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 1

Flowchart summarizing patient cohorts and methods used in this study.

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Flowchart summarizing patient cohorts and methods used in this study. Th...
The flowchart summarizes the study progression and lists the patient cohorts that were used for each analysis. (A) The analysis of somatic HLA loss and discovery of HLA risk alleles were performed in the 505-patient discovery cohort, which was composed of 156 patients from North American Pediatric Aplastic Anemia Consortium (NAPAAC cohort) and 349 patients enrolled in the Center of International Blood and Marrow Transplant Research (CIBMTR-discovery cohort). HLA mutation data generated from the discovery cohort were used for HLA pathogenicity stratification, which led to the identification of HLA risk and non-risk alleles. (B) HLA risk and non-risk alleles identified by studies in A were then evaluated for association with AA using an independent cohort of 6,323 patients with AA and 230,965 matched controls enrolled in the National Marrow Donor Program (NMDP). (C) Analysis of clinical outcomes following immunosuppressive therapy (IST) was performed in the 156-patient NAPAAC cohort, which included both pediatric and adult patients. (D) Analysis of clinical outcomes following allogeneic hematopoietic stem cell transplant (alloHSCT) was performed in an independent cohort (CIBMTR-outcomes cohort) of 484 AA patients who received matched related or unrelated donor (MRD/MUD) alloHSCT and were enrolled in the CIBMTR. Outcomes of haploidentical transplant were evaluated in a separate cohort of 29 patients with AA who underwent haploidentical transplant (CIBMTR-haplo). GVHD, graft-versus-host disease; SAA, severe aplastic anemia.