Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background.
Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background.
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DOI：
10.1007/s00251-022-01276-3
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发表时间：
2023-03
期刊：
影响因子：
3.2
通讯作者：
Ridgway, William M.
中科院分区：
文献类型：
--
作者：
Adams, David E.;Heuer, Luke S.;Rojas, Manuel;Zhang, Weici;Ridgway, William M.
我们之前报道了非肥胖糖尿病（NOD）基因小鼠(NOD。c3c4小鼠)发生了与人类原发性胆道胆管炎（PBC）相似的自身免疫性胆道疾病（ABD），包括抗线粒体抗体和器官特异性胆道淋巴细胞浸润。我们缩小了一种新型NOD可能的发病区域。Abd3基因的小鼠在1号染色体上的B10基因区（“Abd3”）和Abd3上游的突变Pkhd1基因（Pkhd1del36−67），我们通过回交研究表明NOD遗传背景是疾病的必要条件。这里，我们展示NOD。Abd3小鼠产生高水平的抗pdc - e2自身抗体，并且将1号染色体间隔置于scid背景上可以消除疾病，证明适应性免疫系统在发病机制中的关键作用。虽然NOD遗传背景对疾病至关重要，但目前尚不清楚Abd3位点的两个区域中哪一个对疾病是必要和充分的。在这里，我们使用经典的重组育种方法，证明了在NOD背景下，突变的Pkhd1del36−67单独引起ABD。突变序列的进一步表征表明，Pkhd1基因被以反义方向插入35号内含子的etii - β反转录转座子破坏。纯合子Pkhd1突变显著影响生存能力，使后代偏离孟德尔分布，倾向于NOD Pkhd1纯合子或杂合子基因型。因此，在易感遗传背景下的细胞特异性异常可以诱导针对受影响细胞的器官特异性自身免疫。未来的工作将旨在描述突变的Pkhd1如何引起这种自身免疫反应。
We previously reported that nonobese diabetic (NOD) congenic mice (NOD.c3c4 mice) developed an autoimmune biliary disease (ABD) with similarities to human primary biliary cholangitis (PBC), including anti-mitochondrial antibodies and organ-specific biliary lymphocytic infiltrates. We narrowed the possible contributory regions in a novel NOD.Abd3 congenic mouse to a B10 congenic region on chromosome 1 (“Abd3”) and a mutated Pkhd1 gene (Pkhd1del36−67) upstream from Abd3, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.Abd3 mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto a scid background eliminates disease, demonstrating the critical role of the adaptive immune system in pathogenesis. While the NOD genetic background is essential for disease, it was still unclear which of the two regions in the Abd3 locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutated Pkhd1del36−67 alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that the Pkhd1 gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. Homozygous Pkhd1 mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NOD Pkhd1 homozygous or heterozygous genotypes. Cell-specific abnormalities, on a susceptible genetic background, can therefore induce an organ-specific autoimmunity directed to the affected cells. Future work will aim to characterize how mutant Pkhd1 can cause such an autoimmune response.
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