PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr.
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.
Xie
Chun
C
Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Patel
Rahul
R
Wu
Tianfu
T
Zhu
Jiankun
J
Henry
Tamika
T
Bhaskarabhatla
Madhavi
M
Samudrala
Renuka
R
Tus
Katalin
K
Gong
Yimei
Y
Zhou
Hui
H
Wakeland
Edward K
EK
Zhou
Xin J
XJ
Mohan
Chandra
C
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D004843:Epistasis, Genetic; D000068338:Everolimus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D005810:Multigene Family / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D019014:fas Receptor / Q000235:genetics*
D001323:Autoantibodies; D007166:Immunosuppressive Agents; D019014:fas Receptor; D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus