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Development of Murine Systemic Lupus Erythematosus in the Absence of BAFF.
Arthritis & Rheumatology ( IF 13.3 ) Pub Date : 2019-12-26 , DOI: 10.1002/art.41097
William Stohl 1 , Ning Yu 1 , Samantha Chalmers 2 , Chaim Putterman 2 , Chaim O Jacob 1
Affiliation  

OBJECTIVE To determine whether systemic lupus erythematosus (SLE) can develop in the absence of BAFF in an SLE-prone host. METHODS Starting with C57BL/6 mice that express a human BCL2 transgene (Tg) in their B cells (thereby rendering B cell survival largely independent of BAFF-triggered signals), we introgressed this Tg into NZM 2328 mice genetically deficient in BAFF (NZM.Baff-/- ) to generate NZM.Baff-/- .Bcl2Tg mice. Expression of human Bcl-2 and lymphocyte profiles were assessed by fluorescence-activated cell sorting, and serologic profiles were determined by enzyme-linked immunosorbent assay. Immunofluorescence and histologic analyses were performed to assess renal immunopathologic features in the mice, and clinical disease was assessed according to the outcomes of severe proteinuria and death. RESULTS In comparison to their non-Tg NZM.Baff-/- littermates (n ≥ 7), NZM.Baff-/- .Bcl2Tg mice (n ≥ 8) overexpressed Bcl-2 in their B cells and developed significantly increased percentages and numbers of B cells and plasma cells, serum levels of IgG autoantibodies, glomerular deposition of IgG and C3, and severity of glomerular and tubulointerstitial inflammation, culminating in severe proteinuria and death (all P < 0.05 versus NZM.Baff-/- littermates). The time course for development of SLE-like features in NZM.Baff-/- .Bcl2Tg mice was more rapid than has been previously observed in NZM 2328 wild-type mice (median age at death 4.5 months versus 7.5 months). NZM.Baff-/- .Bcl2Tg mice remained responsive to BAFF, since reintroduction of the Baff gene into these mice further accelerated the course of disease (median age at death 3 months). CONCLUSION The role of BAFF in the development of SLE-like disease may be dispensable as long as B cell survival is preserved via a BAFF-independent pathway. This may help explain the limited and variable clinical success with BAFF antagonists in human SLE. Thus, NZM.Baff-/- .Bcl2Tg mice may serve as a powerful murine model for the study of BAFF-independent SLE.

中文翻译:

缺乏BAFF的小鼠系统性红斑狼疮的发展。

目的确定易发生SLE的宿主中,在没有BAFF的情况下是否可以发展系统性红斑狼疮(SLE)。方法从在其B细胞中表达人BCL2转基因(Tg)的C57BL / 6小鼠开始(从而使B细胞的存活很大程度上独立于BAFF触发的信号),我们将此Tg引入到遗传上BAFF(NZM。 Baff-/-)生成NZM.Baff-/-.Bcl2Tg小鼠。通过荧光激活细胞分选评估人Bcl-2的表达和淋巴细胞概况,并通过酶联免疫吸附测定法确定血清学概况。进行了免疫荧光和组织学分析,以评估小鼠的肾脏免疫病理特征,并根据严重蛋白尿和死亡的结果评估了临床疾病。结果与他们的非Tg NZM相比。Baff-/-同窝白蚁(n≥7),NZM.Baff-/-.Bcl2Tg小鼠(n≥8)在其B细胞中过表达Bcl-2,并显着增加了B细胞和浆细胞的百分比和数量,血清水平IgG自身抗体,IgG和C3的肾小球沉积以及肾小球和肾小管间质炎症的严重程度,最终导致严重的蛋白尿和死亡(与NZM相比,所有P <0.05)。NZM.Baff-/-。Bcl2Tg小鼠出现SLE样特征的时程比以前在NZM 2328野生型小鼠中观察到的要快(死亡时的中位年龄为4.5个月对7.5个月)。NZM.Baff-/-。Bcl2Tg小鼠对BAFF仍然有反应,因为将Baff基因重新引入这些小鼠进一步加速了病程(中位死亡年龄3个月)。结论只要通过不依赖BAFF的途径保持B细胞存活,BAFF在SLE样疾病发展中的作用就可能是必需的。这可能有助于解释在人类SLE中使用BAFF拮抗剂的有限而可变的临床成功。因此,NZM.Baff-/-。Bcl2Tg小鼠可以作为功能强大的小鼠模型,用于研究不依赖BAFF的SLE。
更新日期:2019-12-27
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