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 5

Pathogenicity stratification of 18 HLA class I risk alleles with identified somatic mutations and other alleles analyzed in at least 20 patients.

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Pathogenicity stratification of 18 HLA class I risk alleles with identif...
Shown is a pairwise comparison matrix of relative mutation frequencies per individual HLA alleles HLA alleles are listed along the x axis, grouped by pathogenicity ranking. High-risk, high-intermediate, low-intermediate, and low-risk alleles are shown in decreasing intensity of red and non-risk alleles in green. B*38:02 and B*50:02 were insufficiently prevalent in the cohort for analysis — these were listed as indeterminate. The number of patient cases with mutations, total patients with listed allele, percentage mutation frequency, and median number of mutations per patient are listed in the header rows below each allele. Pairwise comparison of mutation frequencies is shown as a correlation matrix. Comparisons were performed by Fisher’s exact tests, with P value listed for each pair of alleles. P values < 0.05 are shaded in dark red for comparison OR > 1 or dark green for OR < 1. Trends with P ≥ 0.05 and P < 0.1 are shown in light red for OR > 1 and light green for OR < 1.