Brown-Norway rats autoimmune response

Brown Norway rat HgCl2 AU-salts D-Penicillamine Nevirapine HCB IC-glomerulonephritis Skin pathology, dermatitis Polyclonal IgE AutoAb (Type IV-collagen, ANA, 1 anti-ACh, thyroglobulin) Systemic inflamatory response with autoimmune symptoms... 

Prigent P, Saoudi A, PannetierC,Graber P, Bonnefoy Y, Druet P, Flirsch F Mercuric chloride, a chemical responsible forTh2-medi-ated autoimmunity in Brown-Norway rats, directly triggers T cells to produce IL-4. J. Clin. Invest. 1995 96 1484-9. 

Autoimmune responses to TCE in susceptible mice were demonstrated including significant increases in antinuclear antibodies and total serum globulin among other parameters. Some indications of an autoimmune response have also been reported in Brown Norway rats. 

The autoimmune-related effects that have been observed in the Brown Norway rat model are only partly compound specific and include both local (glomerulonephritis, splenomegaly, skin rashes, inflammatory responses in lungs) and systemic effects (hyper-immunoglobulinaemia, in particular IgE, and increased levels of autoantibodies). Derangements in Brown Norway rats are accompanied by polyclonal lymphoproliferation (both T and B cells)... 

Hirsch et al., 1982, 1986). However, it is not yet known if these effects are autoimmune mediated. Brown Norway rats are known as so-called Th2-prone animals (e.g. they are activated to produce high levels of IgE and to display many characteristics of type 2 immune response). This properly and/or the underlying genetic trait may be responsible for the high susceptibility of this strain to chemical-induced autoimmune effects. This point is often discussed as a limitation of using this strain. However, as for disease-prone mouse strains, it can also be argued that the inherent susceptibility of this rat strain resembles the inherent susceptibility in human cases of chemical-induced autoimmune disorders. 

Autoimmune-like phenomena in Brown Norway rats induced by mercuiy(II) chloride peak around day 10 after the last of five subcutaneous injections. After 20 days, immune alterations are mostly at control level, and the kidney effects (e.g. proteinuria) are clearly less than on day 10 (Aten et al., 1988). In addition, low-dose pretreatment of Brown Norway rats with mercuiy(II) chloride prevents development of adverse immunity (Szeto et al., 1999), and neonatal injection of mercury(II) chloride in Brown Norway rats renders them tolerant to mercury-induced (but not gold-induced) autoimmune phenomena (Field et al., 2000). These phenomena, transience of autoimmune effects as well as low-dose protection, are shown to be due at least in part to the development of regulatory immune cells. In the case of mercury(II) chloride, these cells have been identified as either IFN-y-producing CD8+CD45RC high regulatory T cells (Pelletier et al., 1990 Mathieson et al., 1991 Szeto et al., 1999 Field et al., 2003) or RT6.2+ T cells (Kosuda et al., 1994). In view of this, it is relevant to note that Lewis rats that produce predominantly CD8+ regulatory T cells ( suppressor T cells) in response to mercury(II) chloride are resistant to mercury-induced autoimmunity and instead display a polyclonal immunosuppressive response (Pelletier et al., 1987). Based on these differences in strain sensitivity, it is clear that susceptibility to mercury-induced autoimmune effects is dependent on MHC class II haplo-type (Aten et al., 1991). 

The Brown Norway rat has also been used to study the adverse immune response to D-penicillamine, with effects similar to those seen in some patients (Tournade et al., 1990). Recently, a series of studies have further explored D-penicillamine-induced autoimmunity in the Brown Norway rat, in particular with respect to immunoregulation (Masson Uetrecht, 2004). Interestingly, only 60-80% of all treated Brown Norway rats develop the autoimmune disease in addition, low-dose pretreatment with D-penicillamine has been shown to tolerize the animals to subsequent normally auto-immunogenic doses (Donker et al., 1984 Masson Uetrecht, 2004). It appeared that the observed tolerance is mediated by immune cells, including T and non-T cells. This again illustrates that idiosyncracy also occurs in animals and moreover that these diseases are subject to regulatory mechanisms. 

The reasons why LEW rats are resistant to the development of gold-induced autoimmunity are unknown. However, two points are interesting 1) LEW MHC is permissive since Brown-Norway.IL rats, which have the same MHC as LEW rats and non MHC genes from the BN background, develop gold-induced disease as Brown-Norway rats and 2) administration of anti-IFN-y mAb render LEW rats partially susceptible to allochrysine-induced autoimmunity with the appearance of anti-laminin antibodies even if their titer is 5 times lower than in Brown-Norway rats [76]. This mild response could explain why IgG deposits are not found in the kidneys of LEW rats injected with allochrysine and anti-IFN-Y antibodies. 

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