A National Institutes of Health (NIH) team has identified in mice a critical role for the cell-signaling molecule interleukin-17 (IL-17) in the development of lupus nephritis, a potentially fatal kidney disease. Although IL-17 has been found in kidney biopsies of people with lupus nephritis, this is one of the first studies to suggest that it might directly contribute to disease progression. The team’s findings appear in the November 1 issue of Immunity.
Systemic lupus erythematosus (SLE), also known as lupus, is an autoimmune disease caused by the production of antibodies against a person’s own cells and tissues (autoantibodies). These autoantibodies can attack various organs of the body, and the kidneys are one of the primary targets. Approximately 50 percent of people with SLE may develop kidney disease, which can lead to organ failure. Current treatments for lupus nephritis aim to prevent or delay kidney failure, but there is no known cure for the disease.
In healthy people, IL-17 contributes to the body’s defenses by helping to recruit certain types of immune cells to infection sites. Researchers also have observed increased levels of IL-17 gene expression in the tissues of people with autoimmune diseases, including the kidneys of those with lupus nephritis. It is unclear, however, if lupus nephritis is causing the increase in IL-17 or if IL-17 is contributing to the disease.
An NIH team, led by Ulrich Siebenlist, Ph.D., chief of the Immune Activation Section in the NIAID Laboratory of Immunoregulation, used mouse models to explore the role that IL-17 may have in lupus nephritis.
The team first compared an SLE mouse model to an SLE mouse modified so that it did not produce an adaptor protein required for IL-17 function. During a one-year observation period, all but one of the 13 SLE mice died from lupus nephritis, while 9 of the 12 modified SLE mice survived. The team also found that SLE mice that did not produce IL-17 were similarly protected from developing lupus nephritis as the mice that did not make the IL-17 adaptor protein.
After examining the SLE and modified SLE mice, the team discovered that both groups of mice produced autoantibodies indicative of disease initiation. They also found that the autoantibodies had been deposited in the kidneys. However, in most of the mice that lacked the IL-17 adaptor protein or that did not express IL-17, lupus nephritis did not occur, whereas kidney disease was the cause of death in most of the SLE mice. These results suggested that IL-17 plays a key role in the development of SLE-induced kidney disease.
There are limited treatment options for SLE, and the first new drug in over 50 years was only recently approved for the treatment of SLE. Although a promising treatment for some people, the drug does not work for everyone and has not been tested to treat lupus nephritis. Identifying new and broadly effective therapeutics for lupus, particularly lupus nephritis, would greatly improve the lives of those affected by the disease.
Although the NIH study was performed in mouse models, the results show that blocking IL-17 significantly prevents lupus nephritis. Because an increase in IL-17 expression has been observed in patient tissue samples, the team speculates that it is likely that the molecule has a similar function in human disease. Targeting IL-17 could be a viable therapeutic for treating SLE in people, though more work is needed.
The team is now working with animal models of SLE to understand the link between autoantibodies that target the kidneys and IL-17 production. They also plan to investigate how IL-17 may contribute to disease development and what the consequences are of blocking IL-17 in ongoing disease. Finally, they intend to explore ways to block the IL-17 adaptor protein from functioning in people.
Pisitkun P, Ha H, Wang H, Claudio E, Tivy CC, Zhou H, Mayadas TN, Illei GG, Siebenlist U. IL-17 cytokines are critical in development of fatal lupus glomerulonephritis. Immunity. Nov. 1, 2012 (online ahead of print).
Dr. Siebenlist’s Lab
Last Updated October 09, 2012