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 6

Comparisons of peptide-binding pocket residues and peptide repertoire motifs for AA risk and non-risk HLA alleles.

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Comparisons of peptide-binding pocket residues and peptide repertoire mo...
(A) A high-resolution crystal structure of HLA-B*14:02 (Protein Data Bank 3BVN; ref. 50), highlighting the location of previously established key residues (shown in yellow, listed in B) within the peptide-binding groove, which determines peptide-binding specificity for each allele. (B and C) Alignment of key residues in the HLA-binding groove showing peptide-binding pocket structure for groups of AA risk (B) and non-risk (C) alleles. Amino acids in alignment are listed using a single-letter amino acid code and colored using the “Rasmol/shapely” color scheme according to amino acid properties: D, E — bright red; C, M — bright yellow; K, R — medium blue; S, T — orange; F, Y — dark blue; Q, N — cyan, G — light gray; L, V, I — green; A — dark gray; W — pink; H — pale blue. Three risk alleles (HLA-B*55:02, HLA-B*54:01, and HLA-A*02:05), previously reported by other groups (11, 13, 15, 16, that share peptide-binding pocket structures with our identified risk alleles are included in the analysis. (D and E) Shown are the logo plots of 9–amino acid HLA class I peptides plotted based on experimentally obtained immunopeptidome data from HLA class I monoallelic cell lines (23). Logo plots for identified risk alleles with available immunopeptidome data are shown in D and for non-risk alleles in E. Alleles are grouped by HLA supertype assignment and peptide-binding pocket identify. Risk and non-risk (NR) supermotifs characterizing groups of alleles based on peptide-binding pocket identity are labeled. Of note, non-risk alleles HLA-B*44:02 and HLA-B*44:03 share the B44 supermotif with HLA-B*40:02 but have distinct requirements for aromatic and polar residues at the C-terminus.