{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T13:23:01Z","timestamp":1794489781852,"version":"4.9.1"},"reference-count":74,"publisher":"American Society of Hematology","issue":"26","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR \u03b2 and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.<\/jats:p>","DOI":"10.1182\/blood.2021012900","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T15:50:52Z","timestamp":1636386652000},"page":"2781-2798","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":45,"title":["The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders"],"prefix":"10.1182","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4688-2478","authenticated-orcid":false,"given":"Simona","family":"Pagliuca","sequence":"first","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"},{"name":"University of Paris, Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-5544","authenticated-orcid":false,"given":"Carmelo","family":"Gurnari","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Awada","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwin","family":"Kishtagari","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, 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OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8002-5141","authenticated-orcid":false,"given":"Yihong","family":"Guan","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"LaFramboise","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7660-5255","authenticated-orcid":false,"given":"Babal K.","family":"Jha","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhumika J.","family":"Patel","sequence":"additional","affiliation":[{"name":"Leukemia Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty K.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Blood and Marrow Transplant Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7082-891X","authenticated-orcid":false,"given":"Navneet S.","family":"Majhail","sequence":"additional","affiliation":[{"name":"Blood and Marrow Transplant Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3146-9816","authenticated-orcid":false,"given":"Sofie","family":"Lundgren","sequence":"additional","affiliation":[{"name":"Hematology Research Unit Helsinki, University of Helsinki\u2013Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;"},{"name":"Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0816-8241","authenticated-orcid":false,"given":"Satu","family":"Mustjoki","sequence":"additional","affiliation":[{"name":"Hematology Research Unit Helsinki, University of Helsinki\u2013Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;"},{"name":"Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland;"},{"name":"ICAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9757-1031","authenticated-orcid":false,"given":"Yogen","family":"Saunthararajah","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Visconte","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Chan","sequence":"additional","affiliation":[{"name":"Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5445-0109","authenticated-orcid":false,"given":"Chao-Yie","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias L.","family":"Lenz","sequence":"additional","affiliation":[{"name":"Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Pl\u00f6n, Germany; and"},{"name":"Research Unit for Evolutionary Immunogenomics, Department of Biology, University of Hamburg, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslaw P.","family":"Maciejewski","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, 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