B Cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice.
B Cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice.
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DOI：
10.4049/jimmunol.1000466
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发表时间：
2011-04-15
期刊：
影响因子：
--
通讯作者：
Stohl W
中科院分区：
文献类型：
--
作者：
Jacob N;Guo S;Mathian A;Koss MN;Gindea S;Putterman C;Jacob CO;Stohl W
干扰素α是一种有效的天然免疫和获得性免疫激活剂，其对自身免疫前期(NZBxNZW)F1小鼠的治疗可促进致病性系统性红斑狼疮(SLE)疾病的发生。鉴于已知B细胞和baff对系统性红斑狼疮的贡献，我们评估了干扰素α给药在野生型(WT)、B细胞缺陷和baff缺陷的NZM2328小鼠中的致病能力。而WT小鼠在注射干扰素α后迅速发展为增殖性肾小球肾炎(GN)，显著的蛋白尿，并增加死亡率，而B细胞缺陷小鼠既没有肾脏病理，也没有临床疾病。此外，BAFF基因缺陷的小鼠，尽管发生了有限的肾小球免疫球蛋白和补体C3沉积，但仍然没有发生组织学上的肾小球肾炎和临床疾病。值得注意的是，尽管WT和BAFF缺陷小鼠的病理和临床反应不同，但经AdV-干扰素治疗的WT和BAFF缺陷小鼠的T细胞增殖和血清免疫球蛋白反应相似，而激活的B细胞数量在WT小鼠中增加，而在BAFF缺陷小鼠中则不增加。尽管如此，经ADV-干扰素治疗的WT小鼠肾脏中的B细胞、浆细胞和T细胞的浸润与ADV对照组WT小鼠相似。尽管干扰素α能够促进WT小鼠的系统性红斑狼疮疾病，但它未能推动自然病程中发生的CD_4+记忆T细胞的优先扩增，肾小球巨噬细胞的浸润也未能与疾病的发展相关联。这些结果表明，即使在干扰素α高表达的状态下，针对红斑狼疮的BAFF和/或B细胞的靶向治疗也可能是成功的。此外，我们的结果证明了干扰素α驱动的和自发的“自然”系统性红斑狼疮之间的重要生物学差异。
IFNα is a potent activator of innate and adaptive immunity, and its administration to pre-autoimmune (NZBxNZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFNα administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis (GN), marked proteinuria, and increased mortality in response to IFNα administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological GN and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in Adv-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFNα administration failed to drive the preferential expansion of CD4+ memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFNα overexpression. Moreover, our results document important biological differences between IFNα-driven and spontaneous “natural” SLE disease.
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通讯作者：
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全身IFN-α在B6.SLE123小鼠中驱动肾脏肾炎。
影响因子：
5.4
作者：
Fairhurst, Anna-Marie;Mathian, Alexis;Connolly, John E.;Wang, Andrew;Gray, Hillery F.;George, Tiffany A.;Boudreaux, Christopher D.;Zhou, Xin J.;Li, Quan-Zhen;Koutouzov, Sophie;Banchereau, Jacques;Wakeland, Edward K.
通讯作者：
Wakeland, Edward K.
DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V