SLE (NZB X NZW F1, MRL, BXSB, TMPD)
Numerous mouse strains have been studied over the years as animal models of SLE. Some strains develop lupus spontaneously, such as NZB X NZW (F1) (NZB/W) hybrid mice, MRL mice, and BXSB male mice. Other models, such as tetramethyl-pentadecane (TMPD, pristane) induced lupus, are inducible with chemicals. The spontaneous models afford hope that if the genetic defect(s) responsible for lupus-like disease in these mice can be identified, similar defects will be found in human lupus. However, the inducible TMPD model more closely mimics the abnormali-ties in interferon (IFN) α and β production seen in most lupus patients.
The NZB/W model was the first murine model of lupus nephritis. New Zealand Black (NZB) mice develop AIHA and the female New Zealand White (NZW) mice develop mesangial glomerulonephri-tis late in life. In contrast, the F1 hybrid (NZB/W) develops early-onset severe (proliferative, immune complex-medi-ated) glomerulonephritis along with ANA, antichromatin, and anti-dsDNA antibod-ies. However, these mice lack other classic clinical and serological manifestations of SLE, such as arthritis, inflammatory skin rashes, serositis, and anti-Sm autoanti-bodies. Extensive genetic analysis of this strain has revealed three major susceptibil-ity intervals on chromosomes 1, 4, and 7. Each of these intervals appears to contain multiple disease-susceptibility genes and several candidate genes have been identi-fied. NZB/W mice have been used widely for preclinical studies of various therapeu-tic interventions for lupus nephritis.
MRL mice, an inbred strain derived from several other strains, develop ANAs and late-onset glomerulonephritis remi-niscent of SLE. A spontaneously occurring mutation led to impressive lymphoprolif-eration (lpr mutation), severe, early-onset nephritis closely resembling proliferative lupus nephritis, the development of ero-sive arthritis (more characteristic of RA than SLE), salivary gland inflammation (reminiscent of Sjögren’s syndrome), vas-culitis, and skin disease resembling cuta-neous lupus. Both MRL and MRL lpr/lpr mice develop a host of autoantibodies
characteristic of SLE, including anti-Sm and anti-dsDNA as well as severe hyper-gammaglobulinemia. These autoantibodies develop earlier in the presence of the lpr mutation, which generally accelerates the onset of lupus-like disease in this strain. The abnormalities caused by the lpr mutation are due to an ETn retrotransposon inser-tion into the Fas gene, which encodes an important protein mediator of apoptosis. Defective apoptosis of lymphocytes leads to the accumulation of CD3+CD4−CD8− (“double negative”) T cells, accounting for the massive lymphoproliferation seen in MRLlpr/lpr mice.
This strain was created by crossing male SB/Le and female C57BL/6J mice. Male, but not female, BXSB mice develop severe glomerulonephritis, lymphade-nopathy, splenomegaly, AIHA, and anti-dsDNA autoantibodies. Thus, the sex predilection is an important difference from human lupus and most other murine lupus models. A mutant gene located on the Y chromosome, designated Yaa (Y chromosome-linked autoimmune accel-eration), causes accelerated lupus-like dis-ease in male BXSB mice. A recent study showed that the Yaa mutation results from translocation of a 4-megabase portion of the X chromosome to the Y chromosome, leading to increased expression of several genes that are normally X linked, includ-ing TLR7.
Intraperitoneal injection of pristane (2, 6, 10, 14 tetramethylpentadecane, TMPD) can induce a lupus-like syndrome in non-autoimmune-prone mice characterized by proliferative glomerulonephritis, erosive arthritis, pulmonary vasculitis, and a variety of lupus autoantibodies, including anti-dsDNA and anti-Sm.
All or nearly all immunocompetent mouse strains are susceptible to lupus induced by this hydrocarbon oil. This inducible model of lupus is, at least so far, unique in reproducing the increased levels of IFN-α and IFN-β seen in the majority of lupus patients. The disease is largely abrogated in type I interferon receptor-deficient mice.