University of Southern California Keck School of Medicine, Los Angeles.
Albert Einstein College of Medicine, Bronx, New York.
Arthritis Rheumatol. 2020 Feb;72(2):292-302. doi: 10.1002/art.41097. Epub 2019 Dec 26.
To determine whether systemic lupus erythematosus (SLE) can develop in the absence of BAFF in an SLE-prone host.
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 .Bcl2 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.
In comparison to their non-Tg NZM.Baff littermates (n ≥ 7), NZM.Baff .Bcl2 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 .Bcl2 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 .Bcl2 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).
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 .Bcl2 mice may serve as a powerful murine model for the study of BAFF-independent SLE.
在易患系统性红斑狼疮（SLE）的宿主中，确定是否可以在没有 BAFF 的情况下发生系统性红斑狼疮。
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 细胞的存活在很大程度上独立于 BAFF 触发的信号），我们将该 Tg 导入在 BAFF 中遗传缺乏的 NZM 2328 小鼠（NZM.Baff）中，以产生 NZM.Baff.Bcl2 小鼠。通过荧光激活细胞分选评估人 Bcl-2 和淋巴细胞谱的表达，并通过酶联免疫吸附试验确定血清谱。进行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临床疾病。
与非 Tg NZM.Baff 同窝仔（n≥7）相比，NZM.Baff.Bcl2 小鼠（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 的沉积以及肾小球和肾小管间质炎症的严重程度，最终导致严重蛋白尿和死亡（所有 P<0.05 与 NZM.Baff 同窝仔相比）。NZM.Baff.Bcl2 小鼠出现类似 SLE 特征的时间进程比以前在 NZM 2328 野生型小鼠中观察到的更快（死亡时的中位年龄为 4.5 个月，而 7.5 个月）。NZM.Baff.Bcl2 小鼠仍然对 BAFF 有反应，因为将 Baff 基因重新引入这些小鼠中进一步加速了疾病的进程（死亡时的中位年龄为 3 个月）。
只要通过 BAFF 独立途径保存 B 细胞存活，BAFF 在 SLE 样疾病发展中的作用可能是可有可无的。这可能有助于解释在人类 SLE 中 BAFF 拮抗剂的有限和可变的临床疗效。因此，NZM.Baff.Bcl2 小鼠可能作为研究 BAFF 独立的 SLE 的有力的小鼠模型。
