Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci.

Abstract

SummaryIn MILL mice, the mostly recessive lpr mutation results in both the accumulation of CD4-, identified differences in ILNA expression and differences in the genomic organization of the Fas gene between normal and lpr mice, and confirm the recent report that a mutation in the Fas apoptosis gene is the Ipr mutation. However, our results also indicate that the Fas gene is expressed in spleen cells from normal mice, and spleen and lymph node ceils from mice with a second mutation at the Ipr locus (Ipr% Together these results suggest that altered Fas transcription results in the failure of lymphocytes to undergo programmed cell death and may lead to an altered immune cell repertoire. This mechanism may explain certain central and peripheral defects in tolerance that are present in autoimmune disease. The current study also demonstrates the profound effect of background genes on the degree of nephritis, lymphadenopathy, and anti-DNA antibody production. Of major note, our studies suggest the identification of chromosomal positions for genes that modify nephritis. Analysis of the backcross mice for markers covering most of the mouse genome suggests that over 50% of the variance in renal disease is attributable to quantitative trait loci on mouse chromosomes 7 and 12. Moreover, this study provides a model for dissecting the complex genetic interactions that result in manifestations of autoimmune disease.

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

“…Previous linkage analyses using autoimmune (NZB, MRL and BXSB) and non-autoimmune strains (NZW, C57BL and B10) did not test the combination of OPN allotypes as in the present study (MRL vs. C3H) [2,3,5] except of a few studies [4,6,17]. In the study of BXSB Â B10 crosses [4,17], to detect the loci with additive mode of inheritance in disease susceptibility might be difficult since authors used BXSB Â (B10 Â BXSB)F 1 or B10 Â (BXSB Â B10)F1 backcrosses, not F 2 crosses.…”

“…In the initial step of this study, three loci were found to be associated significantly with GN, and one of them, Agnm3, turned out to be a novel locus that did not share a chromosomal region with any lupus susceptibility loci reported previously [2][3][4][5][6]8], although some phenotypic loci referring to immune traits were reported such as Lprm4 (lymphoproliferation modifier 4, 54 cM) that was designated by spleen weight in MCN 2 mice [12] and Tsz1 (Thymus size 1, 56 cM) that was designated by thymus size [13]. It should be noted that another study using progenies from B6/lpr and MRL/lpr mice did not show any linkage of GN to Agnm3, even though we employed the same conditions for mouse breeding and histopathologic GN grading as in this study (Zhang et al, manuscript in preparation).…”

“…A study with (MRL/Mp-Fas lpr/lpr (MRL/lpr)  Cast/Ei)F 1  MRL/lpr backcross mice (N 2 ) indicated GN susceptibility loci in Chr 7 and 12 [2]. Several studies with (MRL/lpr  C57BL/6-Fas lpr/lpr (B6/lpr))F 2 mice, BXSB  (B10  BXSB)F 1 backcross mice (N 2 ), (NZB  NZW)F 2 mice, NZW  (NZW  C57BL/6)F 1 (N 2 ), and (BXSB  NZW)F 2 mice indicated susceptibility loci in Chr 10, designated Lmb4 [3], Chr 1 and 3 [4], Chr 1 and 4 [5], and Chr 6 [6], respectively.…”

Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

“…However, other lpr congenic strains of mice that possess the lpr mutation develop lymphoproliferation but not always the lupus disease, depending on their genetic background [44]. At least two additional susceptibility loci in the MRL background have been mapped that are associated with nephritis [45]. We show here that anti-DNA responses followed by a lupus-like disease can be induced in the susceptible MRL/+ mouse strain independent of the Fas defect, and without the associated lymphoproliferation.…”

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

“…The cause of the disease is likely to be multi-factorial, including a single mutation (lpr) of the fas gene and background susceptible genes from the MRL strain [36,37]. The lpr (fas) mutation is believed to be the cause of the lymphoproliferative disorder that interferes with thymic lymphocyte development and differentiation, but its effect on Treg is unclear.…”