Genetic elimination of α3(IV) collagen fails to rescue anti-collagen B cells
Genetic elimination of α3(IV) collagen fails to rescue anti-collagen B cells
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DOI：
10.1016/j.imlet.2011.09.004
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发表时间：
2011-12-30
影响因子：
4.4
通讯作者：
Foster, Mary H.
中科院分区：
文献类型：
--
作者：
Clark, Amy G.;Mackin, Katherine M.;Foster, Mary H.
针对 IV 型胶原蛋白 α 3 链的非胶原蛋白 1 结构域的自身抗体的器官沉积会导致抗肾小球基底膜疾病中的严重肾和肺损伤。这些高致病性自身抗体的起源和调节仍然未知。预计抗 α 3(IV) 胶原 B 淋巴细胞会在不知道靶抗原的情况下在体内成熟，因为 α 3(1V) 胶原表达受到组织的高度限制，并且致病性表位是隐秘的。然而，最近对抗 α 3(IV)NCI 胶原蛋白自身抗体转基因小鼠模型的分析表明，发育中的 B 细胞通过骨髓中的删除和编辑而迅速沉默。为了剖析胶原蛋白在该模型中作为中央耐受原的作用，我们确定了遗传上缺乏 α 3(IV) 胶原蛋白的自身抗体转基因小鼠中 B 细胞的命运。我们发现，组织靶标自身抗原的缺失对抗 α 3(IV)NC1 B 细胞的命运几乎没有影响。这意味着预防抗肾小球基底膜疾病的调节机制比之前认为的更为复杂，包括骨髓中存在的第二种抗原参与并耐受抗α3(IV)NC1胶原蛋白B细胞的可能性。由 Elsevier B.V. 出版
Organ deposition of autoantibodies against the noncollagenous-1 domain of the alpha 3 chain of type IV collagen leads to severe kidney and lung injury in anti-glomerular basement membrane disease. The origin and regulation of these highly pathogenic autoantibodies remains unknown. Anti-alpha 3(IV) collagen B lymphocytes are predicted to mature in vivo ignorant of target antigen because alpha 3(1V) collagen expression is highly tissue restricted and pathogenic epitopes are cryptic. However, a recent analysis of an anti-alpha 3(IV)NCI collagen autoantibody transgenic mouse model revealed that developing B cells are rapidly silenced by deletion and editing in the bone marrow. To dissect the role of collagen as central tolerogen in this model, we determined B cell fate in autoantibody transgenic mice genetically lacking alpha 3(IV) collagen. We found that absence of the tissue target autoantigen has little impact on the fate of anti-alpha 3(IV)NC1 B cells. This implies a more complex regulatory mechanism for preventing anti-glomerular basement membrane disease than has been previously considered, including the possibility that a second antigen present in bone marrow engages and tolerizes anti-alpha 3(IV)NC1 collagen B cells. Published by Elsevier B.V.