Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia

Yoshitaka Zaimoku, Hiroyuki Takamatsu, Kazuyoshi Hosomichi, Tatsuhiko Ozawa, Noriharu Nakagawa, Tatsuya Imi, Hiroyuki Maruyama, Takamasa Katagiri, Hiroyuki Kishi, Atsushi Tajima, Atsushi Muraguchi, Koichi Kashiwase and Shinji Nakao
This article has an Erratum 130(8):1072

Key Points

  • Somatic mutations of HLA-B*40:02 are very frequently detected in granulocyte of patients with acquired aplastic anemia.

  • Antigen presentation via HLA-B4002 may play a critical role in the pathophysiology of acquired aplastic anemia.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


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[+] and 16 6pLOH[−]) 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(+) 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 (B4002A+), suggesting the frequent coexistence of granulocytes that underwent mutations restricted to HLA-B*40:02 with 6pLOH(+) (B4002A) granulocytes. Deep sequencing of the HLA-B*40:02 of sorted B4002A+ 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.

  • Submitted November 21, 2016.
  • Accepted February 20, 2017.
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