Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease.
Dysregulation of the "intrinsic" apoptotic pathway is associated with the development of cancer and autoimmune disease. Bak and Bax are two proapoptotic members of the Bcl-2 protein family with overlapping, essential roles in the intrinsic apoptotic pathway. Their activity is critical for the control of cell survival during lymphocyte development and homeostasis, best demonstrated by defects in thymic T-cell differentiation and peripheral lymphoid homeostasis caused by their combined loss. Because most bak(-/-)bax(-/-) mice die perinatally, the roles of Bax and Bak in immunological tolerance and prevention of autoimmune disease remain unclear. We show that mice reconstituted with a Bak/Bax doubly deficient hematopoietic compartment develop a fatal systemic lupus erythematosus-like autoimmune disease characterized by hypergammaglobulinemia, autoantibodies, lymphadenopathy, glomerulonephritis, and vasculitis. Importantly, these mice also develop a multiorgan autoimmune disease with autoantibodies against most solid glandular structures and evidence of glandular atrophy and necrotizing vasculitis. Interestingly, similar albeit less severe pathology was observed in mice containing a hematopoietic compartment deficient for only Bak, a phenotype reminiscent of the disease seen in patients with point mutations in BAK. These studies demonstrate a critical role for Bak and an ancillary role for Bax in safeguarding immunological tolerance and prevention of autoimmune disease. This suggests that direct activators of the intrinsic apoptotic pathway, such as BH3 mimetics, may be useful for treatment of diverse autoimmune diseases.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052,  Australia.
Kylie D
KD
Mason
Ann
A
Lin
Lorraine
L
Robb
Emma C
EC
Josefsson
Katya J
KJ
Henley
Daniel H D
DH
Gray
Benjamin T
BT
Kile
Andrew W
AW
Roberts
Andreas
A
Strasser
David C S
DC
Huang
Paul
P
Waring
Lorraine A
LA
O'Reilly
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D018925:Chemokines / Q000097:blood; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006652:Histological Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000276:immunology*
D001323:Autoantibodies; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D018925:Chemokines; D016207:Cytokines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein