Skip Navigation


International Immunology Advance Access originally published online on March 15, 2007
International Immunology 2007 19(4):509-522; doi:10.1093/intimm/dxm017
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
19/4/509    most recent
dxm017v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Xie, C.
Right arrow Articles by Mohan, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xie, C.
Right arrow Articles by Mohan, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr

Chun Xie1,*, Rahul Patel1,*, Tianfu Wu1,*, Jiankun Zhu1, Tamika Henry1, Madhavi Bhaskarabhatla1, Renuka Samudrala1, Katalin Tus2, Yimei Gong1, Hui Zhou3, Edward K. Wakeland2, Xin J. Zhou3,* and Chandra Mohan1,*

1 Division of Rheumatology, Department of Internal Medicine
2 Center for Immunology
3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

Correspondence to: X. J. Zhou, E-mail: Joseph.zhou{at}utsouthwestern.edu; C. Mohan, E-mail: Chandra.mohan{at}utsouthwestern.edu

Previous studies have demonstrated that the NZM2410/NZW ‘z’ allele of Sle1 on telomeric murine chromosome 1 led to lymphoproliferative autoimmunity, when acting in concert with the FASlpr defect on the C57BL/6 background. The present report shows that the Sle1b sub-locus, harboring the NZM2410/NZW ‘z’ allele of SLAM, in epistasis with FASlpr, may be sufficient to induce lymphoproliferative autoimmunity. Disease in this simplified genetic model is accompanied by significant activation of the AKT signaling axis in both B- and T cells, as evidenced by increased phosphorylation of AKT, mTOR, 4EBP-1 and p70S6K, resulting from increased PI3K and reduced PTEN activity. In addition, blocking this axis using RAD001, an mTOR inhibitor, ameliorated lymphoproliferation and modulated serum IgG anti-nuclear auto-antibodies. Finally, mTOR inhibition also dampened signaling via parallel axes, including the MAPK and NFkB pathways. Hence, hypersignaling via the PI3K/AKT/mTOR axis appears to be an important mechanism underlying autoimmune lymphoproliferative disease, presenting itself as a potential target for therapeutic intervention.

Keywords: auto-antibodies, kinases/phosphatases, signal transduction, systemic lupus erythematosus

* These authors have contributed equally as lead authors.

Transmitting editor: P. Ohashi

Received 27 June 2006, accepted 24 January 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Leukoc. Biol.Home page
J. Kang, S. J. Huddleston, J. M. Fraser, and A. Khoruts
De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR
J. Leukoc. Biol., May 1, 2008; 83(5): 1230 - 1239.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.