Conserved Epigenetic Programming and Enhanced Heme Metabolism Drive Memory B Cell Reactivation

Abstract

Memory B cells (MBCs) have enhanced capabilities to differentiate to plasma cells and generate a rapid burst of antibodies upon secondary stimulation. To determine if MBCs harbor an epigenetic landscape that contributes to increased differentiation potential, we derived the chromatin accessibility and transcriptomes of influenza-specific IgM and IgG MBCs compared to naïve cells. MBCs possessed an accessible chromatin architecture surrounding plasma cell specific genes, as well as altered expression of transcription factors and genes encoding cell cycle, chemotaxis, and signal transduction processes. Intriguingly, this MBC signature was conserved between humans and mice. MBCs of both species possessed a heightened heme signature compared to naïve cells. Differentiation in the presence of hemin enhanced oxidative phosphorylation metabolism and MBC differentiation into antibody secreting plasma cells. Thus, these data define conserved MBC transcriptional and epigenetic signatures that include a central role for heme and multiple other pathways in augmenting MBC reactivation potential.

Immune System Modulation by the Adjuvants Poly (I:C) and Montanide ISA 720

“…B cells from Montanide-adjuvanted mice showed increased expression of the transferrin receptor TFRC-1, which mediates the immune cells uptake of transferrin-bound iron from serum ( 27 ). Iron uptake, in turn, is closely related to the activation of Heme biosynthesis ( 57 ). It has been shown that Heme physically interacts with Bach2, an essential transcription factor that regulates the fate of B lymphocytes.…”

“…They found that genes involved in Plasma Cell differentiation showed accessible chromatin in their surroundings. The heme biosynthesis signature is also conserved between rodents and humans, and treatment with Hemin promoted the changes in the metabolism of memory B cells, stimulating oxidative phosphorylation and differentiation to Plasma cells ( 57 ).…”

COVID‐19 and plasma cells: Is there long‐lived protection?*

“…Although interesting, the progressive upregulation this pathway had been previously appreciated in B cell to ASC differentiation. 120 , 121 …”

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

“…Integrative analysis of transcriptome factors, including mRNAs, miRNAs, lncRNAs, chromatin accessibility, and cis-regulatory elements, revealed a core mRNA-noncoding RNA transcriptional signature of human memory B cells [ 100 ]. Memory B cells have an accessible chromatin architecture around several plasma cell-specific genes, including Xbp1 , Prdm1 , and Irf4 , suggesting the reactivation potential of memory B cells [ 101 ].…”