Volume 16 Supplement 1

Lupus 2014: New Targets, New Approaches

Open Access

mTOR activation triggers proinflammatory expansion of IL-4-producing and necrosis-prone double-negative T cells, precedes flares, and serves as target for treatment in patients with systemic lupus erythematosus

  • Zhi-Wei Lai1,
  • Rebecca Borsuk1,
  • Ashwini Shadakshari1,
  • Jianghong Yu1,
  • Maha Dawood1,
  • Ricardo Garcia1,
  • Lisa Francis1,
  • Hajra Tily1,
  • Adam Bartos1,
  • Stephen V Faraone1,
  • Paul Phillips1 and
  • Andras Perl1Email author
Arthritis Research & Therapy201416(Suppl 1):A25

https://doi.org/10.1186/ar4641

Published: 18 September 2014

Background

Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and the mechanistic target of rapamycin (mTOR), serine/threonine protein kinase, undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N-acetylcysteine, blocks mTOR activation and improves disease activity in lupus-prone mice and patients with SLE. While mTOR has been also recognized as an effector of T-cell lineage development, its role in autoimmunity and disease activation remain unclear.

Methods

Here, we prospectively examined mitochondrial dysfunction and mTOR in PBL relative to SLEDAI and BILAG disease activity indices during 274 visits of 59 patients and 54 healthy subjects matched for each patient blood donation. A total of 212 metabolic biomarkers and traditional biomarkers, anti-DNA, C3, and C4, were evaluated by partial least-square discriminant analysis (PLS-DA). False discovery rate (FDR) P values were determined for each contributing biomarker and considered significant at P < 0.000236 with correction for multiple comparisons (0.05/212). Medication use was compared between patient groups exhibiting flare and remission with chi-square and Fischer's exact tests.

Results

PLS-DA identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (P < 0.0005); increased mitochondrial mass of CD3+/CD4-/CD8- double-negative (DN) T cells (P = 1.1 × 10-22) and FoxP3 depletion in CD4+/CD25+ T cells were top contributors (P = 6.7 × 10-7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+ B cells. Rapamycin treatment in vivo reduced SLEDAI and BILAG, blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25+/CD4+T cells, and expanded CD25+/CD19+ B cells.

Conclusions

These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells, predictor of disease flares, and effective target for treatment in patients with SLE.

Declarations

Acknowledgements

This work was supported in part by grants AI072648 and AT04332 from the National Institutes of Health, the Alliance for Lupus Research, and the Central New York Community Foundation [http://ClinicalTrials.gov:NCT00775476, http://ClinicalTrials.gov:NCT00779194].

Authors’ Affiliations

(1)
State University of New York, Upstate Medical University, College of Medicine

Copyright

© Lai et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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