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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月30日

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

摘要

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.