OP0027 Abnormal B Cell Activation through Cellular Metabolic Reprogramming and Its Relevance To The Pathogenesis of SLE

免疫球蛋白D B细胞 TLR9型 免疫学 生发中心 细胞分化 BCL6公司 生物 分子生物学 医学 抗体 DNA甲基化 基因表达 生物化学 基因
作者
Masataka Torigoe,S. Iwata,K. Sakata,Shingo Nakayamada,Yoshiki Tanaka
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:75 (Suppl 2): 63.1-63
标识
DOI:10.1136/annrheumdis-2016-eular.2223
摘要

Background

B cells play a pivotal role in autoimmune diseases. In SLE, IFN signature is displayed and aberrant function of Toll-like receptors (TLR) for recognizing nucleic acids contributes to its pathology. Peripheral plasmablasts increase in active SLE, but the relevance of cellular metabolisms to B cell differentiation to plasmablasts remains unclear.

Objectives

To examine the mechanism by which cellular metabolic reprogramming regulates human B cell differentiation in vitro, and its involvement in pathological processes of SLE.

Methods

Human B cells were obtained from peripheral blood of healthy donors (HDs), and separated into 3 subsets; naïve (IgD+CD27), IgM memory (IgD+CD27+) and class-switched (CS) memory B cells (IgDCD27+). Each subset was cultured with CpG DNA (ligand of TLR9) and/or IFN-α. Plasmablast (CD27hi) differentiation, immunoglobulin (IgM, IgG), and cytokine production (IL-6, IL-10), and cellular metabolism (mTORC1, AMPK, glycolysis) were assessed.

Results

When IgM memory B cells and CS memory B cells were stimulated with CpG, robust production of IL-6 and IL-10 as well as differentiation to plasmablasts were induced. The gene expression of IRF4, XBP1 and PRDM1 was increased by CpG, whereas that of BACH2 and BCL6 was decreased. These responses were amplified by IFN-α, which was abrogated by anti-IFNAR2 Abs. A JAK inhibitor tofacitinib did not attenuate CpG-induced B cell differentiation to plasmablasts, indicating that JAK-mediated signaling by autocrine IL-6 and IL-10 was not relevant to the differentiation. Next, we analyzed cellular metabolic reprogramming during B cell differentiation, which was recently highlighted for its involvement in T cell differentiation. CpG stimulation strongly induced p-mTORC1 and lactic acid production, indicating that there is a metabolic shift to glycolysis in B cells. IFN-α further augmented this pathway. However, a glycolysis inhibitor, 2-deoxy-D-glucose and an mTORC1 inhibitor, rapamycin significantly abrogated lactic acid production, cytokine production and plasmablast differentiation of B cells in a dose-dependent manner. AMPK activators, metformin and AICAR, which are known to indirectly inhibit mTORC1, not only suppressed plasmablast differentiation but also induced IgDCD27 memory B cells. These results indicate that CpG and IFN-α shifted mTORC1/AMPK balance toward mTORC1 activation and glycolysis, leading to plasmablast differentiation. Interestingly, p-mTORC1 was significantly enhanced in B cells of SLE patients, compared to HDs (p<0.05), and it positively correlated with percentage of peripheral plasmablasts (r =0.709, p<0.01) and SLEDAI score (r =0.453, p<0.05), and negatively correlated with CH50 (r = -0.452, p<0.05).

Conclusions

CpG and IFN-α shifted mTORC1/AMPK balance toward mTORC1 activation and glycolysis, resulting in plasmablast differentiation, especially in memory B cells. The metabolic shift to anabolism supplied sufficient proteins and nucleic acids for rapid cell proliferation, permitting efficient differentiation to plasmablasts. Abnormal B cell activation through cellular metabolic reprogramming could contribute to SLE pathology. Thus, we first propose the disturbance of “immunometabolism” in B cells, and the regulation of B cell metabolism can provide a new therapeutic strategy against SLE.

Disclosure of Interest

M. Torigoe: None declared, S. Iwata: None declared, K. Sakata Employee of: Mitsubishi Tanabe Pharma, S. Nakayamada: None declared, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Consultant for: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
还单身的湘完成签到,获得积分10
2秒前
fyjlfy完成签到 ,获得积分10
2秒前
深情安青应助Nayvue采纳,获得10
3秒前
研友_Y59785完成签到,获得积分0
3秒前
Xiaoxiao发布了新的文献求助10
4秒前
初初见你完成签到,获得积分10
11秒前
14秒前
思源应助淡淡月饼采纳,获得20
14秒前
dd完成签到 ,获得积分10
15秒前
Nayvue发布了新的文献求助10
19秒前
未来的幻想完成签到,获得积分10
21秒前
Kvolu29完成签到,获得积分10
22秒前
长理物电强完成签到,获得积分10
23秒前
若安在完成签到,获得积分10
24秒前
完美世界应助潘特采纳,获得10
25秒前
拼搏问薇完成签到 ,获得积分10
25秒前
单薄乐珍完成签到 ,获得积分0
28秒前
张静枝完成签到 ,获得积分10
28秒前
六步郎完成签到,获得积分10
28秒前
啊怙纲完成签到 ,获得积分10
30秒前
量子星尘发布了新的文献求助10
32秒前
scott_zip完成签到 ,获得积分10
33秒前
gxl完成签到,获得积分0
37秒前
xxx完成签到 ,获得积分10
40秒前
40秒前
努力生活的小柴完成签到,获得积分10
42秒前
44秒前
tangyong完成签到,获得积分10
46秒前
长安发布了新的文献求助10
46秒前
SucceedIn完成签到,获得积分10
47秒前
48秒前
51秒前
海洋岩土12138完成签到 ,获得积分10
52秒前
lzz完成签到 ,获得积分10
52秒前
冬雪完成签到,获得积分10
56秒前
woommoow完成签到,获得积分10
56秒前
aaatan完成签到 ,获得积分10
56秒前
lynn完成签到,获得积分10
57秒前
ABC发布了新的文献求助10
57秒前
回忆完成签到,获得积分10
58秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038184
求助须知:如何正确求助?哪些是违规求助? 3575908
关于积分的说明 11373872
捐赠科研通 3305715
什么是DOI,文献DOI怎么找? 1819255
邀请新用户注册赠送积分活动 892662
科研通“疑难数据库(出版商)”最低求助积分说明 815022