Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia

Muto, Hiroyuki; Katagiri, Takamasa; Kashiwase, Koichi; Shiina, Takashi; Sato‐Otsubo, Aiko; Zaimoku, Yoshitaka; Maruyama, Kana; Hosokawa, Kohei; Ishiyama, Ken; Yamazaki, Hirohito; Inoko, Hidetoshi; Ogawa, Seishi; Nakao, Shinji

doi:10.1016/j.exphem.2016.05.013

Cited by 22 publications

(15 citation statements)

References 27 publications

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“…1 A large body of in vitro evidence suggests the essential role of T cells in the development of AA, which includes the presence of T cells with particular T-cell receptor clonotypes, [2][3][4][5][6][7] cytotoxic T-cell clones capable of killing hematopoietic stem/progenitor cells (HSPCs), 2,4 and leukocytes that lack HLA class I antigens because of copy-number neutral loss of heterozygosity in the short arm of chromosome 6 (6pLOH). [8][9][10][11][12] Among these suggestive findings, the presence of 6pLOH (1) leukocytes is considered to be the most compelling evidence that cytotoxic T cells (CTLs) are involved in the development of bone marrow failure, because it represents the escape of HSPCs with 6pLOH from the attack of CTLs that are specific to autoantigens presented by the lacked HLA class I alleles. However, the incidence of 6pLOH in AA patients shown by several studies was at most 13%, and it is therefore unclear to what extent the HSPC-specific CTLs contribute to the development of AA and which HLA proteins are the most critically involved in the autoantigen presentation.…”

Section: Introductionmentioning

confidence: 99%

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

Zaimoku

Takamatsu

Hosomichi

et al. 2017

Blood

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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 to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[+] and 16 6pLOH[-]) patients with 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 with 6pLOH(+) (B4002A) granulocytes. Deep sequencing of the 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 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.

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Section: Introductionmentioning

confidence: 99%

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

Zaimoku

Takamatsu

Hosomichi

et al. 2017

Blood

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“…They found that 18 of 71 (25.4%) newly diagnosed patients and 25 of 73 (34.2%) previously treated AA patients had HLA-A allele-lacking leukocytes. These strongly suggest that HLA is involved in the pathogenesis of AA [62]. González-Galarza FF et.al determined that the frequency of HLA-B*40:02 was higher in Asian healthy controls, i.e.…”

Section: Genetic Susceptibilitymentioning

confidence: 95%

Pathogenesis of aplastic anemia

Wang

Liu

2019

Hematology

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Aplastic anemia (AA) is a rare and life-threatening bone marrow failure (BMF) that results in peripheral blood cytopenia and reduced bone marrow hematopoietic cell proliferation. The symptoms are similar to myelofibrosis, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) making diagnosis of AA complicated. The pathogenesis of AA is complex and its mechanism needs to be deciphered on an individualized basis. This review summarizes several contributions made in trying to understand AA pathogenesis in recent years which may be helpful for the development of personalized therapies for AA.

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“…[22][23][24] Another potential marker of an immunemediated aetiology for bone marrow failure is the presence of leukocytes lacking HLA-A alleles (HLA-LLs). 25,26 These cells develop from HSPCs with copy number-neutral loss of heterozygosity of the HLA-class I allele(s) owing to 6pUPD (uni-parental disomy of the short arm of chromosome 6). 25 It is important to consider these clones are present in normal bone marrow before immunemediated bone marrow failure develops and are selected because of the failure of non-mutated HSPCs.…”

Section: Can We Develop a Therapy Strategy Based On Pathophysiology Rmentioning

confidence: 99%

Are mild/moderate acquired idiopathic aplastic anaemia and low-risk myelodysplastic syndrome one or two diseases or both and how should it/they be treated?

Nakao

Gale

2016

Leukemia

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Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia

Cited by 22 publications

References 27 publications

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

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

Pathogenesis of aplastic anemia

Are mild/moderate acquired idiopathic aplastic anaemia and low-risk myelodysplastic syndrome one or two diseases or both and how should it/they be treated?

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