Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease

Date

2013

Authors

Mason, K.D.
Lin, A.
Robb, L.
Josefsson, E.C.
Henley, K.J.
Gray, D.H.D.
Kile, B.T.
Roberts, A.W.
Strasser, A.
Huang, D.C.S.

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Journal article

Citation

Proceedings of the National Academy of Sciences of the United States of America, 2013; 110(7):2599-2604

Statement of Responsibility

Kylie D. Mason, Ann Lin, Lorraine Robb, Emma C. Josefsson, Katya J. Henley, Daniel H. D. Gray, Benjamin T. Kile, Andrew W. Roberts, Andreas Strasser, David C. S. Huang, Paul Waring and Lorraine A. O’Reilly

Conference Name

DOI

10.1073/pnas.1215097110

Abstract

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.

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For volumes 106–114 (2009–September 2017), the author(s) retains copyright to individual articles, and NAS retains an exclusive License to Publish these articles and holds copyright to the collective work. Volumes 90–105 (1993–2008) are copyright National Academy of Sciences. For volumes 1–89 (1915–1992), the author(s) retains copyright to individual articles, and NAS holds copyright to the collective work.

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Grant ID

http://purl.org/au-research/grants/nhmrc/461221
 http://purl.org/au-research/grants/nhmrc/461219
 http://purl.org/au-research/grants/nhmrc/637353
 http://purl.org/au-research/grants/nhmrc/516701
 http://purl.org/au-research/grants/nhmrc/637309
 http://purl.org/au-research/grants/nhmrc/575535
 http://purl.org/au-research/grants/nhmrc/637332
 http://purl.org/au-research/grants/nhmrc/1009145
 http://purl.org/au-research/grants/nhmrc/361646

Published Version

https://doi.org/10.1073/pnas.1215097110

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Persistent link to this record

http://hdl.handle.net/2440/121745