Combination CTLA4Ig and Anti-CD40 Ligand Treatment Modifies T and B Cell Metabolic Profiles and Promotes B Cell Receptor Remodeling in a Mouse Model of Systemic Lupus Erythematosus.
Combination CTLA4Ig and Anti-CD40 Ligand Treatment Modifies T and B Cell Metabolic Profiles and Promotes B Cell Receptor Remodeling in a Mouse Model of Systemic Lupus Erythematosus.
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组合CTLA4IG和抗CD40配体处理可修饰T和B细胞代谢谱，并在全身性红斑狼疮的小鼠模型中促进B细胞受体重塑。
DOI：
10.4049/jimmunol.2100792
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发表时间：
2023-03-01
期刊：
影响因子：
--
通讯作者：
Davidson A
中科院分区：
文献类型：
--
作者：
Raparia C;Quach TD;Zeumer-Spataro L;Choi SC;Yi Z;Zhang W;Morel L;Davidson A
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，具有显著的发病率，需要进一步检查诱导耐受的治疗。用CTLA 4 Ig和抗-CD 40 L的组合而不是单独的单一治疗短期治疗狼疮易感性NZ B/WF 1小鼠，通过调节B和T细胞功能抑制疾病> 6个月，同时维持对外源性抗原的免疫应答。在2周联合共刺激阻断疗程后3个月，我们发现与未治疗对照组相比，联合和单次治疗组中活化T和B细胞的数量适度减少。然而，仅联合治疗小鼠显示脾B和T细胞的备用呼吸能力降低50%。对生发中心（GC）B细胞的RNA测序和基因集富集分析证实了联合治疗组中氧化磷酸化特征的减少。该队列还表现出在用抗IgG和抗CD 40刺激后GC B细胞中B细胞受体（BCR）相关信号分子的表达增加和PLCγ的磷酸化增加。来自联合治疗小鼠的GC B细胞也显示出涉及GPI连接的表面蛋白重塑的特征。因此，我们发现老年NZ B/W小鼠的类别转换记忆B细胞上抑制分子CD 24的细胞表面表达减少，并在联合治疗队列中得到纠正。由于BCR信号传导的显著降低和免疫细胞代谢的重塑都增强了狼疮易感小鼠的耐受性丧失，我们的研究结果有助于解释短期联合共刺激阻断后观察到的耐受性恢复。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant morbidity - demanding further examination of tolerance inducing treatments. Short-term treatment of lupus-prone NZB/WF1 mice with combination CTLA4Ig and anti-CD40L but not single treatment alone, suppresses disease for > 6 months via modulation of B and T cell function while maintaining immune responses to exogenous antigens. Three months after a 2-week course of combination costimulatory blockade, we found a modest decrease in the number of activated T and B cells in both combination and single treatment cohorts compared to untreated controls. However, only combination treatment mice showed a 50% decrease in spare respiratory capacity of splenic B and T cells. RNA-sequencing and gene set enrichment analysis of germinal center (GC) B cells confirmed a reduction in the oxidative phosphorylation signature in the combination treatment cohort. This cohort also manifested increased expression of B Cell Receptor (BCR) associated signaling molecules and increased phosphorylation of PLCγ in GC B cells after stimulation with anti-IgG and anti-CD40. GC B cells from combination treatment mice also displayed a signature involving remodeling of GPI-linked surface proteins. Accordingly, we found a decrease in cell surface expression of the inhibitory molecule CD24 on class-switched memory B cells from aged NZB/W mice that corrected in the combination treatment cohort. Since both a profound decrease in BCR signaling and remodeled immune cell metabolism enhance loss of tolerance in lupus-prone mice, our findings help to explain the restoration of tolerance observed after short-term combination costimulatory blockade.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
16.6
作者：
Choi SC;Titov AA;Abboud G;Seay HR;Brusko TM;Roopenian DC;Salek-Ardakani S;Morel L
通讯作者：
Morel L
影响因子：
7.3
作者：
Kim SJ;Lee K;Diamond B
通讯作者：
Diamond B
影响因子：
4.4
作者：
Suzuki, T;Kiyokawa, N;Fujimoto, J
通讯作者：
Fujimoto, J
影响因子：
30.5
作者：
Luo, Wei;Hawse, William;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.