title: Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia.
abstract: To gain insight into the origin and clinical significance of leukocytes that lack human leukocyte antigen A (HLA-A) allele expression caused by a copy-number-neutral loss of heterozygosity in the short arm of chromosome 6 in patients with acquired aplastic anemia (AA), we used a high-sensitivity flow cytometry assay to investigate the presence of HLA-A allele-lacking leukocytes (HLA-LLs) in 144 AA patients. HLA-LLs, accounting for 0.2-99.8% of each leukocyte population, were detected in 18 of 71 (25.4%) newly diagnosed patients and in 25 of 73 (34.2%) previously treated patients. The lineage combination patterns of the HLA-LLs in the 43 HLA-LL(+) patients were granulocytes (Gs), monocytes (Ms), B cells (Bs), and T cells (Ts; GMBT) in 13 cases, GMB in 16 cases, GM in 11 cases, and B alone in three cases. The response rate to antithymocyte globulin plus cyclosporine therapy (100%) and the 2-year, failure-free survival rate (100%) in 8 newly diagnosed HLA-LL(+) patients were significantly higher than in 23 HLA-LL(-) patients (52.2% for both). These data suggest that HLA-LLs are a useful marker of the presence of immune pathophysiology in AA and that T-cell attacks against hematopoietic progenitor cells, rather than against hematopoietic stem cells, can trigger bone marrow failure in AA patients.
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Clinical Laboratory Science, Division of Health Sciences, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Katagiri
authors.affiliation: Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tatsumi, Koto-ku, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiina
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoecho, Sakyo-ku, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Zaimoku
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Hosokawa
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishiyama
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoecho, Sakyo-ku, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan. Electronic address: snakao8205@staff.kanazawa-u.ac.jp.
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 / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D015415:Biomarkers; D019070:Cell Lineage / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use; D056915:DNA Copy Number Variations; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D015415:Biomarkers; D015234:HLA-A Antigens; D016572:Cyclosporine