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 2

Somatic HLA loss in patients with AA.

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Somatic HLA loss in patients with AA. (A) Bar chart showing the frequenc...
(A) Bar chart showing the frequency of somatic HLA loss in patients with AA in the discovery cohort (CIBMTR-discovery and NAPAAC). Somatic HLA loss was detected as somatic mutations (red and purple bars) and/or acquired 6pCN-LOH (purple and blue bars) in 18.6% of NAPAAC cohort and 12.3% of CIBMTR-discovery cohort. (B) A schematic showing 86 somatic HLA mutations identified in the discovery cohort. The domains of HLA molecules include signal peptide (SP), the alpha-1 and alpha-2 domains forming the HLA peptide-binding pocket, and alpha-3 and transmembrane (TM) domains. Loss-of-function mutations due to loss of start (p.M1?), frameshift (fs), splice site (p.? splice), and nonsense variants (*) are shown in blue above the respective genes. Missense and in-frame deletion variants are shown in red below. The numbers refer to the amino acids in the full HLA protein. (C) A pie chart showing the breakdown of identified somatic HLA mutations by type. (D) Representative flow histograms showing surface HLA expression of mutant HLA alleles. Mutant (red and green) and wild-type (WT, blue) alleles were transfected into cell lines lacking endogenous HLA expression (untransfected, shown in dark gray). n = 3–4 replicates per allele, as shown. On the right is the summary analysis showing mean ± standard deviation for percentage of surface HLA expression normalized to the corresponding WT alleles. *P < 0.05, ****P < 0.0001, using ordinary 1-way ANOVA (nonparametric or mixed) in GraphPad Prism.