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Therefore the aims of our study were to explore the expression of anergy\u2010related factors in <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4<jats:sup>+<\/jats:sup> T cells in relationship with regulatory T cells (Tregs) frequency in <jats:styled-content style=\"fixed-case\">SLE<\/jats:styled-content> patients and to identify strategies to redress these defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Casitas B\u2010cell lymphoma b (Cbl\u2010b) and \u2018gene related to anergy in lymphocytes' (GRAIL) proteins were analyzed in peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy donors (HD) by immunoblotting. cbl\u2010b, grail, growth response factors (egr)2 and egr3 messenger RNAs (<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>s) were evaluated by real\u2010time polymerase chain reaction in SLE and HD PBMCs and CD4<jats:sup>+<\/jats:sup> T cells. Phenotypic and functional characterization of CD4<jats:sup>+<\/jats:sup> T cells was performed by flow cytometry. Tregs expansion protocol consisted in culturing CD4<jats:sup>+<\/jats:sup> T cells for 14 or 21\u00a0days of experimental activation with anti\u2010CD3 and anti\u2010CD28 monoclonal antibodies, human recombinant interleukin (hrIL)\u20102, in the absence or presence of rapamycin (Rapa) or 1,25\u2010(OH)2D3 (vitamin D: VitD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SLE PBMCs expressed low levels of Cbl\u2010b and GRAIL proteins. Both SLE PBMCs and CD4<jats:sup>+<\/jats:sup> T cells expressed low levels of egr2\/3 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>s. SLE patients had a reduced number of Tregs with impaired suppressive activity. An association between egr2 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> level in CD4<jats:sup>+<\/jats:sup> T cells and Tregs percentage was identified. Experimental activation of CD4<jats:sup>+<\/jats:sup> T cells in the presence of hrIL\u20102 and Rapa or VitD induced the expansion of SLE Tregs. However, on long\u2010term, only Rapa exposure of SLE CD4<jats:sup>+<\/jats:sup> T cells yielded high numbers of Tregs with sustained suppressive activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results suggest a new strategy to correct defects in <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4<jats:sup>+<\/jats:sup> T cell tolerance mechanisms that may prove beneficial in <jats:styled-content style=\"fixed-case\">SLE<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1756-185x.12509","type":"journal-article","created":{"date-parts":[[2014,10,28]],"date-time":"2014-10-28T13:43:55Z","timestamp":1414503835000},"page":"1294-1303","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dysregulation of anergy\u2010related factors involved in regulatory <scp>T<\/scp> cells defects in Systemic Lupus Erythematosus patients: Rapamycin and Vitamin <scp>D<\/scp> efficacy in restoring regulatory <scp>T<\/scp> cells"],"prefix":"10.1111","volume":"19","author":[{"given":"Leontina M.","family":"Banica","sequence":"first","affiliation":[{"name":"Cantacuzino National Institute of Research and Development for Microbiology and Immunology, Cellular and Molecular Immunity Laboratory Bucharest Romania"},{"name":"Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest Bucharest Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alina N.","family":"Besliu","sequence":"additional","affiliation":[{"name":"Cantacuzino National Institute of Research and Development for Microbiology and Immunology, Cellular and Molecular Immunity Laboratory Bucharest Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gina C.","family":"Pistol","sequence":"additional","affiliation":[{"name":"Cantacuzino National Institute of Research and Development for Microbiology and Immunology, Cellular and Molecular Immunity Laboratory Bucharest Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crina","family":"Stavaru","sequence":"additional","affiliation":[{"name":"Cantacuzino National Institute of Research and Development for Microbiology and Immunology, Cellular and Molecular Immunity Laboratory Bucharest Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Violeta","family":"Vlad","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Internal Medicine Sf. 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