Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF
Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF
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DOI：
10.4049/jimmunol.177.4.2671
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发表时间：
2006-08-15
影响因子：
4.4
通讯作者：
Stohl, William
中科院分区：
文献类型：
--
作者：
Jacob, Chaim O.;Pricop, Luminita;Stohl, William
肿瘤坏死因子家族B细胞激活因子(BAFF)的结构性过表达促进了系统性红斑狼疮(SLE)的发生，而BAFF拮抗剂对SLE小鼠的治疗可改善疾病。为了确定系统性红斑狼疮(SLE)是否可以在BAFF缺乏的宿主中重新发生，我们建立了BAFF缺乏的新西兰混合(NZM)2328(NfZM.Baff(-/-))小鼠。NZM.Baff(-/-)小鼠脾B细胞(包括CD5(+)B1B细胞和CD5(-)B1B细胞)、生发中心、Ig分泌细胞和T细胞较NZM.Bar(+/+)小鼠减少。血清总Ig和自身抗体水平在4-6个月时下降，但随着年龄的增长接近野生型水平，表明即使完全没有BAFF，自身反应性B细胞仍能存活并分泌自身抗体。至少这些自身抗体中的一些是亲肾的，因为在12-13个月龄的NZM.Baff(-/-)小鼠的肾小球中，总的IgG和IgG1(而不是IgG2a、IgG2b或C3)大量沉积。尽管增殖性肾小球肾炎在NZM中很常见，表现为广泛的肾小球透明血栓，但6-7个月龄的Baff(-/-)小鼠严重蛋白尿和死亡率显著降低。这些结果表明，终生缺乏BAFF并不能保护NZM2328小鼠免受血清学自身免疫和肾脏病理的影响。然而，肾脏病理的特征发生了改变，小鼠在很大程度上避免了临床上的明显疾病(严重的蛋白尿和过早死亡)。这些观察结果可能会对BAFF拮抗剂在人类SLE和相关疾病中的使用产生深远的影响。
Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NfZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice., spleen B cells (including CD5(+) Bla and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Bar(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.