Timothy S Olson, Children's Hospital of Philadelphia
Benjamin F Frost, University of Pennsylvania
Jamie L Duke, Children's Hospital of Philadelphia
Marian Dribus, Tulane University School of Medicine
Hongbo M Xie, Children's Hospital of Philadelphia
Zachary D Prudowsky, Baylor College of Medicine
Elissa Furutani, Harvard Medical School
Jonas Gudera, Dr. von Hauner Children's Hospital
Yash B Shah, Thomas Jefferson UniversityFollow
Deborah Ferriola, Children's Hospital of Philadelphia
Amalia Dinou, Children's Hospital of Philadelphia
Ioanna Pagkrati, Children's Hospital of Philadelphia
Soyoung Kim, Medical College of Wisconsin
Yixi Xu, National Marrow Donor Program/Be The Match
Meilun He, National Marrow Donor Program/Be The Match
Shannon Zheng, University of Pennsylvania
Sally Nijim, University of Pennsylvania
Ping Lin, University of Pennsylvania
Chong Xu, University of Pennsylvania
Taizo A Nakano, Children's Hospital Colorado
Joseph H Oved, Memorial Sloan Kettering Cancer Center
Beatriz M Carreno, University of Pennsylvania
Yung-Tsi Bolon, National Marrow Donor Program/Be The Match
Shahinaz M Gadalla, National Cancer Institute
Steven Ge Marsh, Anthony Nolan Research Institute and University College London Cancer Institute
Sophie Paczesny, Medical University of South Carolina
Stephanie J Lee, Fred Hutchinson Cancer Research Center
Dimitrios S Monos, University of Pennsylvania
Akiko Shimamura, Harvard Medical School
Alison A Bertuch, Baylor College of Medicine
Loren Gragert, Tulane University School of Medicine
Stephen R Spellman, National Marrow Donor Program/Be The Match
Daria V Babushok, University of Pennsylvania

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This article is the author’s final published version in JCI Insight, Volume 7, Issue 22, November 2022, Article number e163040.

The published version is available at Copyright © Olson et al.


Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.

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Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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