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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\u2013discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p &amp;lt; 0.0005); increased mitochondrial mass of CD3+\/CD4\u2212\/CD8\u2212 double-negative (DN) T cells (p = 1.1 \u00d7 10\u221222) and FOXP3 depletion in CD4+\/CD25+ T cells were top contributors (p = 6.7 \u00d7 10\u22127). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase \u2265 4) relative to 61 visits of remission (SLEDAI decrease \u2265 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1301005","type":"journal-article","created":{"date-parts":[[2013,8,3]],"date-time":"2013-08-03T05:06:52Z","timestamp":1375506412000},"page":"2236-2246","source":"Crossref","is-referenced-by-count":148,"title":["Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus Erythematosus"],"prefix":"10.1093","volume":"191","author":[{"given":"Zhi-Wei","family":"Lai","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Borsuk","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwini","family":"Shadakshari","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghong","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Dawood","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Garcia","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Francis","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajra","family":"Tily","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Bartos","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen V","family":"Faraone","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Phillips","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andras","family":"Perl","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"},{"name":"Department of Microbiology and Immunology, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"},{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Upstate Medical University, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,9,1]]},"reference":[{"key":"2025032405232955600_r1","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1056\/NEJMra1100359","article-title":"Systemic lupus erythematosus","volume":"365","author":"Tsokos","year":"2011","journal-title":"N. 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