A novel mouse model expressing human forms for complement receptors CR1 and CR2

Background 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, includingCR1andCR2. Genetic variation inCR1andCR2have been implicated in modifying disease states but the mechanisms are not known. Results To decipher the roles of humanCR1andCR2in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murineCr2with human complement receptors,CR1andCR2(B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frtandCre-loxP) two of the most common alleles (referred to here asCR1(long)andCR1(short)) can be replicated within this mouse model, along with aCR1knockout allele (CR1(KO)). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for eitherCR1(long), CR1(short)orCR1(KO). Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated byCR1(long),but notCR1(short)orCR1(KO). Conclusion The B6.CR2CR1mouse model provides a novel tool for determining the relationship between human-relevantCR1alleles and disease.