Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Medicine, Division of Immunology, and Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Rep. 2020 Nov 3;33(5):108330. doi: 10.1016/j.celrep.2020.108330.
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.
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。尽管补体蛋白 C4 与 SLE 有关，但它的同工型（C4A 和 C4B）在其影响上并不相等。尽管具有 99%的同源性，但遗传研究表明 C4A 比 C4B 更具保护作用。通过生成表达人 C4A 或 C4B 的基因编辑小鼠品系，并将这些品系与 564lgi 狼疮品系杂交，我们表明，总体而言，C4A 样 564Igi 小鼠比 C4B 样 564Igi 小鼠发展出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 在诱导自身抗原清除方面的更高效率与自身反应性 B 细胞的滤泡排除有关。这些结果解释了 C4A 同工型如何在狼疮中具有保护作用，并提示 C4A 可能是狼疮的一种潜在替代治疗方法。
