NEW YORK, N.Y.—July 30, 2007
Our immune system is able to defeat disease-causing viruses and bacteria every day using chemical weapons, like interferon-alpha, that have been honed over time. But like anything else, we can have too much of a good thing.
Using blood samples from two large repositories, rheumatologist Mary K. Crow, M.D., and her colleagues at Hospital for Special Surgery compared 266 patients with systemic lupus erythematosus (SLE), an autoimmune disease, with 405 of their healthy relatives. Specifically, Dr. Crow, who is director of Rheumatology Research and associate chief of the Division of Rheumatology at Hospital for Special Surgery, and her team were looking at levels of interferon-alpha. The researchers found that when an SLE patient had high blood levels, so did many of their healthy first degree family members. There was a genetic link.
The study, which is now online in advance of print, will be in the September issue of Genes and Immunity.
“There were a number of first degree relatives of patients with SLE that had high interferon-alpha levels,” says Timothy Niewold, M.D., first author of the study and a former rheumatology fellow at Hospital for Special Surgery. “But otherwise, those family members looked and felt perfectly fine. All of their diagnostics were normal.”
Our immune system works by distinguishing self from non-self, so that it preferentially attacks foreign microbes. Interferon-alpha is normally a helpful molecule in this regard, leading the fight against invading viruses. Genes producing high levels of interferon-alpha have probably been selected over time to help fight infection. But high levels of interferon-alpha in some individuals may also confuse the immune system so that it doesn’t know self from non-self anymore – turning and attacking its own tissue as in SLE.
As far back as the 1970s, doctors had known that a characteristic of patients with SLE, who are mainly women in their childbearing years, was an abnormally high blood level of interferon-alpha. However, they didn’t know if the high interferon levels were the cause of the disease or just an associated side-effect.
“A role for interferon-alpha in lupus has been suggested for a number of years,” says Dr. Crow, who is also director of the Autoimmunity and Inflammation Research Program and co-director of the Mary Kirkland Center for Lupus Research at Hospital for Special Surgery. “However, all of the studies to date had focused on how the levels of interferon-alpha were controlled and what the effects of such high levels were. The real question was whether interferon-alpha was playing a primary role in the disease or not.”
The blood samples showed that some family members of patients with high levels of interferon-alpha also had higher levels than unrelated healthy individuals, irrespective of their ethnic background. This observation supported the idea that high interferon-alpha levels play an important primary role in the disease.
Next, the researchers examined the samples for two types of autoantibodies common to SLE patients. SLE patients with low levels of interferon-alpha were more likely to have neither of the characteristic autoantibodies, while patients with the highest levels were more likely to have both. However, the healthy family members with high interferon-alpha did not have either autoantibody. This led the scientists to propose a “two-hit” model for the development of lupus. Genetics that cause high levels of interferon-alpha may predispose a person to SLE, but the disease appears only when something else, perhaps an environmental factor, pushes the immune system to the breaking point and causes the production of the damaging autoantibodies.
“The high level of interferon-alpha doesn’t always cause the disease, because many healthy family members have high levels,” says Dr. Niewold, who is now an Instructor in the Section of Rheumatology at the University of Chicago. “We think, however, that those levels somehow prime the immune system, lowering the threshold, so that when the wrong stimulus comes along, the cells of the immune system begin making the autoantibodies and the person develops SLE.”
The researchers are now working to identify the other players that are involved in the progression of SLE. They hope that as they know more, they may be able to identify those at high risk and diagnose the condition early enough to intervene and reverse the disease. Observational and genetic studies of families with high levels of interferon-alpha will also help them to pinpoint the other factors, including the relevant genetic variations that determine why one family member develops the disease while another doesn’t.
“The hope is that we may be able to use interferon-alpha levels as a measurement to predict who might be at risk to develop this disease,” says Dr. Crow, who is the immediate past president of the American College of Rheumatology. “We can’t do that yet, but the success of this study is very encouraging.”
Jing Hua and Thomas J.A. Lehman at the Mary Kirkland Center for Lupus Research at Hospital for Special Surgery and John B. Harley at the Oklahoma Medical Research Foundation in Oklahoma City also contributed to this paper. This research was funded by the National Institutes of Health, the Alliance for Lupus Research, the Lupus Research Institute and the Mary Kirkland Center for Lupus Research at HSS.
About HSS | Hospital for Special Surgery
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the eighth consecutive year) and No. 3 in rheumatology by U.S. News & World Report (2017-2018). Founded in 1863, the Hospital has one of the lowest infection rates in the country and was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center four consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State. In 2017 HSS provided care to 135,000 patients and performed more than 32,000 surgical procedures. People from all 50 U.S. states and 80 countries travelled to receive care at HSS. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The culture of innovation is accelerating at HSS as 130 new idea submissions were made to the Global Innovation Institute in 2017 (almost 3x the submissions in 2015). The HSS Education Institute is the world’s leading provider of education on the topic on musculoskeletal health, with its online learning platform offering more than 600 courses to more than 21,000 medical professional members worldwide. Through HSS Global Ventures, the institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally.