Background/Purpose: Amino acids play an important role in various metabolic processes. However, the role of amino acid metabolism in the regulation of human B cell function remains elusive. To determine the role of essential amino acids in human B cell differentiation and relevance to the pathogenesis of SLE.

Methods:  In the in vitro arm of the study, purified CD19⁺B cells from healthy donors were cultured withTLR7/9 ligand (LOX or CpG),IFN-α and B cell receptor (BCR) cross-linking, in the presence or absence of amino acids. We determined 1) the types of amino acids that are important for PB differentiation, 2) the amino acid transporters that are important for PB differentiation, 3) the main signaling pathway(s) involved in the presence of amino acids, 4) the transcriptional factors used in the presence of amino acids. In the clinical arm of the study, peripheral blood mononuclear cells (PBMCs) were obtained from 24 patients with RA, 35 patients with SLE, and 21 age-matched healthy controls, and subjected to flow cytometric analysis to determine the expression of amino acids-related markers.

Results:  1) Stimulation with the combination of BCR, IFN-α and TLR7/9 ligand induced PB differentiation accompanied by uptake of amino acids. PB differentiation was abrogated in the absence of essential amino acid methionine, and to a lesser extent leucine, but not in non-essential amino acid cystine. 2) LAT1 and CD98 are known amino acid transporters. The process of plasmablast differentiation encompassed a trade-off balance between upregulation of CD98 and downregulation of LAT1. 3) BCR and mTORC1 signals were susceptible to methionine, while mTORC1 signals were susceptible to leucine. In the presence of methionine, activation of Syk and mTORC1 signals synergistically induced methyltransferase EZH2 expression. EZH2 induced H3K27me3 at BACH2 loci and suppressed BACH2 expression, leading to induction of BLIMP1, XBP1 expression, and plasmablast differentiation. 4)Assessment of the expression of amino acid transporters CD98, LAT1 and EZH2 in B cells in RA and SLE patients showed overexpression of CD98 and EZH2, but not LAT1, in SLE, compared with RA and control. In SLE patients, EZH2 expression level correlated with that of CD98 in B cells. EZH2 expression also correlated with disease activity scores, such as of SLEDAI and BILAG and anti-dsDNA antibodies in patients with SLE.

Conclusion: The results indicate that methionine activates signaling by controlling immunological metabolism in B cells and plays an important role in differentiation of B cells to plasmablasts through epigenome modification through the induction of EZH2, suggesting that methionine is closely related to the pathogenesis of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methionine-commits-immunometabolism-and-epigenetic-regulation-of-bach2-loci-in-b-cells-resulting-in-biases-toward-plasmablast-differentiation-in-the-pathogenesis-of-sle/