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• W1995741752 abstract "The cause of idiopathic aplastic anaemia (AA) has not been clarified, but some evidence supports the role of T cell-mediated autoimmune destruction of haematopoietic stem/progenitor cells (HSPCs; Young & Maciejewski, 1997). The condition of approximately 70% of patients with idiopathic AA has been observed to improve after immunosuppressive therapy (IST; Bacigalupo et al, 2000; Kojima et al, 2000). In vitro monoclonal or oligoclonal expansion of CD8+ T-cells has been noted in patients with idiopathic AA (Risitano et al, 2004). However, the target antigens of T cells have not been clearly identified. Katagiri et al (2011) reported that a considerable proportion of Japanese patients with idiopathic AA acquired copy number-neutral loss of heterozygosity of the 6p arms (6pLOH), leading to loss of one human leucocyte antigen (HLA) haplotype. Moreover, the missing haplotype was concentrated in particular alleles: HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. Furthermore, Japanese patients with idiopathic AA typically inherited only those four HLA alleles (Katagiri et al, 2011). These findings suggest that these HLA alleles are the target antigens of T cells in the pathogenesis of idiopathic AA and 6pLOH is the mechanism by which HSPCs escape from autoreactive cytotoxic T-lymphocytes (CTL). In this study, we report a patient with idiopathic AA who carried a nonsense mutation in an HLA allele. Tracing the case history with fluctuations in her HLA typing illustrated how HSPCs escape from autoimmune insult. A 2-year-old girl was diagnosed with severe acquired AA. Neither chromosomal abnormalities nor morphological dysplasia was observed in her bone marrow cells. Serological HLA typing was performed using the Terasaki–NIH Standard method, revealing that her phenotypes (A24/-, B55/B61, DR8/DR9) completely matched those of her father. She received immunosuppressive therapy for 20 months, leading to partial remission, but she relapsed with thrombocytopenia 7 months after discontinuing IST. Although she was retreated with IST, regular blood transfusions had been required since the age of 5 years. Therefore, stem cell transplantation was scheduled at the age of 7 years. Confirmation of her HLA type by high-resolution sequencing-based typing of a peripheral blood sample, revealed a nonsense mutation (CAG to TAG) at codon 54 in exon 2 of either HLA-B*40:02 or HLA-B*55:02 (Fig 1A). In contrast, no mutation in HLA-B alleles was found in either of her parents. To resolve the discrepancy, we re-examined the serological HLA typing by the same method. Analysis of her blood sample demonstrated that the HLA-B61 antigen, corresponding to HLA-B*40:02, became serologically poor; 5/6 anti-HLA-B61 antisera were negative (11–20% were dead cells) and the remainder was weakly positive (21–40% dead cells), whereas anti-HLA-B55 antisera were strongly positive (81–100% dead cells) (data not shown). For a closer examination, we performed cloning analysis of HLA-B DNA from peripheral blood mononuclear cells and buccal epithelial cells. We observed that the mutation was located in HLA-B*40:02, inherited from her mother, and the mosaicism of wild-type and mutant HLA-B*40:02 alleles was restricted to blood cells (Fig 1B,C). The patient received bone marrow transplantation from her father (HLA-B allele-mismatched donor). The bone marrow graft was eventually rejected after initial engraftment. Therefore, she received peripheral blood stem cell transplantation from the same donor. Fortunately, the second transplantation succeeded, despite the development of severe graft-versus-host disease. We confirmed that she was a complete donor chimera with no HLA-B*40:02 mutant signals 4 years after transplantation (data not shown). We identified the acquisition of a nonsense mutation in HLA-B*40:02 in a patient with idiopathic AA refractory to IST. Because HLA-B*40:02 is a possible target antigen of T cells in idiopathic AA (Katagiri et al, 2011), we assume that acquisition of this mutation is not an accidental event but is caused by immunological escape and selection. In other words, after discontinuing IST, activated CTLs killed HSPCs that expressed HLA-B*40:02, whereas HSPCs carrying the mutation survived with a growth advantage over other HSPCs, expressing HLA-B*40:02. Therefore, nonsense mutation is presumed to be a novel mechanism by which HSPCs can evade autoreactive CTLs similarly to that observed for 6pLOH. In conclusion, our case suggests that HLA-B*40:02 is one of the target antigens of T cells in idiopathic AA and a nonsense mutation in a particular HLA allele is a possible molecular origin of clonal escape with no involvement of 6pLOH. Further research is required to confirm our conclusion. The authors thank the patient, her parents and paediatricians including T. Suzuki, F. Yamazaki and Y. Sato of the Fuji Heavy Industries Health Insurance Society, Ota General Hospital for contributing to this study. T. Osumi and H. Shimada designed the study and wrote the paper, M. Miharu and H. Shimada were responsible for the patient's overall treatment, H. Saji, Y. Kusunoki and H. Kojima performed the mutation analysis, J. Nakamura performed the serological HLA typing, H. Saji and H. Shimada performed critical interpretation and all authors approved the final version of the manuscript. No conflicts of interest to declare." @default.
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• W1995741752 title "Nonsense mutation in<i>HLA-B*40:02</i>in a case with acquired aplastic anaemia: a possible origin of clonal escape from autoimmune insult" @default.
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