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A single-cell atlas of bone marrow B cells reveals defective central B-cell tolerance in immune thrombocytopenia

Sheng, Zi ; Jiang, Nan ; Gao, Yan ; Zhang, Yuhan ; Zhang, Xiaoyu ; Li, Nailin ; Feng, Qi ; Zhang, Yanqi ; Wang, Limei and Semple, John W. LU , et al. (2025) In Blood
Abstract

Immune thrombocytopenia (ITP) is characterized by the overproduction of antiplatelet autoantibodies. Although B-cell depletion therapies show promise in ITP, their high relapse rates suggest a potential de novo breakdown of tolerance during an early stage of B-cell development. Here, we investigated how central B-cell tolerance mechanisms affect autoantibody production in ITP. Paired single-cell RNA/B-cell receptor (BCR) sequencing and bulk BCR sequencing revealed reduced V-J genomic distances in immunoglobulin kappa-chain (IGK) genes within bone marrow and peripheral B cells from patients with ITP, along with decreased expression of recombination-activating gene in the immature B cells, suggesting insufficient receptor editing.... (More)

Immune thrombocytopenia (ITP) is characterized by the overproduction of antiplatelet autoantibodies. Although B-cell depletion therapies show promise in ITP, their high relapse rates suggest a potential de novo breakdown of tolerance during an early stage of B-cell development. Here, we investigated how central B-cell tolerance mechanisms affect autoantibody production in ITP. Paired single-cell RNA/B-cell receptor (BCR) sequencing and bulk BCR sequencing revealed reduced V-J genomic distances in immunoglobulin kappa-chain (IGK) genes within bone marrow and peripheral B cells from patients with ITP, along with decreased expression of recombination-activating gene in the immature B cells, suggesting insufficient receptor editing. Single-cell antibody cloning demonstrated increased autoreactive and polyreactive naïve B cells in ITP, indicating defective central B-cell tolerance. Through an in vivo study, we established a causal link between receptor editing defects and antiplatelet antibody production, validating the immature B-cell stage as the key phase of dysregulation. These findings suggest that insufficient receptor editing of immature B cells triggers central B-cell tolerance deficiency and autoantibody accumulation in ITP.

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publishing date
type
Contribution to journal
publication status
in press
subject
in
Blood
publisher
American Society of Hematology
external identifiers
  • scopus:105026089931
  • pmid:41032749
ISSN
0006-4971
DOI
10.1182/blood.2025028960
language
English
LU publication?
yes
id
ee6af26b-2a87-45b8-9e56-485cfe6796f3
date added to LUP
2026-02-23 10:24:33
date last changed
2026-06-02 00:18:05
@article{ee6af26b-2a87-45b8-9e56-485cfe6796f3,
  abstract     = {{<p>Immune thrombocytopenia (ITP) is characterized by the overproduction of antiplatelet autoantibodies. Although B-cell depletion therapies show promise in ITP, their high relapse rates suggest a potential de novo breakdown of tolerance during an early stage of B-cell development. Here, we investigated how central B-cell tolerance mechanisms affect autoantibody production in ITP. Paired single-cell RNA/B-cell receptor (BCR) sequencing and bulk BCR sequencing revealed reduced V-J genomic distances in immunoglobulin kappa-chain (IGK) genes within bone marrow and peripheral B cells from patients with ITP, along with decreased expression of recombination-activating gene in the immature B cells, suggesting insufficient receptor editing. Single-cell antibody cloning demonstrated increased autoreactive and polyreactive naïve B cells in ITP, indicating defective central B-cell tolerance. Through an in vivo study, we established a causal link between receptor editing defects and antiplatelet antibody production, validating the immature B-cell stage as the key phase of dysregulation. These findings suggest that insufficient receptor editing of immature B cells triggers central B-cell tolerance deficiency and autoantibody accumulation in ITP.</p>}},
  author       = {{Sheng, Zi and Jiang, Nan and Gao, Yan and Zhang, Yuhan and Zhang, Xiaoyu and Li, Nailin and Feng, Qi and Zhang, Yanqi and Wang, Limei and Semple, John W. and Wang, Shuwen and Li, Song and Peng, Jun}},
  issn         = {{0006-4971}},
  language     = {{eng}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{A single-cell atlas of bone marrow B cells reveals defective central B-cell tolerance in immune thrombocytopenia}},
  url          = {{http://dx.doi.org/10.1182/blood.2025028960}},
  doi          = {{10.1182/blood.2025028960}},
  year         = {{2025}},
}