Lupus Study Finds Abnormal Alpha-Interferon Secretion May Lead To Better Gene Therapies For Immune-System Disease

The finding, published in today's issue of Science, is a major step toward explaining how systemic lupus erythematosus deceives the body's immune system into destroying healthy cells and could lead to enhanced therapies, said Dr. Virginia Pascual, assistant professor of pediatrics at UT Southwestern and an assistant investigator at the Baylor Immunology Institute.

Dr. Karolina Palucka, an associate investigator at the Baylor Immunology Institute and a researcher on the study, said, "The study is the first to identify how the interaction between lymphoid and myeloid dendritic cells -- which play fundamental roles to initiate immune responses to bacteria, viruses and other invading antigens -- can go wrong in lupus patients."

Pascual said the normal process appears to be altered in lupus patients as the dendritic cells are hyperactivated by alpha interferon, one of three main classes of specialized protein weapons activated in the body's otherwise normal war against viruses.

"Once that virus-fighting job is done, the interferon normally disappears, but not in lupus patients," she said.

Pascual said blocking the abnormal alpha-interferon secretion could be the key to developing better lupus therapies than the currently prescribed steroids, other anti-inflammatory agents and chemotherapy. More research is needed to test that theory, she said.

For the study, laboratory analyses were run on blood samples taken from 70 7- to 18-year-old lupus patients and a similar number of age-matched children and youth in control groups at Texas Scottish Rite Hospital for Children and Children's Medical Center of Dallas.

Palucka said the tests showed that alpha interferon plays a key role in the immune process going haywire as the dendritic cells activate B and T cells, two types of white blood cells, against infectious agents.

"The dendritic cells in their resting state are also critical for establishing tolerance, that is, the lack of immune responses to our own tissues," said Dr. Jacques Banchereau, senior author of the study, Baylor Immunology Institute director and adjunct professor of microbiology at UT Southwestern. "But, when stimulated with interferon as in lupus, the dendritic cells can induce strong immunity, eventually leading to autoimmunity, when body tissues are mistakenly attacked by the patient's own immune system."

The analyses, he said, revealed that dendritic cells are produced very efficiently when blood cells from normal donors were cultured with the serum from lupus patients. Then the researchers identified alpha interferon as the primary substance responsible for this effect, he said.

The researchers found that the young patients' dendritic cells capture blood-carried debris of normal cells that have died, Pascual said. Dead-cell components, she added, normally are removed by scavenger cells, and the immune system never encounters that waste. But this is not true in lupus patients, she said.

It is that abnormal reaction that can lead to the lupus patient's immune system attacking healthy cells and causing chronic inflammation that may affect skin, heart, lungs, joints, nervous system and, more often, the kidneys, Pascual said.

Dr. Patrick Blanco, a fellow at the Baylor Immunology Institute, and Dr. Michelle Gill, a fellow in pediatric infectious diseases at UT Southwestern, also worked on the project. Blanco, a physician from France, was the first to find that lupus white cells included a large number of dendritic cells.

The findings in the pediatric study, the researchers said, should also apply to adult lupus patients, who are predominantly women. Overall, the lupus incidence rate rivals that of multiple sclerosis, striking about 1 in 2,000 Americans. About 25 percent of all systemic cases start before age 18, and children tend to suffer more severe effects than adult patients, Pascual said.

Her earlier studies had demonstrated that the B cells, white blood cells that may mature into plasma cells to generate antibodies to fight infection, also pool abnormally in the blood of lupus patients. Other lupus studies had found abnormalities with the T cells. Those findings led to the latest study because B and T cells are activated by interaction with the dendritic cells, Pascual said.

The work was funded by the Baylor Health Care System Foundation, the Centre Hospitalo-Universitaire de Bordeaux in France and the National Institutes of Health.