title: Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia.
abstract: To identify HLA alleles closely involved in the autoantigen presentation in acquired aplastic anemia (AA), we studied the HLA allelic loss frequencies of 312 AA patients, including 43 patients with loss of heterozygosity of 6p chromosome (6pLOH). An analysis of the HLA alleles contained in the lost haplotype revealedHLA-B*40:02to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[+] and 16 6pLOH[-]) patients withHLA-B*40:02for the presence of leukocytes lacking HLA-B4002 (B4002-) using a new monoclonal antibody specific to this allele, B4002-granulocytes were detected not only in all 6pLOH(+) patients but also in 9 (56%) of the 16 6pLOH(-) patients. Furthermore, 10 (83%) of the 12 6pLOH(+) patients possessed 1.0% to 78% B4002-granulocytes that retained the HLA-A allele on the same haplotype (B4002-A+), suggesting the frequent coexistence of granulocytes that underwent mutations restricted toHLA-B*40:02with 6pLOH(+) (B4002-A-) granulocytes. Deep sequencing of theHLA-B*40:02of sorted B4002-A+granulocytes revealed various somatic mutations, such as frameshift, nonsense, and splice site mutations, in all 15 patients studied. Surprisingly, missense mutations in the α-3 domain ofHLA-B*40:02that are not involved in the antigen presentation were detected exclusively in the B4002+granulocytes of 3 patients possessing B4002-granulocytes. The markedly high prevalence of leukocytes lacking HLA-B4002 as a result of either 6pLOH or structural gene mutations, or both, suggests that antigen presentation by hematopoietic stem/progenitor cells to cytotoxic T cells via the HLA-B allele plays a critical role in the pathogenesis of AA.
authors.affiliation: Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.|Department of Internal Medicine, Keiju Medical Center, Nanao, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Zaimoku
authors.affiliation: Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hosomichi
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Noriharu
authors.initials: N
authors.lastname: Nakagawa
authors.affiliation: Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Imi
authors.affiliation: Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Clinical Laboratory Science, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan; and.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Katagiri
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishi
authors.affiliation: Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
authors.affiliation: Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
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 / Q000473:pathology; D017951:Antigen Presentation / Q000235:genetics*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000473:pathology; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D059947:HLA-B40 Antigen / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D001324:Autoantigens; D015234:HLA-A Antigens; D059947:HLA-B40 Antigen