title: In vivo transformation of mouse conventional CD8alpha+ dendritic cells leads to progressive multisystem histiocytosis.
abstract: Division and proliferation of dendritic cells (DCs) have been proposed to contribute to homeostasis and to prolonged antigen presentation. Whether abnormal proliferation of dendritic cells causes Langerhans cell histiocytosis (LCH) is a highly debated topic. Transgenic expression of simian virus 40 (SV40) T antigens in mature DCs allowed their transformation in vivo while maintaining their phenotype, function, and maturation capacity. The transformed cells were differentiated splenic CD8 alpha-positive conventional dendritic cells with increased Langerin expression. Their selective transformation was correlated with higher steady-state cycling compared with CD8 alpha-negative DCs in wild-type and transgenic mice. Mice developed a DC disease involving the spleen, liver, bone marrow, thymus, and mesenteric lymph node. Surprisingly, lesions displayed key immunohistologic features of Langerhans cell histiocytosis, including expression of Langerin and absence of the abnormal mitoses observed in Langerhans cell sarcomas. Our results demonstrate that a transgenic mouse model with striking similarities to aggressive forms of multisystem histiocytosis, such as the Letterer-Siwe syndrome, can be obtained by transformation of conventional DCs. These findings suggest that conventional DCs may cause some human multisystem LCH. They can reveal shared molecular pathways for human histiocytosis between humans and mice.
authors.affiliation: Department of Biochemistry, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
authors.forename: Quynh-Giao
authors.initials: QG
authors.lastname: Steiner
authors.forename: Luc A
authors.initials: LA
authors.lastname: Otten
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Gürkan
authors.initials: G
authors.lastname: Kaya
authors.forename: Frederic
authors.initials: F
authors.lastname: Grosjean
authors.forename: Estelle
authors.initials: E
authors.lastname: Saeuberli
authors.forename: Christine
authors.initials: C
authors.lastname: Lavanchy
authors.forename: Friedrich
authors.initials: F
authors.lastname: Beermann
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: McClain
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000235:genetics; D016827:CD8 Antigens / Q000276:immunology*; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology*; D005819:Genetic Markers; D049452:Green Fluorescent Proteins / Q000235:genetics; D006646:Histiocytosis, Langerhans-Cell / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D039521:CD11c Antigen; D016827:CD8 Antigens; C431698:CD8alpha antigen; D017931:DNA Primers; D005819:Genetic Markers; D049452:Green Fluorescent Proteins