Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice

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.

Genetic dissection of vasculitis in MRL/lpr lupus mice: a novel susceptibility locus involving theCD72c allele

“…Vasculitis in the kidneys of MRL/lpr mice is histopathologically characterized by granulomatous arterial lesions associated with mononuclear cell infiltration in perivascular regions, and destruction of external elastic lamina, followed by destruction of the internal elastic lamina, sometimes resulting in significant internal thickening, as described previously [15,21] (Fig. 1).…”

“…Arteritic lesions with only periarterial mononuclear cell infiltrates were considered negative according to the criteria described previously [20,21] since C3H/lpr mice manifested similar lesions which never progressed to the destruction of the external elastic lamina of the arterial wall. As shown in Table 1, the incidence of vasculitis (grade 1 or 2) in parental, F1 and N2 mice were almost the same as those previously reported [20,21]. However, the incidence in (MRL/lpr × C3H/lpr)F2 mice was much lower than in N2 backcross mice.…”

“…A genome-wide screening of the background genes for collagen diseases using MRL/lpr × (MRL/lpr × C3H/ lpr)F1 backcross mice suggested that each of the diseases is under the control of a different set of genes [20,21]. These studies reported two loci, one each on chromosome (Chr) 4 and 3 [20], or 4 and 2 [21], associated with the development of vasculitis in the kidney, both of which were distinct from the loci affecting other lesions.…”

“…These studies reported two loci, one each on chromosome (Chr) 4 and 3 [20], or 4 and 2 [21], associated with the development of vasculitis in the kidney, both of which were distinct from the loci affecting other lesions. However, their map positions for defining the candidate genes for vasculitis are still inaccurate since the numbers of N2 backcross mice used (n=82) were limited and the analysis of the F2 progeny has not yet been performed.…”

Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system

“…To demonstrate proof of concept, we have developed MXH10/Mo-lpr/lpr (MXH10/Mo/lpr) inbred mice [1][2][3][4], and metastatic tumor cell lines able to grow in the mice. The phenotype of the lpr (lymphproliferation) gene is characterized by the accumulation of a large number of polyclonal CD4 -CD8 -T cells in the LNs and spleen [5]; the lpr gene is recognized as a "promoting factor" for collagen disease in MRL mice due to Fas-mediated apoptotic insufficiency, and the causative genes of collagen disease are considered to be the background genes of MRL mice [6]. The MXH10/Mo/lpr mouse strain is a substrain of the recombinant inbred strain of the MXH/lpr mouse [7].…”