{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:33:03Z","timestamp":1759365183642,"version":"build-2065373602"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018502","name":"Kanazawa University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018502","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>T-cell-mediated severe aplastic anemia (SAA) is typically fatal without prompt hematopoietic stem cell transplantation or intensive immunosuppressive therapy. Although rare cases of spontaneous remission have been reported, the underlying mechanisms remain poorly understood. A 24-year-old woman was incidentally found to have mild pancytopenia during a routine workplace health checkup. Over the subsequent 12 months, her pancytopenia gradually worsened, resulting in exertional dyspnea, purpura, and a diagnosis of SAA. Remarkably, her blood counts began to improve spontaneously 11 days after the diagnosis without any treatment or transfusions. She no longer met the criteria for SAA by day 27 and achieved complete hematologic normalization within three months. At 22 months, flow cytometry and targeted sequencing revealed that 69% of her granulocytes lacked the <jats:italic>HLA-A*02:01<\/jats:italic>-<jats:italic>C*03:04<\/jats:italic>-<jats:italic>B*40:02<\/jats:italic>-<jats:italic>DRB1*14:54<\/jats:italic> haplotype due to acquired loss of heterozygosity, while 23% were glycosylphosphatidylinositol-deficient owing to <jats:italic>PIGA<\/jats:italic> mutations. Retrospective digital polymerase chain reaction of diagnostic bone marrow demonstrated that nearly all non-lymphoid cells had already been replaced by HLA allele-lacking clones, whereas glycosylphosphatidylinositol-deficient erythrocytes constituted only 0.25%. These findings suggest that hematologic recovery occurred through the selective expansion of mutant hematopoietic stem cells capable of evading persistent T-cell-mediated destruction. Early identification of HLA allele-lacking leukocytes may help predict spontaneous remission and avoid unnecessary intensive therapy in patients with SAA.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1635943","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:50:02Z","timestamp":1759297802000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case report: Spontaneous remission of severe aplastic anemia mediated by mutant hematopoietic stem cells evading T-cell attack"],"prefix":"10.3389","volume":"16","author":[{"given":"Kohei","family":"Shiroshita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitaka","family":"Zaimoku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Himari","family":"Kudo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoshi","family":"Obara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuyoshi","family":"Hosomichi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yui","family":"Kano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miku","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eriko","family":"Morishita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Takamatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaaki","family":"Toyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Nakao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1413485","article-title":"Aplastic anemia","volume":"379","author":"Young","year":"2018","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198301203080301","article-title":"Antithymocyte globulin treatment in patients with aplastic anemia: a prospective randomized trial","volume":"308","author":"Champlin","year":"1983","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-08-693481","article-title":"How I treat acquired aplastic anemia","volume":"129","author":"Bacigalupo","year":"2017","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-274019","article-title":"How I treat acquired aplastic anemia","volume":"120","author":"Scheinberg","year":"2012","journal-title":"Blood"},{"key":"B5","article-title":"Spontaneous remission of aplastic anemia: a retrospective analysis","volume":"86","author":"Lee","year":"2001","journal-title":"Haematologica"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/1024533021000024067","article-title":"Pregnancy associated aplastic anemia\u2013a series of 10 cases with review of literature","volume":"7","author":"Choudhry","year":"2002","journal-title":"Hematology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/s0165-4608(02)00519-8","article-title":"Spontaneous clinical and cytogenetic remission of aplastic anemia in a patient with del(13q)","volume":"136","author":"Saitoh","year":"2002","journal-title":"Cancer Genet Cytogenet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-06-2485","article-title":"Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia","volume":"107","author":"Sugimori","year":"2006","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.15443","article-title":"Advances in understanding the pathogenesis of acquired aplastic anaemia","volume":"182","author":"Luzzatto","year":"2018","journal-title":"Br J Haematol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-11-314393","article-title":"SNP array-based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes","volume":"117","author":"Afable","year":"2011","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-365189","article-title":"Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia","volume":"118","author":"Katagiri","year":"2011","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-11-752378","article-title":"Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia","volume":"129","author":"Zaimoku","year":"2017","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017010918","article-title":"Somatic HLA mutations expose the role of class I-mediated autoimmunity in aplastic anemia and its clonal complications","volume":"1","author":"Babushok","year":"2017","journal-title":"Blood Adv"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.247809","article-title":"A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia","volume":"106","author":"Mizumaki","year":"2021","journal-title":"Haematologica"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012895","article-title":"HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia","volume":"138","author":"Zaimoku","year":"2021","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.163040","article-title":"Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities","volume":"7","author":"Olson","year":"2022","journal-title":"JCI Insight"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01723-w","article-title":"Molecular landscape of immune pressure and escape in aplastic anemia","volume":"37","author":"Pagliuca","year":"2023","journal-title":"Leukemia"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199511093331904","article-title":"Natural history of paroxysmal nocturnal hemoglobinuria","volume":"333","author":"Hillmen","year":"1995","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017013953","article-title":"Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia","volume":"2","author":"Imi","year":"2018","journal-title":"Blood Adv"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020010586","article-title":"HLA class I allele-lacking leukocytes predict rare clonal evolution to MDS\/AML in patients with acquired aplastic anemia","volume":"137","author":"Hosokawa","year":"2021","journal-title":"Blood"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19712","article-title":"Haematopoietic regeneration by HLA-A*0206-deficient clones in severe aplastic anaemia without definitive immunosuppressive treatment","volume":"205","author":"Zaimoku","year":"2024","journal-title":"Br J Haematol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1182\/bloodadvances.2017013342","article-title":"Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack","volume":"2","author":"Espinoza","year":"2018","journal-title":"Blood Adv"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004201","article-title":"The predictive value of PNH clones, 6p CN-LOH, and clonal TCR gene rearrangement for aplastic anemia diagnosis","volume":"5","author":"Shah","year":"2021","journal-title":"Blood Adv"},{"key":"B24","doi-asserted-by":"publisher","first-page":"281.e1","DOI":"10.1016\/j.jtct.2023.11.013","article-title":"HLA class I allele loss and bone marrow transplantation outcomes in immune aplastic anemia","volume":"30","author":"Zaimoku","year":"2024","journal-title":"Transplant Cell Ther"},{"key":"B25","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1056\/NEJMoa1414799","article-title":"Somatic mutations and clonal hematopoiesis in aplastic anemia","volume":"373","author":"Yoshizato","year":"2015","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.1182\/blood-2024-193818","article-title":"Efficacy and safety of eltrombopag added to rabbit anti-human thymocyte globulin+cyclosporine in aplastic anemia: results from a prospective multicenter phase II study [abstract","volume":"144","author":"Ishiyama","year":"2024","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01202-8","article-title":"Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia","volume":"35","author":"Yoroidaka","year":"2021","journal-title":"Leukemia"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-06-1669","article-title":"Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria","volume":"100","author":"Murakami","year":"2002","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01549-6","article-title":"Frequent HLA-DR loss on hematopoietic stem progenitor cells in patients with cyclosporine-dependent aplastic anemia carrying HLA-DR15","volume":"36","author":"Tsuji","year":"2022","journal-title":"Leukemia"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024025975","article-title":"Pathogenesis of paroxysmal nocturnal hemoglobinuria","author":"Luzzatto","year":"2025","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1635943\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:50:03Z","timestamp":1759297803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1635943\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,1]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2025.1635943"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1635943","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,1]]},"article-number":"1635943"}}