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

Autor:	Bracken SJ; Division of Rheumatology and Immunology, Department of Medicine, Duke University Medical Center, Durham, NC., Suthers AN; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC., DiCioccio RA; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC., Su H; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC., Anand S; Division of Hematology and Medical Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI., Poe JC; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC., Jia W; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC., Visentin J; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC.; Department of Immunology and Immunogenetics, Bordeaux University Hospital, Bordeaux, France.; UMR CNRS 5164 ImmunoConcEpT, Bordeaux University, Bordeaux, France., Basher F; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC., Jordan CZ; Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham NC., McManigle WC; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham NC., Li Z; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham NC.; Duke Cancer Institute, Duke University Medical Center, Durham NC., Hakim FT; Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD., Pavletic SZ; Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD., Bhuiya NS; Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD., Ho VT; Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Horwitz ME; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC.; Duke Cancer Institute, Duke University Medical Center, Durham NC., Chao NJ; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC.; Duke Cancer Institute, Duke University Medical Center, Durham NC.; Department of Integrated Immunobiology, Duke University School of Medicine, Durham, NC., Sarantopoulos S; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC.; Duke Cancer Institute, Duke University Medical Center, Durham NC.; Department of Integrated Immunobiology, Duke University School of Medicine, Durham, NC.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Feb 13; Vol. 8 (3), pp. 667-680.
DOI:	10.1182/bloodadvances.2023010362
Abstrakt:	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. (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)
Databáze:	MEDLINE
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