TY - JOUR
T1 - Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia
AU - Zaimoku, Yoshitaka
AU - Takamatsu, Hiroyuki
AU - Hosomichi, Kazuyoshi
AU - Ozawa, Tatsuhiko
AU - Nakagawa, Noriharu
AU - Imi, Tatsuya
AU - Maruyama, Hiroyuki
AU - Katagiri, Takamasa
AU - Kishi, Hiroyuki
AU - Tajima, Atsushi
AU - Muraguchi, Atsushi
AU - Kashiwase, Koichi
AU - Nakao, Shinji
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/5/25
Y1 - 2017/5/25
N2 - 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 revealed HLA-B∗40:02 to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[1] and 16 6pLOH[2]) patients with HLA-B∗40:02 for 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(1) patients but also in 9 (56%) of the 166pLOH(2) patients. Furthermore, 10 (83%) of the 12 6pLOH(1) 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 to HLA-B∗40:02 with 6pLOH(1) (B4002-A-) granulocytes. Deep sequencing of the HLA-B∗40:02 of 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 of HLA-B∗40:02 that 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.
AB - 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 revealed HLA-B∗40:02 to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[1] and 16 6pLOH[2]) patients with HLA-B∗40:02 for 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(1) patients but also in 9 (56%) of the 166pLOH(2) patients. Furthermore, 10 (83%) of the 12 6pLOH(1) 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 to HLA-B∗40:02 with 6pLOH(1) (B4002-A-) granulocytes. Deep sequencing of the HLA-B∗40:02 of 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 of HLA-B∗40:02 that 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.
UR - http://www.scopus.com/inward/record.url?scp=85019661382&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-11-752378
DO - 10.1182/blood-2016-11-752378
M3 - 学術論文
C2 - 28232583
AN - SCOPUS:85019661382
SN - 0006-4971
VL - 129
SP - 2908
EP - 2916
JO - Blood
JF - Blood
IS - 21
ER -