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Nonsense mutation in HLA‐B*40:02 in a case with acquired aplastic anaemia: a possible origin of clonal escape from autoimmune insult

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, HLAA*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