Targets of Autoimmune Attack in Acquired Aplastic Anemia

Identifying the autoantigens and T cell clonotypes driving immune attack in aplastic anemia to enable more precise diagnostics and targeted therapies.
Completed Cross-Cutting & Special Populations Other Rare Autoimmune Diseases Adaptive Immunity Autoantigens Biological & Mechanistic Biomarker Discovery Data-Driven & Quantitative Experimental Platforms & Models Human Genetics Immune Profiling In Vitro Models Machine Learning & AI T Cell Biology Therapeutic Development Translational & Clinical

Funding Year: 2023

Project Overview

Aplastic anemia is a rare autoimmune disease in which the immune system attacks the bone marrow, causing dangerous drops in blood cell production. Current treatments — bone marrow transplant or broad immunosuppression — are ineffective for many patients and carry significant toxicity. This project investigates the specific autoantigens targeted by T and B lymphocytes in AA, using immunopeptidomic analysis, machine learning, and a novel in vitro model of HLA-restricted T cell expansion to identify candidate autoantigens and autoreactive T cell clonotypes. Key findings reveal that somatic missense HLA mutations enable hematopoietic stem cell survival by disrupting immune recognition through three mechanisms: loss of surface expression, peptide binding alterations, and disruption of CD8 co-receptor engagement — providing functional evidence for HLA-mediated immune escape in AA.

Impact & Innovation

Decoding the autoimmune attack at the root of aplastic anemia.

 

By combining immunopeptidomics, computational antigen prediction, and patient-derived T cell expansion models, this project identifies the molecular targets of immune attack in AA — laying the groundwork for precise diagnostics, relapse monitoring, and targeted therapies.

  • Reveals that somatic missense HLA mutations drive immune escape in AA through three distinct mechanisms, refining the search for candidate autoantigens and advancing autoimmune disease modeling broadly
  • Establishes a patient-derived iPSC platform for autoreactive T cell expansion, with findings extending beyond AA to T cell-mediated, tissue-specific autoimmune mechanisms across conditions
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving autoantigen discovery and HLA allele characterization directly toward diagnostic assays, relapse monitoring tools, and targeted therapy development
Research Approach

A framework designed for discovery

This project integrates immunopeptidomic analysis, computational antigen prediction, and patient-derived in vitro T cell modeling to identify the autoantigens and autoreactive T cell clonotypes driving immune attack in aplastic anemia. The work combines structural biology, machine learning, and functional immunology to advance from mechanistic discovery toward translational applications.

Immunopeptidomic analysis of mutant and wild-type HLA alleles using engineered hematopoietic cell lines expressing single HLA alleles; comparative peptide-binding analysis to distinguish antigens linked to disease; machine learning and computational modeling for candidate autoantigen prioritization; development and validation of an in vitro HLA-restricted T cell expansion model using patient-derived CD8+ T cells; and TCR sequencing to identify autoreactive T cell clonotypes.

Patient-derived CD8+ T cells expanded using engineered hematopoietic cell lines expressing single risk and non-risk HLA alleles; immunopeptidomic datasets comparing mutant and wild-type HLA alleles; computational antigen prediction datasets; TCR sequencing data identifying dominant autoreactive clonotypes; and patient-derived iPSC platform data for autoreactive T cell expansion.

Identification of candidate autoantigens and autoreactive T cell clonotypes in AA, with translational goals including development of diagnostic assays, relapse monitoring tools, and targeted therapies. Findings extend to broader autoimmune disease modeling, and the iPSC platform supports expansion into tissue-specific autoimmune mechanisms. A $1.3M Department of the Army grant has been awarded to continue this work through 2027.

Investigators & Institutions

Powering the science

Principal Investigator

Daria Babushok, MD, PhD, Colton Consortium Member

Assistant Professor, Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Publications

Origins of T-cell-mediated autoimmunity in acquired aplastic anaemia.

British Journal of Haematology
Enache, A; Carty, SA; Babushok, DV January 2025
Adaptive ImmunityAutoantigensBiological & MechanisticImmune ToleranceT Cell BiologyCross-Cutting & Special PopulationsOtherRare Autoimmune DiseasesUniversity of Pennsylvania

Additional Outputs

Department of the Army Grant HT94252410445 — $1.3M (10/1/2024–9/30/2027): Advancing mechanistic understanding of autoimmunity in aplastic anemia through HLA allele specificity.

  • Gupta S, Zheng S, Papaioannou J, Lin P, Nijim S, Yu A, Fazelinia H, Spruce LA, Babushok D. Insights into functional significance of somatic HLA class I variants in acquired aplastic anemia through structural modeling. 4th Structural Biology Symposium, University of Pennsylvania, Philadelphia, PA, May 21, 2025.
  • Zheng S, Papaioannou J, Lin P, Gupta S, Nijim S, Yu A, Fazelinia H, Spruce LA, Babushok D. The Functional Significance of Missense HLA Class I Mutations in Acquired Aplastic Anemia. AAMDSIF Bone Marrow Failure Summit, Bethesda, MD, March 6–7, 2025.

Autoreactive T cells in aplastic anemia; Missense HLA class I mutations uncover candidate aplastic anemia autoantigens.