title: Pre-B cell leukemia homeobox 1 is associated with lupus susceptibility in mice and humans.
abstract: Sle1a.1 is part of the Sle1 susceptibility locus, which has the strongest association with lupus nephritis in the NZM2410 mouse model. In this study, we show that Sle1a.1 results in the production of activated and autoreactive CD4(+) T cells. Additionally, Sle1a.1 expression reduces the peripheral regulatory T cell pool, as well as induces a defective response of CD4(+) T cells to the retinoic acid expansion of TGF-β-induced regulatory T cells. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d overexpression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells and to decrease their apoptotic response to retinoic acid. PBX1-d is expressed more frequently in the CD4(+) T cells from lupus patients than from healthy controls, and its presence correlates with an increased central memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Cuda
authors.forename: Shiwu
authors.initials: S
authors.lastname: Li
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liang
authors.forename: Yiming
authors.initials: Y
authors.lastname: Yin
authors.forename: Hari Hara S K
authors.initials: HH
authors.lastname: Potula
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Xu
authors.forename: Mayami
authors.initials: M
authors.lastname: Sengupta
authors.forename: Yifang
authors.initials: Y
authors.lastname: Chen
authors.forename: Edward
authors.initials: E
authors.lastname: Butfiloski
authors.forename: Henry
authors.initials: H
authors.lastname: Baker
authors.forename: Lung-Ji
authors.initials: LJ
authors.lastname: Chang
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.forename: Eric S
authors.initials: ES
authors.lastname: Sobel
authors.forename: Laurence
authors.initials: L
authors.lastname: Morel
mesh_terms: D000328:Adult; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D020033:Protein Isoforms / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012326:RNA Splicing / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human