, the mice model exhibited glomerular lesions, associated with hematuria and albuminuria like IgA nephropathy. Background IgA nephropathy is the most common primary glomerulonephritis worldwide, and there is emerging evidence linking galactose-deficient IgA1 (Gd-IgA1) to the pathogenesis of the disease. However, mouse models that can be used to study Gd-IgA1's origin of production, biochemical characteristics, and immune reactivity are lacking. Methods We generated a humanized IgA1 mouse model with transgenic expression of the human IGHA1 gene from the mouse chromosomal locus of IgA heavy chain. The IGHA1+/+ mice were crossed with complement factor H heterozygous mutant (FHW/R) to generate IGHA1+/+FHW/R mice. IGHA1+/+ mice were exposed to different levels of environmental pathogens in the first 4 months, as housed in germ-free, specific pathogen–free, or conventional environments. In addition, wild-type C57BL/6J mice, IGHA1+/+ mice, and IGHA1+/+FHW/R mice were inoculated with Lactobacillus casei cell wall extract (LCWE) mixed with complete Freund's adjuvant (CFA) at 2 months of age to develop a mouse model of IgA nephropathy. Results Elevated levels of human IgA1 in blood circulation and mucosal sites were observed in IGHA1+/+ mice from exposure to pathogens. Compared with buffer-treated control mice, LCWE plus CFA-treated mice had moderately elevated levels of circulating human IgA1 (by one-fold) and human IgA1 immune complexes (by two-fold). Serum Gd-IgA1 levels increased four-fold after LCWE treatments. Analyses of the O-glycopeptides of the IgA1 hinge region confirmed hypogalactosylation of IgA1, with the variety of the glycoforms matching those seen in clinical samples. Furthermore, LCWE induced persistent IgA1 and C3 deposition in the glomerular mesangial areas in association with mesangial expansion and hypercellularity, which are frequently observed in IgA nephropathy biopsies. The IGHA1+/+FHW/R mice stimulated with LCWE and CFA developed albuminuria and hematuria. Conclusions We observed elevated plasma Gd-IgA1 levels with kidney deposition of IgA1 in the IGHA1+/+ mice after LCWE and CFA. In conjunction with factor H mutation, the mice exhibited severe glomerular alterations, associated with hematuria and albuminuria in resemblance of clinical IgA nephropathy....

中文翻译：

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干酪乳杆菌细胞壁提取物和半乳糖缺陷型 IgA1 在人源化 IGHA1 小鼠模型中的产生


，小鼠模型表现出肾小球病变，伴有血尿和白蛋白尿样 IgA 肾病。背景 IgA 肾病是世界范围内最常见的原发性肾小球肾炎，有越来越多的证据表明半乳糖缺乏型 IgA1 （Gd-IgA1） 与该病的发病机制有关。然而，缺乏可用于研究 Gd-IgA1 产生来源、生化特征和免疫反应性的小鼠模型。方法 我们从 IgA 重链的小鼠染色体位点生成了人 IGHA1 基因转基因表达的人源化 IgA1 小鼠模型。将 IGHA1 + / + 小鼠与补体因子 H 杂合突变体 （FHW/R） 杂交，生成 IGHA1 + / + FHW/R 小鼠。IGHA1 + / + 小鼠在前 4 个月内暴露于不同水平的环境病原体，如饲养在无菌、无特定病原体或常规环境中。此外，野生型 C57BL/6J 小鼠、IGHA1+/+ 小鼠和 IGHA1+/+FHW/R 小鼠在 2 月龄时接种干酪乳杆菌细胞壁提取物 （LCWE） 与完全弗氏佐剂 （CFA） 混合，以开发 IgA 肾病小鼠模型。结果 在暴露于病原体的 IGHA1+/+ 小鼠中观察到血液循环和粘膜部位人 IgA1 水平升高。与缓冲液处理的对照小鼠相比，LCWE 加 CFA 处理的小鼠循环人 IgA1 水平 （一倍） 和人 IgA1 免疫复合物 （两倍） 水平中度升高。LCWE 治疗后血清 Gd-IgA1 水平增加了 4 倍。对 IgA1 铰链区的 O 糖肽的分析证实了 IgA1 的低半乳糖基化，糖型的种类与临床样本中观察到的糖型相匹配。 此外，LCWE 诱导肾小球系膜区域持续 IgA1 和 C3 沉积，这与系膜扩大和细胞增多有关，这在 IgA 肾病活检中经常观察到。IGHA1 + / + FHW/R 小鼠在 LCWE 和 CFA 刺激下出现白蛋白尿和血尿。结论 我们观察到 LCWE 和 CFA 后 IGHA1+/+ 小鼠血浆 Gd-IgA1 水平升高，IgA1 肾脏沉积。结合因子 H 突变，小鼠表现出严重的肾小球改变，与血尿和白蛋白尿有关，类似于临床 IgA 肾病。