Human autoimmunity at single cell resolution in aplastic anemia before and after effective immunotherapy
Severe immune aplastic anemia is a fatal disease due to the destruction of marrow hematopoietic cells by cytotoxic lymphocytes, serving as a paradigm for marrow failure syndromes and autoimmune diseases. To better understand its pathophysiology, we apply advanced single cell methodologies, including mass cytometry, single-cell RNA, and TCR/BCR sequencing, to patient samples from a clinical trial of immunosuppression and growth factor stimulation. We observe opposing changes in the abundance of myeloid cells and T cells, with T cell clonal expansion dominated by effector memory cells. Therapy reduces and suppresses cytotoxic T cells, but new T cell clones emerge hindering robust hematopoietic recovery. Enhanced cell-cell interactions including between hematopoietic cells and immune cells, in particular evolving IFNG and IFNGR, are noted in patients and are suppressed post-therapy. Hematologic recovery occurs with increases in the progenitor rather than stem cells. Genetic predispositions linked to immune activation genes enhances cytotoxic T cell activity and crosstalk with target cells.
Authors
- Diego Quinones Raffo (ORCID: https://orcid.org/0000-0001-8710-730X)
- Nicolas Sompairac (ORCID: https://orcid.org/0000-0001-8759-2077)
- Desmond Choy (ORCID: https://orcid.org/0009-0001-7318-5996)
- Xingmin Feng (ORCID: https://orcid.org/0000-0001-8018-2366)
- Shouguo Gao (ORCID: https://orcid.org/0000-0002-8275-0598)
- Qingyan Gao (ORCID: https://orcid.org/0000-0002-1168-2719)
- Lemlem Alemu
- Shirin Jamshidi
- Rita Antunes Dos Reis (ORCID: https://orcid.org/0000-0002-0182-6694)
- Shahram Kordasti (ORCID: https://orcid.org/0000-0002-0347-4207)
- Emma M. Groarke (ORCID: https://orcid.org/0000-0002-4648-5926)
- Neal S. Young (ORCID: https://orcid.org/0009-0007-0999-2519)
- Sachiko Kajigaya (ORCID: https://orcid.org/0000-0003-1035-3662)
- Bhavisha A. Patel (ORCID: https://orcid.org/0000-0002-2974-7701)
- Zhijie Wu (ORCID: https://orcid.org/0000-0003-3984-0819)
- Haoran Li (ORCID: https://orcid.org/0000-0002-1304-5334)
Institutions
- Guy's Hospital (GB)
- National Institutes of Health (US)
- King's College London (GB)
- National Heart, Lung, and Blood Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1038/s41467-025-60213-6
- Citations
- 2
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 3.54
Funders
- Cancer Research UK
- King's College London
- National Institutes of Health
- National Heart, Lung, and Blood Institute