Complement C4A Regulates Autoreactive B Cells in Murine Lupus.
Complement C4A Regulates Autoreactive B Cells in Murine Lupus.
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DOI：
10.1016/j.celrep.2020.108330
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发表时间：
2020-11-03
期刊：
影响因子：
8.8
通讯作者：
Carroll MC
中科院分区：
文献类型：
--
作者：
Simoni L;Presumey J;van der Poel CE;Castrillon C;Chang SE;Utz PJ;Carroll MC
系统性红斑狼疮（SLE）是一种由致病性自身抗体介导的严重自身免疫性疾病。虽然补体蛋白 C4 与 SLE 相关，但其亚型（C4A 和 C4B）的影响并不相同。尽管 C4A 具有 99% 的同源性，但基因研究发现 C4A 比 C4B 更具保护性。通过生成表达人类 C4A 或 C4B 的基因编辑小鼠品系并将其与 564lgi 狼疮品系杂交，我们发现总体而言，C4A 样 564Igi 小鼠比 C4B 样 564Igi 小鼠产生更少的体液自身免疫。这包括 GC、自身反应性 B 细胞、自身抗体和记忆 B 细胞数量的减少。 C4A 诱导自身抗原清除的较高效率与滤泡排除自身反应性 B 细胞有关。这些结果解释了 C4A 同工型如何在狼疮中发挥保护作用，并表明 C4A 作为狼疮的可能替代疗法。西蒙尼等人。解决了一个长期存在的问题，即补体 C4A 和 C4B 亚型在自身免疫体内的功能有何不同。他们发现，相对于 C4B，C4A 可以增强体液自身免疫的保护作用。自身抗体多样性同样取决于 C4 蛋白同种型。
Systemic lupus erythematosus (SLE) is a severe autoimmune disease mediated by pathogenic autoantibodies. While complement protein C4 is associated with SLE, its isoforms (C4A and C4B) are not equal in their impact. Despite being 99% homologous, genetic studies identified C4A as more protective than C4B. By generating gene-edited mouse strains expressing either human C4A or C4B and crossing these with the 564lgi lupus strain, we show that, overall, C4A-like 564Igi mice develop less humoral autoimmunity than C4B-like 564Igi mice. This includes a decrease in the number of GCs, autoreactive B cells, autoantibodies, and memory B cells. The higher efficiency of C4A in inducing self-antigen clearance is associated with the follicular exclusion of autoreactive B cells. These results explain how the C4A isoform is protective in lupus and suggest C4A as a possible replacement therapy in lupus. Simoni et al. address a long-standing question about how complement C4A and C4B isoforms differ in function in vivo in autoimmunity. They find that C4A leads to an increased protection in humoral autoimmunity relative to C4B. Autoantibody diversity is likewise dependent on the C4 protein isotype.
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自动发芽中心的克隆进化。
影响因子：
64.5
作者：
Degn SE;van der Poel CE;Firl DJ;Ayoglu B;Al Qureshah FA;Bajic G;Mesin L;Reynaud CA;Weill JC;Utz PJ;Victora GD;Carroll MC
通讯作者：
Carroll MC
影响因子：
13.3
作者：
Chen, Ji Yih;Wu, Yee Ling;Mok, Mo Yin;Wu, Yeong-Jian Jan;Lintner, Katherine E.;Wang, Chin-Man;Chung, Erwin K.;Yang, Yan;Zhou, Bi;Wang, Huanyu;Yu, Denise J. H. C.;Alhomosh, Alaaedin;Jones, Karla;Spencer, Charles H.;Nagaraja, Haikady N.;Lau, Yu Lung;Lau, Chak-Sing;Yu, C. Yung
通讯作者：
Yu, C. Yung
影响因子：
32.4
作者：
Das A;Heesters BA;Bialas A;O'Flynn J;Rifkin IR;Ochando J;Mittereder N;Carlesso G;Herbst R;Carroll MC
通讯作者：
Carroll MC
影响因子：
30.5
作者：
Dogan, Ismail;Bertocci, Barbara;Weill, Jean-Claude
通讯作者：
Weill, Jean-Claude
影响因子：
32.4
作者：
Berland, Robert;Fernandez, Luis;Imanishi-Kari, Thereza
通讯作者：
Imanishi-Kari, Thereza