Histamine H4 receptor antagonists prevent receptor-mediated and EBV-induced B cell proliferation [RNA-Seq]

Epstein-Barr virus (EBV) infects over 90% of individuals worldwide and establishes lifelong latency in memory B cells. While this latency is typically controlled by the immune system in healthy people, it can reactivate leading to cell immortalization and post-transplant lymphoproliferative disorders (PTLD), a frequent and potentially life-threatening condition in immunosuppressed patients. Surprisingly, we show that specific antagonists of the histamine H4 receptor (H4R), a G protein-coupled receptor expressed in immune cells, prevent the activation and proliferation of B cells following antigenic-like stimulation (BCR, TLR9, or CD40 ligands) or EBV infection. The lead compound, A943931, inhibited transcriptional but not epigenetic programs associated with B cell activation. Key metabolic genes, were downregulated, with a marked inhibition of glycolysis and oxidative phosphorylation. EBV-driven B cell immortalization was also blocked by H4R antagonists. A943931 similarly impaired energy production in lymphoblastoid cell lines, albeit to a lesser extent than in receptors-stimulated B cells. Finally, A943931 inhibited the growth of the Burkitt lymphoma Daudi xenografted in NSG mice and the development of B cell lymphoma in EBV-infected humanized mice. These findings highlight promising therapeutic potential of some H4R antagonists for EBV-induced lymphoproliferations such as PTLD and, more broadly, for EBV-linked autoimmune disorders. Overall design: Gene expression profiling was performed using RNA-seq on purified human CD19? B cells subjected to various stimulation and treatment conditions. Cells were stimulated for 24 hours with 5 µg/mL CpG-B ODN2006 (InvivoGen) and 10 µg/mL anti-human IgG + IgM (H+L) antibodies (Oxyme), or left unstimulated as controls. Simultaneously, cells were treated with either 10 µM A-943931 or left untreated (DMSO only).