Fas-Defect MRL Mice as a Model of Systemic Lupus Erythematosus
MRL mice were originally developed by Murphy and Roths at Jackson Laboratories (Murphy and Roths 1978). Two substrains of MRL mice were developed: the MRL/lpr and the MRL/n mouse. These substrains were derived mainly from the LG/J strain with contributions from AKR/J, C3H/Di, and C57BL/6J mouse strains. The spontaneous autosomal recessive mutation Ipr (lymphoproliferation) was first observed at the 12th generation of inbreeding. The lupus-like syndrome is earlier in onset and more acute in females than in males. Virgin female MRL/lpr mice have a 50% mortality rate at 6 months of age, whereas virgin female MRL/n mice have a 50% mortality rate at 18 months of age (Furukawa et al. 1996). The autosomal recessive Ipr gene induces massive CD3+CD4CD8- cell (double-negative T cell) proliferation. This striking proliferation of double-negative T cells is caused by a defect in the Fas antigen, which has been reported to mediate apoptosis (Watanabe-Fukunaga et al. 1992). The Fas defect is believed to accelerate the autoimmunity of MRL/lpr mice, and it results in lupus nephritis and spontaneous LE-like skin lesions beginning at age 3 months, even under pathogen-free conditions (Furukawa et al. 1984, Kanauchi et al. 1991, Murphy and Roths 1978). The congenic MRL/n mouse strain is more than 99.6% homozygous to MRL/lpr mice but lacks the Ipr mutation and is almost normal during the first 6 months of life (Murphy and Roths 1978).
The MRL/lpr Mouse as a Good Model of Cutaneous Lupus Erythematosus
The MRL/lpr mouse is a good model for the spontaneous development of skin lesions similar to those seen in human LE (Furukawa et al. 1984, Horiguchi et al. 1986a,b, Provost and Watson 1993). Macroscopically, these skin lesions have been described as showing "alopecia and scab formation" by Murphy and Roths (Murphy and Roths 1978). Such skin lesions are not observed in NZB, B/W F1, or BXSB mice. Our immunopathologic studies have revealed liquefaction-like changes in basal ker-atinocytes, dermal T-cell infiltration, and vasodilatation (Furukawa et al. 1984), as well as ultrastructural changes very similar to those seen in human LE skin lesions (Horiguchi et al. 1984,1986b). The incidence of IgG deposition at the DEJ of MRL/lpr mice increases with age and reaches more than 80% after age 5 months (Furukawa et al. 1984, Horiguchi et al. 1986a). Subepithelial immunoglobulin deposits are also found in the esophagus and uterus (Furukawa et al. 1986a, Horiguchi 1987a). These subepidermal immounglobulin deposits are eliminated by neonatal thymectomy (Furukawa et al. 1986bc). CD4+ cells are predominant, and the CD4/CD8 ratio is high in dermal infiltrates with increased expression of c-myb and c-myc protooncogenes (Kanauchi et al. 1991, Kitajima et al. 1992). The number of Ia+-Langerhans' cells (LC) is increased significantly in the central portion of these lesions at an early stage and in the peripheral portions of the lesions later on. In contrast, Ia+-LC and Thy-1+-den-dritic epidermal cells are markedly decreased in the skin lesions at a later stage. Therefore, there is a good deal of information that strongly suggests that this mouse model develops cutaneous lesions that are pathologically similar to human CLE lesions (Furukawa 1994, Furukawa 1999, Provost and Watson 1993).
Similarities and Differences in Skin Lesions of MRL/n vs MRL/lpr Mice
It is believed that the Ipr mutation causes an acceleration of the subclinical autoimmune-prone background of MRL/n mice (Theofilopoulos 1995). Although the Ipr mutation has also been reproduced in several other mouse strains, such as the C3H, C57BL/6J, and AKR mouse, these strains do not show the same severity of lupus nephritis, vasculitis, or arthritis as the MRL/lpr mouse, except for the appearance of lymphoproliferation, the presence of rheumatoid factor, and a decrease in interleukin (IL) 2 production (Berney et al. 1992, Izui 1994, Takahashi et al. 1991, Theofilopoulos 1981). Therefore, the autoimmune disease-prone genetic background of the MRL mice is important for the investigation of autoimmune phenomena in MRL/lpr mice.
The skin manifestations of aged MRL/n mice are found on the upper dorsal surface, and a few mice also show necrotic skin lesions on the ears (Fig. 16.1) (Furukawa et al. 1996). One-third of MRL/lpr mice have spontaneous LE-like eruptions at 3 months of age, and the incidence rises to 80% at 5 months of age. In MRL/n mice, at 12 months of age, almost half have skin lesions similar to MRL/lpr mice, and 75% of 21-month-old MRL/n mice have such skin lesions. The histology of these MRL/n mice includes hyperkeratosis, acanthosis, mononuclear cell infiltration into the dermis, an increased number of collagen bundles, and fibrosis.Vasodilatation,bleeding, or liquefaction-like changes, which are common in MRL/lpr mice, are not observed in MRL/n mice. The mononuclear cell infiltration seen in the MRL/n mice is also milder than in the MRL/lpr mice (Furukawa et al. 1996).
In MRL/n mice, immunoglobulin deposits are also found at the DEJ in aged mice, but the incidence is very low compared with that in MRL/lpr mice. A more characteristic finding in aged MRL/n mice is epidermal cell nuclear staining on direct immunofluorescence with a homogeneous pattern (Furukawa et al. 1996). In humans, such unique immunofluorescence results are often observed in patients with mixed
Fig. 16.1. Macroscopic and immuno-pathologic characteristics of the aged MRL/n mouse. Nuclear stainings are shown in the skin (bottom left) and the kidney (bottom right)
connective tissue diseases and in one third of patients with SLE with a slightly different staining pattern (Burrows et al. 1993, Velthuis et al. 1990). At 21 months of age, 50% of the MRL/n mice show epidermal cell nuclear staining, which is not observed in any of the MRL/lpr mice. The epidermal cell nuclear staining is always associated with nuclear staining in the kidney, lung, and spleen. In addition, sera from aged MRL/n mice show homogeneously positive binding to the nuclei of keratinocytes cultured from newborn MRL/n mice. This in vitro binding to the keratinocytes also correlates with epidermal cell nuclear staining using direct immunofluorescence.
From these studies, we can conclude that the Ipr mutation accelerates the progression of a mild type of systemic and cutaneous connective tissue disease into a more severe type, such as SLE (Fig. 16.2). Furthermore, skin lesions from aged MRL/n mice can provide new insights into the long-standing controversy over whether epidermal cell nuclear staining occurs in vivo. Based on the little evidence of the cellular penetration of anti-RNP IgGs through Fc receptors (Alarcon-Segovia et al. 1978), and the in vivo binding of antiribonucleoprotein and anti-DNA antibodies to a cell suspension of live keratinocytes (Galoppin and Saurat 1981), epidermal nuclear staining may indeed be an in vivo immunologic event.
Lessons from MRL Mice for Human Cutaneous Lupus Erythematosus
Because the MRL/lpr mouse is a macroscopic and immunohistologic model for CLE, it is possible to elucidate the role of the Ipr mutation in the development of LE-like
skin lesions in MRL mice. The basic analysis was conducted according to our previous genetic studies in NZ mice (Furukawa 1985b, Maruyama et al. 1983, Shirai et al. 1986). The results from the F1 hybrids (MRL/lprxMRL/n) and F2 (F1 xF1) hybrid mice indicated that the Ipr mutation regulated lymphoproliferation and subepidermal immunoglobulin deposition at the DEJ. Interestingly, the appearance of macroscopic skin lesions was not regulated by the Ipr mutation alone (Furukawa 1997, Furukawa et al. 1996). Previously, we demonstrated that subepidermal immunoglo-bulin deposits are completely eliminated by neonatal thymectomy but that macroscopic LE-like lesions are not (Furukawa et al. 1986b, c). In addition, the transfer of proliferative double-negative T cells from MRL/lpr mice to MRL/n mice can induce perivascular lymphocyte infiltration in the dermis, and additional treatment with polyclonal B-cell activators can successfully reproduce the subepidermal immuno-globulin deposits, in which macroscopic skin lesions do not develop (Furukawa et al. 1993b). Rheumatoid factors of the cryoprecipitable IgG3 subclass derived from MRL/lpr mice can also induce skin leukocytoclastic vasculitis (Berney et al. 1992). Based on these results, the appearance of macroscopic LE-like skin lesions can therefore be speculated to be due to the Ipr mutation plus an additional factor, which probably affects the induction of these macroscopic skin lesions in an autosomal dominant fashion (Fig. 16.3). Candidates for such an additional factor may include environmental stimuli such as changes in temperature, UV light, and biological stress (Furukawa et al. 1993a, Horiguchi et al. 1987b).
Fig. 16.3. Association between the Ipr mutation and lupus dermatoses in the MRL/Mp-lpr/lpr mouse. Subepidermal IgG deposition, written as LBT(+), is regulated by the Ipr mutation in an autosomal recessive manner. Spontaneous lupus erythe-matosus-like skin lesions, written as lupus dermatoses, are speculated to be regulated by the Ipr mutation in a recessive manner plus an additional factor in a dominant manner
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