Objective To evaluate the dysfunction of B cell metabolism and its involvement in SLE pathology. Methods We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. Results The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, ATP production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. Conclusions Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.
Objective This study aimed to understand the role of mTOR in CD8+ cells in the pathogenicity of rheumatoid arthritis (RA) and the changes after treatment with biologic drugs. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro. Results Patients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, GNLY, TNF-α, and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of GNLY and IFN-γ was not affected by the TNF inhibitors. Conclusion These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease involving multiple organs in which B cells perform important functions such as antibody and cytokine production and antigen presentation. B cells are activated and differentiated by the primary B cell receptor, co-stimulatory molecule signals—such as CD40/CD40L—, the Toll-like receptors 7,9, and various cytokine signals. The importance of immunometabolism in the activation, differentiation, and exerting functions of B cells and other immune cells has been widely reported in recent years. However, the regulatory mechanism of immunometabolism in B cells and its involvement in SLE pathogenesis remain elusive. Similarly, the importance of the PI3K-Akt-mTOR signaling pathway, glycolytic system, and oxidative phosphorylation has been demonstrated in the mechanisms of B cell immunometabolic activation, mainly in mouse studies. However, the activation of the mTOR pathway in B cells in patients with SLE, the induction of plasmablast differentiation through metabolic and transcription factor regulation by mTOR, and the involvement of this phenomenon in SLE pathogenesis are unclear. In our studies using activated B cells derived from healthy donors and from patients with SLE, we observed that methionine, an essential amino acid, is important for mTORC1 activation. Further, we observed that splenic tyrosine kinase and mTORC1 activation synergistically induce EZH2 expression and plasmablasts by suppressing BACH2 expression through epigenomic modification. Additionally, we identified another mechanism by which the glutaminolysis-induced enhancement of mitochondrial function promotes plasmablast differentiation in SLE. In this review, we focused on the SLE exacerbation mechanisms related to the activation of immune cells—especially B cells—and immunometabolism and reported the latest findings in the field.
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