Insights from Mouse Research Point to Better Lupus Drugs

Crampton SP, Morawski PA, Bolland S. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus. Disease Models & Mechanisms (2014) 7:1033-1046. doi:10.1242/dmm.016451

When biological pathways described in mouse models of systemic lupus erythematosus (SLE) are linked with human susceptibility genes, the resulting mechanistic discoveries may lead to new therapeutic options for SLE patients, according to the authors of a new review.

The researchers describe a cross between two inbred species of mice in which a lupus-like syndrome developed that is biased to females. Symptoms include:

•   lymphadenopathy
•   splenomegaly
•   elevated anti-nuclear antibody titers, and
•   immune-complex-mediated glomerulonephritis.

Although such mice have an average lifespan of only 10 months, they are an ideal model of SLE because they demonstrate the long-term presence of autoantibodies.

Additional insights can be gained by studying mice that have been subjected to knockout or transgenic genetic modifications that significantly affect a single SLE susceptibility gene, according to the researchers.

In humans, various SLE susceptibility genes have been identified that affect the activation of autoreactive lymphocytes by:

•  increasing antigen presentation of self-antigens
•  lowering thresholds for activation, and
•  allowing survival of lymphocytes in suboptimal conditions.

Other susceptibility genes may enhance innate responses that are either spontaneous or occur in response to environmental triggers. Such genes also may alter the activation of IgG immune complexes and promote tissue destruction.

This research is yielding insights that may bear important messages for development of treatment. For instance:

Importantly, combining knowledge from human and mouse research suggests that anti-DNA autoantibodies, a key focus of lupus gene research, are not necessarily the sold factors involved in end-organ failure. When human HLA-DR2 and HLA-DR3 genes are transferred to and expressed in lupus-prone mice, HLA-DR2 but not DR3 does accelerate the production of anti-double-stranded DNA (dsDNA) antibodies. But this has no effect on mortality. Something else is going on.

Also, in SLE patients, several current studies are assessing the safety and efficacy or monoclonal antibody therapies against either interferon (IFN) receptors. Unfortunately, mouse studies show that IFN-receptor deficiency only reduces but does not eliminate SLE symptoms, suggesting that IFN blockage may have limited effectiveness in severe cases of human SLE.