UCSF Scientist and Colleagues Develop Diagnostic Aid for Rare Inherited Immune System Disorder

Inherited diseases of the immune system are rare, but important, not only for the families who have them, but also because they teach scientists about how our bodies fight infection and provide clues to the development of new treatments. During the past 15 years more than 140 immune deficiency disease genes have been found, but one very puzzling condition, hyper-IgE syndrome, has resisted all attempts at gene identification-until now. When first described in the 1960's, hyper-IgE syndrome was also called "Job's Syndrome," because the symptoms of afflicted individuals include skin boils like the Biblical character. Additional features of the syndrome include severe pneumonias that do not heal properly, leaving cavities in the lung tissue, as well as extremely high blood levels of one type of antibody, IgE. UCSF Professor of Pediatrics and Human Genetics Jennifer Puck, MD, has studied the condition for many years and, with her colleagues at the National Institutes of Health (NIH) in Bethesda, Maryland, developed a clinical scoring system to aid in diagnosis. Her group described for the first time in 1999 that hyper-IgE syndrome is actually a multi-system disorder-patients have fragile bones that break easily and are loose-jointed and prone to curvature of the spine. Their baby teeth often don't fall out at the normal time and so must be pulled by a dentist so that the permanent teeth can come in properly. Despite studies of white blood cells and attempts to trace the defect through generations in families, the cause of hyper-IgE syndrome remained unknown until this year when Puck and her group, as well as a group in Japan led by Hajime Karasuyama, MD, and Yoshiyuki Minegishi, MD, learned that patients with the syndrome have mutations in the STAT3 gene, encoding a protein that carries signals from the surface to the interior of cells. Puck is co-senior author of the study published in the New England Journal of Medicine that appeared online last week. The breakthrough for this team was a study using microarray chips to show differences in gene expression by comparing a large group of patients with hyper-IgE syndrome them to normal controls subjects. The hyper-IgE patients' white blood cells were overactive in some ways, but had low responses to a signaling compound, or cytokine, called interleukin-6, that works on cells by activating STAT3. Patient mutations in STAT3 cause a defective protein to be made that blocks transmission of signals. STAT3 is important not only in the immune system, but also in the skin, lung, bones and other organs. In fact, mice that lack STAT3 do not survive. "Now that the hyper-IgE disease gene is known to be STAT3," Puck said, "we can see why patients have the particular problems they do with boils of the skin and lung tissue damage following their infections." The next challenge will be to understand why IgE levels are so high. But meanwhile being able to do a gene test for the condition will let doctors diagnose children with hyper-IgE syndrome early. Then, antibiotic treatment at the first sign of infection will keep them free of complications later in life.

STAT3 Mutations in the Hyper-IgE Syndrome Jennifer M. Puck, MD, Bodo Grimbacher, MD, et al. New England Journal of Medicine, published online September 19, 2007 Abstract | Full Text | Full Text (PDF)

Related Links: UCSF Celebrates Opening of Jeffrey Modell Center for Primary Immunodeficiency UCSF Today, May 24, 2007 Jennifer Puck, Pioneer Researcher in Immunodeficiency and X-SCID UCSF Today, December 27, 2006