NDLI: Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus.

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Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus.

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Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Faraone, Stephen V. Lai, Zhi-Wei Francis, Lisa Tily, Hajra Perl, Andras Shadakshari, Ashwini Yu, Jianghong Garcia, Ricardo Bartos, Adam Phillips, Paul Borsuk, Rebecca Dawood, Maha
Description	Country affiliation: United States Author Affiliation: Lai ZW ( Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York, Syracuse, NY 13210, USA.)
Abstract	The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis 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 with 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 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. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1301005
Journal	The Journal of Immunology
Issue Number	5
Volume Number	191
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Interleukin-4 Lupus Erythematosus, Systemic Immunology T-lymphocytes Tor Serine-threonine Kinases Clinical Trials As Topic Flow Cytometry Immunosuppressive Agents Therapeutic Use Biosynthesis Metabolism Pathology Necrosis Sirolimus Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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