title: Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia.
abstract: Idiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-A expression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents "escapes" hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant auto-antigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA.
authors.affiliation: Clinical Laboratory Science, Division of Health Sciences, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Katagiri
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Satoko
authors.initials: S
authors.lastname: Morishima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mori
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.forename: Kohei
authors.initials: K
authors.lastname: Hosokawa
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ohtake
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000741:Anemia, Aplastic / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D005787:Gene Frequency; D006680:HLA Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006239:Haplotypes; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D006680:HLA Antigens; D015235:HLA-B Antigens