Journal Article

Human autoimmunity at single cell resolution in aplastic anemia before and after effective immunotherapy

Gao, Shouguo, Jamshidi, Shirin, Choy, Desmond, Kajigaya, Sachiko, Wu, Zhijie, Raffo, Diego Quinones, Groarke, Emma M., Kordasti, Shahram, Feng, Xingmin, Patel, Bhavisha A., Young, Neal S., Sompairac, Nicolas, Li, Haoran, Reis, Rita Antunes Dos, Alemu, Lemlem, Gao, Qingyan

2025

Overview

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. The transcriptional phenotype of immune cells associated with severe aplastic anaemia (SAA) may change post immunotherapy. Here the authors analyse single cell transcriptomics of hematopoietic and immune cells from SAA patients and assess how these phenotypes change after treatment showing alterations in myeloid cells and TCR clonal abundance correlate with robustness of hematopoietic response.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 38/39 / 38/43 / 49 / 49/39 / 631/250/232 / 631/250/2502 / 631/250/38 / 692/699/1541 / 692/699/249/1313 / Adult / Anemia / Anemia, Aplastic - genetics / Anemia, Aplastic - immunology / Anemia, Aplastic - therapy / Aplastic anemia / Autoimmune diseases / Autoimmunity / Autoimmunity - immunology / Cell activation / Cell interactions / Cytometry / Cytotoxicity / Effector cells / Female / Gene sequencing / Growth factors / Hematopoietic stem cells / Hematopoietic Stem Cells - immunology / Humanities and Social Sciences / Humans / Immune system / Immunosuppression / Immunotherapy / Immunotherapy - methods / Interferon-gamma - immunology / Interferon-gamma - metabolism / Lymphocytes / Lymphocytes T / Male / Memory cells / multidisciplinary / Myeloid cells / Myeloid Cells - immunology / Patients / Phenotypes / Progenitor cells / Recovery / Science / Science (multidisciplinary) / Single-Cell Analysis - methods / Stem cells / T cell receptors / T-Lymphocytes, Cytotoxic - immunology / Transcription activation / Transcriptomics