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 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.

Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications

“…Indeed, while our manuscript was in preparation, Zaimoku and colleagues used flow cytometric methods to identify recurrent HLA-B *40:02 mutations in 28 Japanese aAA patients carrying HLA-B *40:02 allele 53 , pointing to the involvement of HLA-B *40:02 allele in aAA in Japan, which has a more restricted HLA pool and a significantly higher frequency of HLA-B *40:02 (Figure 5). Interestingly, the incidence of aAA is also 2–3-fold higher in East Asia 54 .…”

Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack

“…10 Although the hematopoiesis derived from iCD34 1 cells may be primitive rather than definitive hematopoiesis, the CTL line was able to discriminate WT iCD34 1 cells from B4002-lacking iCD34 1 cells in vitro, suggesting that our xenograft model can serve as an AA model in which antigen-specific T cells may selectively eliminate WT HSPCs in vivo. This study thus added a new piece of evidence to support the immune-mediated destruction of HSCs as a central pathogenic mechanism in this disease and opens new venues for the identification of autoantigens that trigger the autoimmune attack.…”

Molecular pathogenesis of acquired aplastic anemia

“…These recent findings further strengthen the role of HLA class I‐mediated autoimmunity in AA pathogenesis. Among the many identified HLA risk alleles, a version of the HLA‐B gene called HLA‐B*‐ 40:02 plays a critical role in AA pathogenesis . Lack of allele expression of HLA‐B* 40:02, either by loss of heterozygosity of 6p chromosome (6pLOH) or due to various SMs, allows for the escape of HSCs from the attack of cytotoxic T cells that are specific to autoantigens presented by the lacked HLA class I alleles.…”