Activation-induced deaminase-deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis.
Activation-induced deaminase-deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis.
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DOI：
10.1002/art.30230
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发表时间：
2011-04
影响因子：
--
通讯作者：
Diaz, Marilyn
中科院分区：
文献类型：
--
作者：
Jiang, Chuancang;Zhao, Ming-Lang;Scearce, Richard M.;Diaz, Marilyn
我们之前培养的MRL/lpr小鼠缺乏激活诱导脱氨酶（AID），缺乏同型转换和免疫球蛋白高突变。这些小鼠具有高水平的未突变（种系）自身反应性IgM，但与缺乏IgG的MRL/lpr小鼠相比，它们的存活率和狼疮肾炎的改善有所增加。在此，我们验证了高水平的种系自身反应性IgM在这些小鼠中赋予对狼疮肾炎的保护作用的假设。将来自aids - deficit -MRL/lpr小鼠的各种特异性自身反应性IgM抗体（包括针对dsDNA的抗体）给予无症状MRL/lpr小鼠，并检测细胞因子、蛋白尿、肾脏免疫复合物沉积和肾小球肾炎的水平。产生了缺乏任何抗体的新型艾滋病缺陷MRL/lpr小鼠，以与仅分泌IgM的艾滋病缺陷MRL/lpr小鼠进行比较。抗dsdna IgM治疗导致狼疮性肾炎的显著改善。其他自身反应性IgM如抗磷脂和抗史密斯抗原没有改变病理。在接受抗dsdna IgM治疗的小鼠中，巨噬细胞分泌促炎细胞因子、肾脏中炎症细胞和凋亡碎片的水平较低。来自aids -deficient- mrl /lpr小鼠的保护性IgM显示出独特的B细胞库，并偏向于Vh7183家族成员。抗dsdna IgM可能通过阻止导致肾脏损伤的炎症级联来保护MRL/lpr小鼠免受狼疮肾炎的侵害。在来自艾滋病缺陷小鼠的抗dsdna IgM杂交瘤中，Vh的独特使用表明，在这些小鼠中富集了分泌未突变保护性IgM的专用B细胞群。
We previously generated MRL/lpr mice deficient in the activation-induced deaminase (AID) who lack isotype switching and immunoglobulin hypermutation. These mice have high levels of unmutated (germline) autoreactive IgM yet experienced an increase in survival and an improvement in lupus nephritis that exceeded that of MRL/lpr mice lacking IgG. Herein, we test the hypothesis that high levels of germline autoreactive IgM in these mice confer protection against lupus nephritis. Autoreactive IgM antibodies of various specificities including against dsDNA from AID-deficient-MRL/lpr mice were given to asymptomatic MRL/lpr mice and the levels of cytokines, proteinuria, immune complex deposition in the kidneys, and glomerulonephritis were examined. Novel AID-deficient MRL/lpr mice that lack any antibodies were generated to compare to AID-deficient-MRL/lpr mice that secrete only IgM. Anti-dsDNA IgM treatment resulted in a dramatic improvement in lupus nephritis. Other autoreactive IgM’s such as anti-phospholipid and anti-Smith antigen did not alter pathology. Secretion of pro-inflammatory cytokines by macrophages, and the levels of inflammatory cells and apoptotic debris in the kidneys were lower in mice receiving anti-dsDNA IgM. Protective IgM derived from AID-deficient-MRL/lpr mice, displayed a distinct B cell repertoire, with a bias towards members of the Vh7183 family. Anti-dsDNA IgM protected MRL/lpr mice from lupus nephritis likely by stopping the inflammatory cascade leading to kidney damage. A distinct repertoire of Vh usage in anti-dsDNA IgM hybridomas from AID-deficient mice, suggests enrichment in these mice of a dedicated B cell population that secretes unmutated protective IgM.
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影响因子：
15.3
作者：
Mandik-Nayak, L;Seo, SJ;Erikson, J
通讯作者：
Erikson, J
影响因子：
4.4
作者：
Melamed, D;Miri, E;Nemazee, D
通讯作者：
Nemazee, D
DOI：
10.1084/jem.189.10.1639
发表时间：
1999-05-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan OT;Hannum LG;Haberman AM;Madaio MP;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
15.9
作者：
ManheimerLory, AJ;ZandmanGoddard, G;Diamond, B
通讯作者：
Diamond, B
影响因子：
4.4
作者：
Jang, Eun-Jung;Nahm, Dong-Ho;Jang, Young-Ju
通讯作者：
Jang, Young-Ju