TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance.
Publication year
2023Author(s)
Source
Journal of Experimental Medicine, 220, 12, (2023), pp. e20230944, article e20230944ISSN
Publication type
Article / Letter to editor
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Organization
Internal Medicine
Human Genetics
Journal title
Journal of Experimental Medicine
Volume
vol. 220
Issue
iss. 12
Page start
p. e20230944
Subject
Radboudumc 4: lnfectious Diseases and Global Health Human Genetics; Radboudumc 4: lnfectious Diseases and Global Health Internal Medicine; Radboud University Medical CenterAbstract
Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.
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- Academic publications [245381]
- Electronic publications [132857]
- Faculty of Medical Sciences [93208]
- Open Access publications [106387]
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