Interferon-alpha levels may predict who might be at risk to develop lupus

Aug 1 2007

Certain families produce higher levels of a specific molecule, called interferon-alpha, that primes the body's immune system to turn on, and in some cases initiate an autoimmune attack on itself, according to new research from Hospital for Special Surgery in New York City.

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."