The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1long and CR1short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease.

中文翻译：

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一种表达人类补体受体 CR1 和 CR2 形式的新型小鼠模型。


补体级联越来越多地参与多种具有强烈免疫作用的疾病的发生，例如阿尔茨海默病和系统性红斑狼疮。小鼠模型已用于确定补体级联的核心成分（例如 C1q 和 C3）的功能。然而，基因结构的物种差异意味着小鼠无法充分复制人类补体调节因子，包括 CR1 和 CR2。 CR1 和 CR2 的遗传变异与改变疾病状态有关，但其机制尚不清楚。为了破译人类 CR1 和 CR2 在健康和疾病中的作用，我们设计了 C57BL/6J (B6) 小鼠，用人类补体受体 CR1 和 CR2 (B6.CR2CR1) 替代内源性鼠 Cr2。 CR1 在人类群体中具有一系列同种异型，使用传统的重组方法（Flp-frt 和 Cre-loxP），可以在该小鼠模型中复制两个最常见的等位基因（此处称为 CR1long 和 CR1short）以及 CR1敲除等位基因（CR1KO）。脾脏和大脑的转录谱鉴定了 CR1long、CR1short 或 CR1KO 纯合小鼠之间差异表达的基因和通路。基因集富集分析预测造血细胞数量和细胞浸润受 CR1long 调节，但不受 CR1short 或 CR1KO 调节。 B6.CR2CR1 小鼠模型为确定人类相关 CR1 等位基因与疾病之间的关系提供了一种新工具。