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

Chun Xie | Zendy; Rahul Patel | Zendy; Tianfu Wu | Zendy; Jinfang Zhu | Zendy; Thomas Henry | Zendy; Madhavi Bhaskarabhatla | Zendy; Ram Samudrala | Zendy; Katalin Tus | Zendy; Yulong Gong | Zendy; Hui Zhou | Zendy; Edward K. Wakeland | Zendy; Xin Zhou | Zendy; Chandra Mohan | Zendy

Open Access

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

Author(s) -

Chun Xie,

Rahul Patel,

Tianfu Wu,

Jinfang Zhu,

Thomas Henry,

Madhavi Bhaskarabhatla,

Ram Samudrala,

Katalin Tus,

Yulong Gong,

Hui Zhou,

Edward K. Wakeland,

Xin Zhou,

Chandra Mohan

Publication year - 2007

Publication title -

international immunology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.86

H-Index - 134

eISSN - 1460-2377

pISSN - 0953-8178

DOI - 10.1093/intimm/dxm017

Subject(s) - pi3k/akt/mtor pathway , protein kinase b , autoimmunity , lymphoproliferative disease , cancer research , pten , autoimmune lymphoproliferative syndrome , phosphorylation , lymphoproliferative response , allele , immunology , medicine , signal transduction , biology , antibody , apoptosis , lymphoma , microbiology and biotechnology , genetics , programmed cell death , gene , in vitro , peripheral blood mononuclear cell , fas receptor

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 FAS(lpr) 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 FAS(lpr), 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.

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