# The effects of somatic HLA class I allele mutations on antigen presentation in acquired aplastic anemia

> **NIH NIH R03** · UNIVERSITY OF PENNSYLVANIA · 2022 · $81,250

## Abstract

PROJECT SUMMARY
The aim of this proposal is to explore the functional significance of somatic mutations in peptide-binding domains
of Human Leukocyte Antigen (HLA) class I alleles in surviving hematopoietic cells of patients with acquired
aplastic anemia (AA). AA is an autoimmune bone marrow aplasia that occurs in previously healthy individuals
causing life-threatening cytopenias. Multiple lines of evidence, most notably the efficacy of T-cell directed immu-
nosuppressive therapy in AA, implicate T lymphocytes in autoimmune destruction of hematopoietic stem and
progenitor cells (HSPCs) in AA. Despite some progress, AA patients’ outcomes remain poor, and there is a
critical need to develop more effective therapies for AA. The main barrier to progress has been the poor under-
standing of specific mechanisms of autoimmunity in AA. Neither the antigenic target nor the causes of autoim-
munity have been identified. Understanding the immune pathogenesis of AA is essential for developing therapies
that can more effectively treat AA and prevent its complications. In previous studies of acquired mutations in AA,
we identified recurrent mutations in HLA class I alleles in surviving hematopoietic cells of AA patients. The en-
hanced survival of HLA class I-mutant cells underscored the critical role of HLA class I in mediating the autoim-
mune recognition of HSPCs in AA. HLA alleles disrupted by somatic mutations are thought to be responsible for
autoantigen presentation in the affected patients (function as “risk alleles”). Their somatic inactivation allows
mutant HSPCs to evade the autoimmune attack. While 80% of the identified mutations led to the loss of mutant
HLA alleles’ expression, 20% of mutations were predicted to form a functional HLA protein. Notably, eight muta-
tions were amino acid changes located in the alpha (α)-1 and α-2 domains of the HLA peptide-binding pocket,
which could be especially informative about residues critical for AA autoantigen binding. These data support our
central hypothesis that autoimmune attack in AA is directed against AA autoantigen(s) presented by specific
HLA class I alleles, and somatic HLA mutations can disrupt autoantigen presentation in AA by abrogating HLA
risk allele expression or its autoantigen binding. To address our hypothesis, we will evaluate the functional con-
sequences of mutations in peptide-binding domains of HLA alleles in AA patients in two integrated aims. Aim 1
will use cellular assays to determine the effects of HLA missense mutations on HLA processing and surface
stability. Aim 2 will use proteomics to define the HLA class I immunopeptidome of cells expressing wild-type
and mutant HLA alleles. Our results will define structural features of AA HLA risk alleles necessary for autoanti-
gen binding, forming the foundation for future studies of candidate AA autoantigens. AA is a devastating disease,
yet its underlying immunological mechanisms remain unknown. Our studies will fill this critical need...

## Key facts

- **NIH application ID:** 10347646
- **Project number:** 1R03HL160678-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daria Babushok
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $81,250
- **Award type:** 1
- **Project period:** 2022-01-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347646

## Citation

> US National Institutes of Health, RePORTER application 10347646, The effects of somatic HLA class I allele mutations on antigen presentation in acquired aplastic anemia (1R03HL160678-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10347646. Licensed CC0.

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