Pathogenicity and Impact of HLA Class I Alleles in Aplastic Anemia Patients of Different Ethnicities
Document Type
Article
Publication Date
11-22-2022
Abstract
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.
Recommended Citation
Olson, Timothy S; Frost, Benjamin F; Duke, Jamie L; Dribus, Marian; Xie, Hongbo M; Prudowsky, Zachary D; Furutani, Elissa; Gudera, Jonas; Shah, Yash B; Ferriola, Deborah; Dinou, Amalia; Pagkrati, Ioanna; Kim, Soyoung; Xu, Yixi; He, Meilun; Zheng, Shannon; Nijim, Sally; Lin, Ping; Xu, Chong; Nakano, Taizo A; Oved, Joseph H; Carreno, Beatriz M; Bolon, Yung-Tsi; Gadalla, Shahinaz M; Marsh, Steven Ge; Paczesny, Sophie; Lee, Stephanie J; Monos, Dimitrios S; Shimamura, Akiko; Bertuch, Alison A; Gragert, Loren; Spellman, Stephen R; and Babushok, Daria V, "Pathogenicity and Impact of HLA Class I Alleles in Aplastic Anemia Patients of Different Ethnicities" (2022). Department of Medicine Faculty Papers. Paper 397.
https://jdc.jefferson.edu/medfp/397
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
36219480
Language
English
Comments
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 https://doi.org/10.1172/jci.insight.163040. Copyright © Olson et al.