Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities
Timothy S. Olson, … , Stephen R. Spellman, Daria V. Babushok
Timothy S. Olson, … , Stephen R. Spellman, Daria V. Babushok
Published October 11, 2022
Citation Information: JCI Insight. 2022;7(22):e163040. https://doi.org/10.1172/jci.insight.163040.
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Research Article Hematology

Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities

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.

Authors

Timothy S. Olson, Benjamin F. Frost, Jamie L. Duke, Marian Dribus, Hongbo M. Xie, Zachary D. Prudowsky, Elissa Furutani, Jonas Gudera, Yash B. Shah, Deborah Ferriola, Amalia Dinou, Ioanna Pagkrati, Soyoung Kim, Yixi Xu, Meilun He, Shannon Zheng, Sally Nijim, Ping Lin, Chong Xu, Taizo A. Nakano, Joseph H. Oved, Beatriz M. Carreno, Yung-Tsi Bolon, Shahinaz M. Gadalla, Steven G.E. Marsh, Sophie Paczesny, Stephanie J. Lee, Dimitrios S. Monos, Akiko Shimamura, Alison A. Bertuch, Loren Gragert, Stephen R. Spellman, Daria V. Babushok

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Figure 7

Association analysis of risk and non-risk HLA alleles with AA in the NMDP cohort.

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Association analysis of risk and non-risk HLA alleles with AA in the NMD...
Shown are statistically significant associations of between risk and non-risk HLA-A and -B alleles in different racial and ethnic groups, using the higher stringency multiple-testing adjustment FDR Padj < 0.05 (A) and unadjusted P < 0.05 (B). ORs with 95% CI are shown for individual alleles, color-coded for different ethnicities (Asian & Pacific Islander — pink downward triangles; Black — red squares; Hispanic — blue upward triangles; Native American — black diamonds; White — green circles). All details for association study analysis for the risk and non-risk HLA alleles for each of the ethnic groups, including the numbers of patients with AA and controls with each allele; the frequencies of alleles in patients and controls; the ORs; the 95% CIs; and the P values, including P values adjusted for multiple testing, are included in Supplemental Table 5.