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

Area of Science:

• Immunology
• Genetics
• Disease Modeling

Background:

• The complement cascade plays a role in immune-driven diseases such as Alzheimer's disease and Systemic Lupus Erythematosus.
• Existing mouse models do not fully replicate human complement regulators like CR1 and CR2 due to species-specific gene structures.
• Genetic variations in CR1 and CR2 are linked to disease modification, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To develop a mouse model that accurately reflects human complement receptors CR1 and CR2.
• To investigate the functional impact of different human CR1 alleles (CR1^long, CR1^short, CR1^KO) in vivo.
• To establish a tool for studying the relationship between human CR1 variations and disease pathogenesis.

Main Methods:

• Engineered C57BL/6J mice to replace the murine Cr2 gene with human CR1 and CR2.
• Utilized Flp-frt and Cre-loxP recombination to generate mice with specific CR1 alleles: CR1^long, CR1^short, and CR1^KO.
• Performed transcriptional profiling of spleen and brain tissues, followed by gene set enrichment analysis.

Main Results:

• Successfully generated the B6.CR2CR1 mouse model expressing human CR1 and CR2.
• Identified differentially expressed genes and pathways in mice with varying CR1 alleles.
• Gene set enrichment analysis indicated that CR1^long modulates hematopoietic cell numbers and infiltration, while CR1^short and CR1^KO do not.

Conclusions:

• The B6.CR2CR1 mouse model offers a novel platform for studying human CR1 function.
• This model allows for the investigation of how specific human CR1 alleles influence biological processes relevant to disease.
• Provides a foundation for future research into the mechanistic links between CR1 genetics and human diseases.