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Review
. 2023 Aug 23:14:1232820.
doi: 10.3389/fimmu.2023.1232820. eCollection 2023.

B cell metabolism in autoimmune diseases: signaling pathways and interventions

Jingyue Li  1 , Mingjiu Zhao  1 , Wenjun Luo  1 , Jiaqi Huang  1   2 , Bin Zhao  1   3 , Zhiguang Zhou  1
Affiliations
Review

B cell metabolism in autoimmune diseases: signaling pathways and interventions

Jingyue Li et al. Front Immunol. .

Abstract

Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.

Keywords: B cell; B cell differentiation and function; B cell metabolism; autoimmune diseases; autoimmunity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The crucial pathways and regulatory molecules of B cell metabolic reprogramming in autoimmune diseases. The interaction between BAFF and its receptor BAFF-R on B cell membranes triggers activation of the PI3K/AKT/mTOR/HIF-1α pathway. HIF-1α, together with c-Myc, upregulates genes associated with glycolysis, thereby promoting glucose uptake and glycolytic metabolism. TRAF3 inhibits excessive BAFF expression and its activation-related downstream cascades. PTEN inhibits PI3K and its activation-related downstream cascades. AMPK inhibits mTOR and its activation-related downstream cascades. GSK3 inhibits c-Myc and its activation-related downstream cascades. BAFF, B cell activating factor; BAFF-R, B cell activating factor receptor; BCR, B cell receptor; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin complex; HIF-1α, hypoxia-inducible factor 1-alpha; c-Myc, cellular myelocytomatosis oncogene; TRAF3, tumor necrosis factor receptor-associated factor 3; AMP, adenosine monophosphate; ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase; PTEN, phosphatase and tensin homolog; GSK3, glycogen synthase kinase 3; HK2, hexokinase 2; PFK2, phosphofructokinase 2; GLUT1, glucose transport 1; TCA cycle, tricarboxylic acid cycle; OXPHOS, oxidative phosphorylation.
Figure 2
Figure 2
The impact of major metabolic drugs for treating autoimmune diseases on B cell metabolism pathways. Belimumab and ianalumab inhibit overexpression of BAFF and its activation-related downstream cascades. Rapamycin inhibits mTOR and its activation-related downstream cascades. Metformin activates AMPK, thereby inhibiting mTOR and its activation-related downstream cascades. 2DG inhibits glycolysis. WTD blocks the PI3K-AKT-mTOR-HIF-1α pathway and its activation-related downstream cascades. DIM inhibits the AKT/mTOR pathway and its activation-related downstream cascades. Metformin and Bz-423 inhibit oxidative phosphorylation. BAFF, B cell activating factor; BAFF-R, B cell activating factor receptor; BCR, B cell receptor; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR1, mammalian target of rapamycin complex 1; HIF-1α, hypoxia-inducible factor 1-alpha; c-Myc, cellular myelocytomatosis oncogene; AMP, adenosine monophosphate; ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase; WTD, Wutou decoction; DIM, 3’3-Diindolylmethane; 2DG, 2-deoxy-D-glucose; Bz-423, 1,4-benzodiazepine; TCA cycle, tricarboxylic acid cycle; OXPHOS, oxidative phosphorylation.
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Grants and funding

This work was supported by the Natural Science Foundation of China (No.82170795), the Natural Science Foundation of Hunan Province (No.2021JC0003) and the Central South University Research Programme of Advanced Interdisciplinary Studies (No.2023QYJC008).