Paul Elahna, Pozdnyakova Olga O, Mitchell Elizabeth, Carroll Michael C
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Eur J Immunol. 2002 Sep;32(9):2672-9. doi: 10.1002/1521-4141(200209)32:9<2672::AID-IMMU2672>3.0.CO;2-X.
Mice lacking the classical complement component C4 (C4(-/-)) were evaluated for autoreactivity because classical complement deficiencies are major risk factors for human systemic lupus erythematosus (SLE). Naive, 6-month-old C4(-/-) mice have significantly more IgM anti-double-strand DNA antibodies than C4(+/+) controls. By 9 months, IgG anti-dsDNA antibodies are increased and this spontaneous autoreactivity is evident across a mixture of genetic backgrounds. C4(+/-) heterozygous mice also develop autoantibodies, reminiscent of the high incidence of partial C4 deficiency observed in human SLE. Kidneys of C4(-/-) mice have glomerular immune complexes, but progressive renal disease is not apparent in unmanipulated animals. Nonetheless, splenic B cells from C4(-/-) and not C4(+/+) mice as young as 3 months can be triggered to secrete IgM anti-dsDNA antibodies in vitro, before autoantibody titers are significantly elevated in vivo. These findings suggest that C4 normally helps prevent early stages of autoimmune disease and that C4 deficiency predisposes to abnormal regulation of autoreactive B cells.
由于经典补体缺陷是人类系统性红斑狼疮（SLE）的主要风险因素，因此对缺乏经典补体成分C4（C4(-/-)）的小鼠进行了自身反应性评估。未经处理的6个月大的C4(-/-) 小鼠比C4(+/+) 对照小鼠具有明显更多的IgM抗双链DNA抗体。到9个月时，IgG抗双链DNA抗体增加，并且这种自发的自身反应性在多种遗传背景中都很明显。C4(+/-) 杂合小鼠也会产生自身抗体，这让人联想到在人类SLE中观察到的部分C4缺陷的高发生率。C4(-/-) 小鼠的肾脏有肾小球免疫复合物，但在未处理的动物中未出现进行性肾病。尽管如此，早在3个月大的C4(-/-) 小鼠而非C4(+/+) 小鼠的脾脏B细胞，在体内自身抗体滴度显著升高之前，就可以在体外被触发分泌IgM抗双链DNA抗体。这些发现表明，C4通常有助于预防自身免疫疾病的早期阶段，并且C4缺陷易导致自身反应性B细胞的异常调节。
