Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.

Abstract

Abstract

Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1182/bloodadvances.2023010362

Publication Info

Bracken, Sonali J, Amy N Suthers, Rachel A DiCioccio, Hsuan Su, Sarah Anand, Jonathan C Poe, Wei Jia, Jonathan Visentin, et al. (2024). Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions. Blood advances, 8(3). pp. 667–680. 10.1182/bloodadvances.2023010362 Retrieved from https://hdl.handle.net/10161/31278.

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Scholars@Duke

Bracken

Sonali Bracken

House Staff
Basher

Fahmin Basher

House Staff

Fellowship: Duke University, Hematology & Medical Oncology (2021-present)

Residency: University of Miami / Jackson Memorial Hospital (2018-2021)

Medical/Graduate: Medical University of South Carolina (2008-2018)
Doctor of Medicine, May 2018
Doctor of Philosophy in Microbiology & Immunology, May 2018

Undergraduate: University of South Carolina (2004-2008)
Bachelor of Science, Chemical Engineering
Bachelor of Science, Biological Sciences
Minor in Medical Humanities

Li

Zhiguo Li

Associate Professor of Biostatistics & Bioinformatics

survival analysis, dynamic treatment regimes, clinical trials

Horwitz

Mitchell Eric Horwitz

Professor of Medicine

Allogeneic stem cell transplantation with a focus on the use of umbilical cord blood grafts; Allogenic stem cell transplantation for Sickle Cell Disease; Prevention of acute and chronic graft versus host disease; Improving immune recovery following alternative donor stem cell transplantation using donor graft manipulation.


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