title: Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis.
abstract: We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.
authors.affiliation: Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan. ichiro.murakami.09@gmail.com.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Murakami
authors.affiliation: Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, Yonago, 683-8503, Japan. michikohavefun@gmail.com.
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan. iwasakit-path@umin.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan. s.quamoto@gmail.com.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwamoto
authors.affiliation: Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan. makato@med.tottori-u.ac.jp.
authors.forename: Masako
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan. nanamon@theia.ocn.ne.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Department of Pathology, Tottori University Hospital, Yonago, 683-8503, Japan. yhorie-ttr@umin.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Horie
authors.affiliation: Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, 683-8503, Japan. khayashi32@gmail.com.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan. timamura@sa3.so-net.ne.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Pediatrics, Jichi Medical University School of Medicine, Shimotsuke, 329-0498, Japan. akira@jichi.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Morimoto
authors.affiliation: Division of Pediatrics and Hematology, Takasago-seibu Hospital, Takasago, 676-0812, Japan. shinim95@mbox.kyoto-inet.or.jp.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Imashuku
authors.affiliation: Inserm U507 and U1016, Institut Cochin, Paris, 75014, France. jean.gogusev@gmail.com.
authors.forename: Jean
authors.initials: J
authors.lastname: Gogusev
authors.affiliation: University of Paris Descartes (Paris V), Paris, 75006, France. jaubert.francis@live.fr.
authors.forename: Francis
authors.initials: F
authors.lastname: Jaubert
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8530, Japan. katsuyoshi.t@h5.dion.ne.jp.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Takata
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8530, Japan. oka@md.okayama-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8530, Japan. yoshino@md.okayama-u.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002465:Cell Movement; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D007375:Interleukin-1; D020381:Interleukin-17; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6