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

Authors :
Bracken SJ
Suthers AN
DiCioccio RA
Su H
Anand S
Poe JC
Jia W
Visentin J
Basher F
Jordan CZ
McManigle WC
Li Z
Hakim FT
Pavletic SZ
Bhuiya NS
Ho VT
Horwitz ME
Chao NJ
Sarantopoulos S
Source :
Blood advances [Blood Adv] 2024 Feb 13; Vol. 8 (3), pp. 667-680.
Publication Year :
2024

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.<br /> (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Details

Language :
English
ISSN :
2473-9537
Volume :
8
Issue :
3
Database :
MEDLINE
Journal :
Blood advances
Publication Type :
Academic Journal
Accession number :
38113462
Full Text :
https://doi.org/10.1182/bloodadvances.2023010362