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Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice
S Nakatsuru1, M Terada, M Nishihara
1KAN Research Institute, Kyoto, Japan.
Abstract:
An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren's syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/lpr, C3H/lpr, (MRL/lpr x C3H/lpr) F1 intercross, and MRL/lpr x (MRL/lpr x C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.
Insights
Mice with a Fas-deletion mutant gene (lpr) develop autoimmune collagen diseases. Genetic mapping revealed different gene loci control each lesion, indicating polygenic inheritance for these complex conditions.
Area of Science:
- Immunology
- Genetics
- Pathology
Background:
- MRL/lpr mice, a Fas-deletion mutant strain, spontaneously develop autoimmune collagen diseases.
- These include vasculitis, glomerulonephritis, arthritis, and sialoadenitis, serving as models for human conditions like polyarteritis and lupus nephritis.
- Disease development is influenced by host genetic background, as congenic C3H/lpr mice rarely exhibit these lesions.
Purpose of the Study:
- To genetically dissect the complex pathological manifestations of collagen disease in MRL/lpr mice.
- To identify specific gene loci responsible for individual lesions associated with autoimmune collagen disease.
Main Methods:
- Histopathological analysis was performed on MRL/lpr, C3H/lpr, F1 intercross, and backcross mice.
- Genomic DNA from backcross mice underwent association studies using Chi-squared analysis.
- Polymorphic microsatellite loci frequencies were compared between affected and unaffected individuals for each lesion.
Main Results:
- Gene loci recessively associated with each distinct lesion were mapped to different chromosomal positions.
- This indicates that the development of vasculitis, glomerulonephritis, arthritis, and sialoadenitis are controlled by separate genetic factors.
Conclusions:
- Each autoimmune lesion observed in MRL/lpr mice is controlled by a distinct set of genes.
- The complex pathology of collagen disease in this model results from polygenic inheritance.