Division of Rheumatology, University of Washington, Seattle, WA 98109.
Department of Comparative Medicine, University of Washington, Seattle, WA 98109.
J Immunol. 2020 May 15;204(10):2627-2640. doi: 10.4049/jimmunol.1901473. Epub 2020 Apr 1.
Lupus nephritis (LN) is a major contributor to morbidity and mortality in lupus patients, but the mechanisms of kidney damage remain unclear. In this study, we introduce, to our knowledge, novel models of LN designed to resemble the polygenic nature of human lupus by embodying three key genetic alterations: the interval leading to anti-chromatin autoantibodies; , leading to defective clearance of apoptotic cells; and either or , leading to low complement levels. We report that proliferative glomerulonephritis arose only in the presence of all three abnormalities (i.e., in and triple-mutant [TM] strains [ TM and TM, respectively]), with structural kidney changes resembling those in LN patients. Unexpectedly, both TM strains had significant increases in autoantibody titers, Ag spread, and IgG deposition in the kidneys. Despite the early complement component deficiencies, we observed assembly of the pathogenic terminal complement membrane attack complex in both TM strains. In TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Interestingly, enhanced thrombin activation in TM mice and reduction of kidney injury following attenuation of thrombin generation by argatroban in a serum-transfer nephrotoxic model identified thrombin as a surrogate pathway for complement activation in C3-deficient mice. These novel mouse models of human lupus inform the requirements for nephritis and provide targets for intervention.
狼疮肾炎（LN）是导致狼疮患者发病率和死亡率的主要原因，但肾脏损伤的机制仍不清楚。在本研究中，我们引入了三种关键的遗传改变，即导致抗染色质自身抗体产生的间隔、导致凋亡细胞清除缺陷的 ，以及导致补体水平降低的 或 ，以模拟人类狼疮的多基因性质，据我们所知，这是设计狼疮肾炎的新型模型。我们报告称，只有在存在所有三种异常的情况下（即在 和 三重突变体[TM]株[分别为 TM 和 TM]中）才会出现增生性肾小球肾炎，其结构肾脏变化类似于 LN 患者。出乎意料的是，两种 TM 株的自身抗体滴度、抗原扩散和 IgG 在肾脏中的沉积均显著增加。尽管早期存在补体成分缺陷，但我们观察到两种 TM 株均存在致病性末端补体膜攻击复合物的组装。在 TM 小鼠中，MASP-2 和 C3 在肾小球和肾小管中的共定位表明，凝集素途径可能有助于该株的补体激活和组织损伤。有趣的是，在 TM 小鼠中增强了凝血酶的激活，并且在血清转移性肾毒性模型中通过 argatroban 减弱凝血酶生成后减少了肾脏损伤，这表明凝血酶作为 C3 缺陷型小鼠补体激活的替代途径。这些新型的人类狼疮小鼠模型为肾炎提供了信息，并为干预提供了目标。
