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Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

  • Systemic Lupus Erythematosus (G Tsokos, Section Editor)
  • Published:
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Abstract

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.

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Abbreviations

2-DG:

2-Deoxyglucose

5-hmC:

5-Hydroxmethylcytosine

ALT:

Alanine aminotransferase

ANA:

Anti-nuclear antibody

aPL:

Anti-phospholipid

APS:

Anti-phospholipid syndrome

AST:

Aspartate aminotransaminase

BAFF:

B cell-activating factor

CaMK4:

Calcium/calmodulin-dependent protein kinase IV

Cbl-b:

Casitas B-lineage lymphoma b

cGVHD:

Chronic graft versus host disease

CREM-α:

cAMP-responsive element modulator alpha

DN T cell:

CD3+CD4−CD8− double-negative T cell

DNA:

Deoxyribonucleic acid

dsDNA:

Double-stranded DNA

EBF1:

Early B cell factor 1

Egr:

Early growth response protein

ETC.:

Electron transport chain

GRAIL:

Gene related to anergy in lymphocytes

IFNγ:

Interferon gamma

IL-17:

Interleukin 17

iTreg:

inducible Treg

LAM:

Lymphangioleiomyomatosis

LN:

Lupus nephritis

miRNA:

microRNA

mRNA:

Messenger ribonucleic acid

MSC:

Mesenchymal stem cells

mTOR:

Mechanistic target of rapamycin

mTORC1:

mTOR complex 1

mTORC2:

mTOR complex 2

NAC:

N-acetylcysteine

NADH:

Nicotinamide adenine dinucleotide

NDUFS3:

NADH dehydrogenase iron-sulfur protein 3

PBMC:

Peripheral blood mononuclear cell

SLE:

Systemic lupus erythematosus

SLEDAI:

SLE disease activity index

snRNP:

Small nuclear ribonucleoproteins

TAL:

Transaldolase

TET:

Ten-eleven translocation methylcytosine dioxygenase

Tfh:

Follicular helper T cells

Th1:

T helper 1 cell

Th17:

T helper 17 cell

Th2:

T helper 2 cell

TLR7:

Toll-like receptor 7

TNF-α:

Tumor necrosis factor alpha

Treg:

Regulatory T cell

TSC:

Tuberous sclerosis complex

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Acknowledgments

This work was supported in part by grants AI072648, DK078922, AI122176, AI048079, and AR068052 from the National Institutes of Health, Investigator-Initiated Research Grant P0468X1-4470/WS1234172 from Pfizer, the American College of Rheumatology Research Foundation, and the Central New York Community Foundation.

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Authors and Affiliations

  1. Department of Medicine, College of Medicine, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Zachary Oaks, Thomas Winans, Nick Huang & Andras Perl

  2. Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA

    Zachary Oaks, Thomas Winans, Nick Huang & Andras Perl

  3. Department of Pathology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA

    Katalin Banki

  4. Department of Microbiology, and Immunology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA

    Andras Perl

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  1. Zachary Oaks
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Correspondence to Andras Perl.

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Drs. Oaks, Winans, Huang, Banki, and Perl declare no conflicts of interest relevant to this manuscript.

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Oaks, Z., Winans, T., Huang, N. et al. Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years. Curr Rheumatol Rep 18, 73 (2016). https://doi.org/10.1007/s11926-016-0622-8

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