Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.
| dc.contributor.author | Bracken, Sonali J | |
| dc.contributor.author | Suthers, Amy N | |
| dc.contributor.author | DiCioccio, Rachel A | |
| dc.contributor.author | Su, Hsuan | |
| dc.contributor.author | Anand, Sarah | |
| dc.contributor.author | Poe, Jonathan C | |
| dc.contributor.author | Jia, Wei | |
| dc.contributor.author | Visentin, Jonathan | |
| dc.contributor.author | Basher, Fahmin | |
| dc.contributor.author | Jordan, Collin Z | |
| dc.contributor.author | McManigle, William C | |
| dc.contributor.author | Li, Zhiguo | |
| dc.contributor.author | Hakim, Frances T | |
| dc.contributor.author | Pavletic, Steven Z | |
| dc.contributor.author | Bhuiya, Nazmim S | |
| dc.contributor.author | Ho, Vincent T | |
| dc.contributor.author | Horwitz, Mitchell E | |
| dc.contributor.author | Chao, Nelson J | |
| dc.contributor.author | Sarantopoulos, Stefanie | |
| dc.date.accessioned | 2024-07-16T15:46:16Z | |
| dc.date.available | 2024-07-16T15:46:16Z | |
| dc.date.issued | 2024-02 | |
| dc.description.abstract | AbstractChronic 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. | |
| dc.identifier | 506666 | |
| dc.identifier.issn | 2473-9529 | |
| dc.identifier.issn | 2473-9537 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | American Society of Hematology | |
| dc.relation.ispartof | Blood advances | |
| dc.relation.isversionof | 10.1182/bloodadvances.2023010362 | |
| dc.rights.uri | ||
| dc.subject | Animals | |
| dc.subject | Humans | |
| dc.subject | Mice | |
| dc.subject | Immunoglobulin G | |
| dc.subject | Receptors, Antigen, B-Cell | |
| dc.subject | Nucleic Acids | |
| dc.subject | RNA | |
| dc.subject | Toll-Like Receptor 7 | |
| dc.subject | Bronchiolitis Obliterans Syndrome | |
| dc.title | Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Bracken, Sonali J|0000-0003-1814-4099 | |
| duke.contributor.orcid | Li, Zhiguo|0000-0002-9975-6005 | |
| duke.contributor.orcid | Horwitz, Mitchell E|0000-0001-9863-8464 | |
| duke.contributor.orcid | Chao, Nelson J|0000-0001-6725-7220 | |
| pubs.begin-page | 667 | |
| pubs.end-page | 680 | |
| pubs.issue | 3 | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Staff | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Biostatistics & Bioinformatics | |
| pubs.organisational-group | Integrative Immunobiology | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Pathology | |
| pubs.organisational-group | Medicine, Rheumatology and Immunology | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | University Institutes and Centers | |
| pubs.organisational-group | Duke Global Health Institute | |
| pubs.organisational-group | Duke Regeneration Center | |
| pubs.organisational-group | Medicine, Hematologic Malignancies and Cellular Therapy | |
| pubs.organisational-group | Biostatistics & Bioinformatics, Division of Biostatistics | |
| pubs.publication-status | Published | |
| pubs.volume | 8 |
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