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International Immunology Advance Access published online on March 15, 2007
International Immunology, doi:10.1093/intimm/dxm017
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© 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: 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.


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