Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years.
The mechanistic target of rapamycin (mTOR) is a central regulator in cell growth, activation, proliferation, and survival. Activation of the mTOR pathway underlies the pathogenesis of systemic lupus erythematosus (SLE). While mTOR activation and its therapeutic reversal were originally discovered in T cells, recent investigations have also uncovered roles in other cell subsets including B cells, macrophages, and "non-immune" organs such as the liver and the kidney. Activation of mTOR complex 1 (mTORC1) precedes the onset of SLE and associated co-morbidities, such as anti-phospholipid syndrome (APS), and may act as an early marker of disease pathogenesis. Six case reports have now been published that document the development of SLE in patients with genetic activation of mTORC1. Targeting mTORC1 over-activation with N-acetylcysteine, rapamycin, and rapalogs provides an opportunity to supplant current therapies with severe side effect profiles such as prednisone or cyclophosphamide. In the present review, we will discuss the recent explosion of findings in support for a central role for mTOR activation in SLE.
Department of Medicine, College of Medicine, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA.|Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA.
Zachary
Z
Oaks
Department of Medicine, College of Medicine, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA.|Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA.
Thomas
T
Winans
Department of Medicine, College of Medicine, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA.|Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA.
Nick
N
Huang
Department of Pathology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA.
Katalin
K
Banki
Department of Medicine, College of Medicine, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA. perla@upstate.edu.|Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA. perla@upstate.edu.|Department of Microbiology, and Immunology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA. perla@upstate.edu.
Andras
A
Perl
D000111:Acetylcysteine / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000378:metabolism*; D020123:Sirolimus / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000111:Acetylcysteine
Anti-phospholipid antibodies; B cells; Kidney; Liver; Macrophages; Mechanistic target of rapamycin; Mitochondria; Systemic lupus erythematosus; T cells