Phorbol-12-myristate-13-acetate is a potent enhancer of B cells with a granzyme B+ regulatory phenotype

Veh, Johanna; Mangold, Charlotte; Felsen, Anja; Ludwig, Carolin; Gerstner, Lisa; Reinhardt, Peter; Schrezenmeier, Hubert; Fabricius, Dorit; Jahrsdörfer, Bernd

doi:10.3389/fimmu.2023.1194880

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…It, therefore, appears likely that Bregs do not actually represent an independent differentiation lineage of B cells but that various regulatory functional phenotypes can be induced in different B cell subsets. The molecules involved in the induction of Bregs include cytokines such as IL-21 or IL-10 [21,23,24], the B cell receptor (BCR) or downstream activators such as PMA [25] and ligands binding to various pattern recognition receptors, including Toll-like receptor ligands [21,26,27].…”

Section: Diversity Of the Breg Universementioning

confidence: 99%

Regulatory B Cells—Immunopathological and Prognostic Potential in Humans

Veh,

Ludwig,

Schrezenmeier

et al. 2024

Cells

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The aim of the following review is to shed light on the putative role of regulatory B cells (Bregs) in various human diseases and highlight their potential prognostic and therapeutic relevance in humans. Regulatory B cells are a heterogeneous group of B lymphocytes capable of suppressing inflammatory immune reactions. In this way, Bregs contribute to the maintenance of tolerance and immune homeostasis by limiting ongoing immune reactions temporally and spatially. Bregs play an important role in attenuating pathological inflammatory reactions that can be associated with transplant rejection, graft-versus-host disease, autoimmune diseases and allergies but also with infectious, neoplastic and metabolic diseases. Early studies of Bregs identified IL-10 as an important functional molecule, so the IL-10-secreting murine B10 cell is still considered a prototype Breg, and IL-10 has long been central to the search for human Breg equivalents. However, over the past two decades, other molecules that may contribute to the immunosuppressive function of Bregs have been discovered, some of which are only present in human Bregs. This expanded arsenal includes several anti-inflammatory cytokines, such as IL-35 and TGF-β, but also enzymes such as CD39/CD73, granzyme B and IDO as well as cell surface proteins including PD-L1, CD1d and CD25. In summary, the present review illustrates in a concise and comprehensive manner that although human Bregs share common functional immunosuppressive features leading to a prominent role in various human immunpathologies, they are composed of a pool of different B cell types with rather heterogeneous phenotypic and transcriptional properties.

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Section: Diversity Of the Breg Universementioning

confidence: 99%

Regulatory B Cells—Immunopathological and Prognostic Potential in Humans

Veh,

Ludwig,

Schrezenmeier

et al. 2024

Cells

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Predicting Inhibitors of OATP1B1 via Heterogeneous OATP-Ligand Interaction Graph Neural Network (HOLI-GNN)

Mardikoraem,

Eaves,

Belecciu

et al. 2024

Preprint

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Organic anion transporting polypeptides (OATPs) are crucial for hepatic drug uptake, influencing drug efficacy and toxicity. Predicting OATP-mediated drug-drug interactions (DDIs) is challenging due to limited structural data and inconsistent experimental OATP inhibition data across studies. This study introduces Heterogeneous OATP-Ligand Interaction Graph Neural Network (HOLI-GNN), a novel computational approach that integrates molecular modeling with graph neural networks to enhance the prediction of OATP-mediated drug inhibition. By combining ligand molecular features with protein-ligand interaction data, HOLI-GNN outperforms traditional ligand-based methods. HOLI-GNN achieved median F1 and AUC scores of 0.78 and 0.90, respectively, compared to ECFP- and RDKit-based models built upon XGBoost (F1: 0.68 and 0.78, respectively; AUC: 0.70 and 0.75, respectively). Beyond improving inhibition prediction, we characterize protein residues involved in inhibitory versus non-inhibitory drug interactions, specifically highlighting residues T42, F224, I353, F356, and F386. We speculate that local position shifts in these hydrophobic packing residues, or the inhibition thereof, may be an important aspect of competitive inhibition mechanisms. Our model enhances the performance of OATP inhibitor prediction and, critically, offers interpretable interaction information to inform future mechanistic investigations.

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