Development of Murine Systemic Lupus Erythematosus in the Absence of BAFF.
Development of Murine Systemic Lupus Erythematosus in the Absence of BAFF.
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缺乏 BAFF 时小鼠系统性红斑狼疮的发展。
DOI：
10.1002/art.41097
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Jacob,ChaimO
中科院分区：
文献类型：
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作者：
Stohl,William;Yu,Ning;Chalmers,Samantha;Putterman,Chaim;Jacob,ChaimO
目的确定系统性红斑狼疮（SLE）易感宿主在缺乏BAFF的情况下是否会发展。方法从在B细胞中表达人bcl2转基因（Tg）的C57BL/6小鼠（从而使B细胞存活在很大程度上独立于BAFF触发的信号）开始，我们将这种Tg导入BAFF基因缺陷的NZM 2328小鼠（NZM. BAFF - / -）中，产生NZM. BAFF - / - . bcl2tgmice。通过荧光活化细胞分选评估人Bcl - 2的表达和淋巴细胞谱，并通过酶联免疫吸附法测定血清学谱。通过免疫荧光和组织学分析评估小鼠肾脏免疫病理特征，并根据严重蛋白尿和死亡的结果评估临床疾病。结果与非Tg NZM进行比较。Baff−/−littermates (n≥7)，NZM.Baff−/−。Bcl2Tgmice （n≥8）在其B细胞中过度表达Bcl‐2，并显著增加B细胞和浆细胞的百分比和数量、血清IgG自身抗体水平、肾小球IgG和C3沉积以及肾小球和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.Baff - / - littermates相比均p < 0.05）。NZM.Baff - / -中SLE样特征发展的时间进程。Bcl2Tgmice比之前在NZM 2328野生型小鼠中观察到的更快（死亡时中位年龄为4.5个月，而不是7.5个月）。NZM.Baff−−。Bcl2Tgmice仍然对BAFF有反应，因为将baffgene重新引入这些小鼠进一步加速了疾病进程（死亡时中位年龄为3个月）。结论BAFF在SLE样疾病发展中的作用可能是可有可无的，只要通过BAFF独立的途径维持B细胞的存活。这可能有助于解释BAFF拮抗剂治疗人类SLE的临床成功有限且多变。因此,NZM.Baff−−。Bcl2Tgmice可作为研究BAFF非依赖性SLE的强大小鼠模型。
ObjectiveTo determine whether systemic lupus erythematosus (SLE) can develop in the absence of BAFF in an SLE‐prone host.MethodsStarting with C57BL/6 mice that express a humanBCL2transgene (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−/−.Bcl2Tgmice. 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.ResultsIn comparison to their non‐Tg NZM.Baff−/−littermates (n ≥ 7), NZM.Baff−/−.Bcl2Tgmice (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 (allP< 0.05 versus NZM.Baff−/−littermates). The time course for development of SLE‐like features in NZM.Baff−/−.Bcl2Tgmice 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−/−.Bcl2Tgmice remained responsive to BAFF, since reintroduction of theBaffgene into these mice further accelerated the course of disease (median age at death 3 months).ConclusionThe 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−/−.Bcl2Tgmice may serve as a powerful murine model for the study of BAFF‐independent SLE.