Studies on mice with a disease similar to systemic lupus erythematosus, a devastating autoimmune disease that causes chronic inflammation and severe kidney disease, point to a novel therapeutic approach to treating this disease in humans, report scientists from The Rockefeller University in the Feb. 13 Science. These findings force a rethinking of the current scientific literature on this disease, according to the researchers.
Systemic lupus erythematosus affects mostly women between the ages of 20 and 40. The disease develops when the immune system, which normally attacks foreign invaders such as viruses and bacteria, attacks the body's own tissues. The immune system produces antibodies, called autoantibodies, directed against its own cells. Physicians generally prescribe antiinflammatory and immune system-suppressing drugs to treat the disease. These drugs, in addition to causing unwanted side-effects, are generally ineffective and non-specific. The new research identifies a critical link between autoantibodies and inflammation and suggests novel ways of uncoupling this connection.
"These studies show that preventing the activation of antibody receptors by autoantibodies is an effective way to treat autoimmune diseases like lupus," says senior author Jeffrey V. Ravetch, M.D., Ph.D., Theresa and Eugene Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology.
Prior to these studies the current dogma on how autoantibodies caused disease in lupus was based on a component of the immune system called the complement system, which comprises about 25 molecules that work in concert to aid in destroying bacteria. Complement was also thought to trigger inflammation caused by antibody-coated antigens, called immune complexes, which circulate through the bloodstream and are deposited in various tissues and organs in autoimmune diseases. Complement proteins, which can cause blood vessels to become dilated and leaky, contribute to the redness, warmth, swelling, pain and loss of function that characterize an inflammatory response.
Research from the Ravetch lab and elsewhere during the last few years has pointed to an alternative pathway in the immune system reaction in autoimmune diseases like lupus. In this approach, scientists think that Fc receptors, antibody-binding molecules that are crucial to both triggering an immune response and to turning off the response once the threat has been eliminated, play an important role. The role of complement in this pathway appears to be minimal.
In the new research, Ravetch and co-authors Raphael Clynes, M.D., Ph.D., and Calin Dumitru, developed a strain of mice lacking the gamma chain of the Fc receptor, which is responsible for activating immune cells by antibody complexes. When these Fc receptor deficient mice were bred to a strain of mice that spontaneously develop a disease closely matching human lupus, the researchers found a striking difference in the survival rates between mice missing the Fc receptor and those with an intact receptor. Eighty-two percent of mice without the Fc receptor were alive after nine months, as compared to less than 20 percent for lupus mice with an intact Fc receptor.
Ravetch and his colleagues found evidence of immune complexes and a complement protein called C3 in the kidneys of both strains of mice, but the Fc receptor deficient mice showed no evidence of inflammatory disease.
"These results show that despite the presence of immune complexes and C3 in the kidney, the inflammatory response is uncoupled, indicating that Fc gamma receptors are required for the initiation of the inflammatory cascade and complement activation is not sufficient," says Ravetch. "These findings argue for the development of new therapeutic strategies for the treatment of lupus based on blocking Fc receptors."
This work was supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases, both part of the federal government's National Institutes of Health.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. The university recently created six centers to foster collaborations among scientists to pursue investigations of Alzheimer's disease, of biochemistry and structural biology, of human genetics, of immunology and immune diseases, of sensory neurosciences and of the links between physics and biology.