NZ Mouse

Genetic Basis of Subepidermal Immunoglobulin Deposits in NZB and B/W F1 Mice

Bielschowsky et al. (Bielschowsky et al. 1959) first reported the development of autoimmune disease in the inbred NZB mouse strain. The NZB mouse is characterized by many SLE-like symptoms, such as autoimmune hemolytic anemia, hyper-y-globulinemia, hypocomplementemia, occasional lymphoproliferative disorders, and immune complex-type glomerulonephritis. More interesting is the F1 progeny from the NZB and the nonautoimmune NZW strain (B/W F1), which has an earlier onset and a higher incidence of lupus nephritis (Table 16.1) than the parental NZB strain as well as the renal disease associated with higher titers of antinuclear antibodies (Howie and Helyer 1968). This augmented presentation of autoimmune disease has been explained by the involvement of one or more NZW genes, which act to modify the expression of the major autoimmune NZB gene(s) (Shirai 1982, Wandstract and Wakeland 2002). Conventional genetic studies indicate that each parental strain contributes at least one or two genes, one of which is linked to the MHC locus, with heterozygosity (H-2d/z) conferring the maximal susceptibility. Furthermore, molecular technology has enabled us to determine the lupus susceptibility locus (Kono et al. 1994) and to speculate a relationship between this locus and the gene-encoding receptors for tumor necrosis factor (Drake et al. 1994).

NZ mice rarely show macroscopic skin lesions. However, subepidermal immunoglobulin deposition in B/W F1 mice has been reported by Gilliam and associates (Gilliam et al. 1975) and is equivalent to human skin lupus band test (LBT) in patients with SLE. The immunoglobulin deposits are highest in the keratinizing lip (Sontheimer and Gilliam 1979) or tail skin (Furukawa and Hamashima 1982) (Fig. 16.4), which suggests a correlation with epidermal DNA synthesis (Sontheimer and Gilliam 1979). Our previous genetic studies on the LBT showed that the incidence in female NZB, NZW, B/W F1, and B/W F1 xNZW backcross mice was 60%, 0%, 100%, and 42% at 12 months of age, respectively (Furukawa et al. 1985b). B/W F1 mice have not only a higher incidence but also an earlier onset of LBT positivity than the parental NZB mice. Thus, a single dominant locus in the NZB strain determines the appearance of a positive LBT result, and this trait is intensified to a great degree by the involvement

Role of responsible genes

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

Fig. 16.4. Immunoglobulin deposition at the dermoepidermal junction of the tail skin of the F1 progeny from the New Zealand Black and the nonautoimmune New Zealand White strain (B/W F1)

of the NZW gene(s) in B/W F1 mice. Linkage studies reveal that the NZB gene is linked to some extent to the H-2 complex and that there is a significant association between LBT positivity and the appearance of anti-double-stranded DNA antibodies and renal disease in B/W F1 xNZW backcross mice. Therefore, it is postulated that the NZB-LBT gene (provisionally designated Lbt-1), if present on chromosome 17, is closely linked to the occurrence of anti-DNA antibodies and renal disease. There is a lack of retroviral gp70 deposition at the DEJ of NZB and B/W F1 mice, especially given the fact that gp70 is the predominant antigen in the immune complexes of diseased renal glomeruli (Maruyama et al. 1983). It is thus possible that there is a difference in the pathogenesis between lupus dermatoses and lupus nephritis (Furukawa 1997).

NZB/KN Mice as a Model of Autoimmune Alopecia

The NZB/KN mouse was established by Nakamura et al. (Nakamura et al. 1991). This strain is characterized by degenerative polyarthritis in the joints of the forepaw and hindpaw, beginning at age 2 months, which is more frequently observed in male mice than in female mice. NZB/KN is considered to be a model of rheumatoid arthritis. An additional interesting finding is the presence of alopecia over the tail to the lower back regions (Hiroi et al. 2001).Alopecia starts at 3 months of age and appears in 80% of 9-month-old NZB/KN mice (Fig. 16.5). Macroscopically, the alopecia lesion shows no scab formation or erythematous changes, and immunohistologically subepider-mal IgM deposits are frequently demonstrated. These unique points raise the possibility that the NZB/KN mouse is a model of autoimmune alopecia.

There have been no good models of murine autoimmune alopecia. One exception was the NC mouse investigated by Tamada et al. (Tamada et al. 1976). The NC mouse was developed by Japanese investigators (Kondo et al. 1969) and has been considered to be a useful model of a certain type of autoimmune anemia, glomerulonephritis,

Mouse Lupus Model
Fig. 16.5. Alopecia lesions on the upper and lower back of a 9-month-old male New Zealand Black/KN mouse

and amyloidosis. Erythema and diffuse alopecia appears on the face and ears, and alopecia without erythema occurs on the back. Such skin lesions start at age 3 months and appear cumulatively in more than 80% of the mice. However, subepidermal immunoglobulins are not deposited. In this sense, it remains unclear whether the NC mouse is a model of autoimmune alopecia. Interestingly, this inbred strain is now being investigated as a model of atopic dermatitis because of the hyper-IgE in the sera (Matsuda et al. 1997).

As described previously in this review, the MRL mice also show alopecia lesions with erythematous changes, in which histologic changes in the epidermis, vasodilatation, and bleeding are all observed. These changes are similar to the alopecia lesions seen in patients with discoid LE.

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