title: Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis.
abstract: Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kuriyama
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kohno
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Shinya
authors.initials: S
authors.lastname: Daitoku
authors.forename: Goichi
authors.initials: G
authors.lastname: Yoshimoto
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.forename: Junji
authors.initials: J
authors.lastname: Kishimoto
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Abe
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D057899:Cytophagocytosis / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000209:etiology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000235:genetics; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D051997:ADP-ribosyl Cyclase 1