletion of another antiapoptotic, MCL-1, resulted in the loss of B cells throughout their development (21). Among BH3 only molecules, only BIM is implicated in the homeostatic maintenance of lymphocytes. Bim-deficient mice are reported to show abnormal development of T lymphocytes and accumulation of lymphocytes in secondary lymphoid organs (20,22). Bim Ϫ/Ϫ B cells were resistant to apoptosis induced by the absence of IL-7 receptor signaling and by BCR ligation, and showed defective negative selection of B cells in vivo (23,24). In addition, Bi...

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

“…Recently a knockout of the Bcl-2 associated  protein (Bax) gene, located on proximal chromosome 7, was reported to have GN as one of its resulting phenotypes. 27 In light of the data presented herein, one cannot exclude the possibility that the observed GN phenotype may have been due to the surrounding 129 genome, and not the inactive Bax gene.…”

Apoptosis in the development of the immune system

“…50,51 This dramatic resistance appears to be more dramatic than the resistance observed in mice deficient in BIM demonstrating the critical role of BAX and BAK in integrating apoptotic signaling.…”

“…Most dramatically both pro-B-cells and immature B-cells were increased. 51 These developing B-cells were also very resistant to apoptosis induced by BCR crosslinking. The resistance of the BAX and BAK double-deficient cells is somewhat more dramatic than those observed in BIM-deficient B-cells, suggesting that there may the contribution of other BH3-only member(s).…”

“…17 These developmental defects are quite severe, often resulting in embryonic lethality, but the few surviving mice display increased numbers of hematopoietic progenitors, lymphocytes, and exhibit immune cell infiltration of tissues including liver and kidney. 17,51 Thymocytes from these animals are also extremely resistant to a variety of death stimuli demonstrating the critical role of BAX and BAK for modulating death from a variety of intrinsic and extrinsic stimuli. 17 When BAX and BAK doubly-deficient mice were tested to identify the extent of negative selection, they were found to be completely resistant to death induced by endogenous self-antigens.…”

“…48 A conditional BAX allele was generated and bred to BAKdeficient mice to analyze the effect of BAX and BAK loss in the B-cell lineage. 51 Deletion of BAX and BAK in B-cells results in the accumulation of developing B-cells. Most dramatically both pro-B-cells and immature B-cells were increased.…”