Systemic lupus erythematosus, also known as "lupus" or SLE, is an autoimmune disease that can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. In lupus, the immune system attacks one's own tissues as if they were dangerous invaders. So far its cause is unknown, but if researchers can understand the processes of the disease better, they can come closer to the development of new therapies and diagnostic techniques. Now, researchers funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have made an important step toward that end.

Lupus seems to result from a complex interaction of genetic and environmental factors. Previous research has shown that it occurs more often, and with greater severity, among those of non-European descent, and that nine out of ten people with lupus are female. Since the X chromosome represents about 5% of the total DNA in women's cells, and only 2.5% of the DNA in men's cells, scientists speculate that at least some of the genetic factors may be on the X chromosome.

Chaim O. Jacob, M.D., Ph.D., at the University of Southern California School of Medicine, along with an international group of researchers, had previously done innovative work that led them to suspect that one such X-linked factor, IRAK1 (interleukin-1 receptor associated kinase 1), was involved in lupus. Past research had revealed that this gene plays a critical role in the immune response, but its role in autoimmune diseases had not been well identified before now. They investigated genetic information from large groups of individuals representing various ethnic backgrounds, a process known as a "forward" genetic approach. The researchers tested 13 different variants of the IRAK1 gene and found that five of these variants were associated with the disease.

To confirm the involvement of IRAK1 in lupus, the scientists collaborated with the laboratory of Chandra Mohan, M.D., Ph.D., at the University of Texas Southwestern Medical Center, to develop an animal model from a strain of mouse that was prone to develop lupus. When they removed IRAK1 from the animal's genetic makeup, the mice did not develop symptoms of lupus. This "reverse" genetic information gathered from mouse models, together with the data gathered from the forward genetic studies of people with lupus, helped to confirm IRAK1 as a risk factor for lupus.

Forward and reverse genetic analyses have been performed before. But often, many years and more than one published study separate the two approaches. The uniqueness of this study was the ability of the researchers to perform both forward and reverse genetics in close succession, and therefore more definitively establish a relationship between IRAK1 and lupus.

The important work of this team may help scientists develop new ways of diagnosing those at risk for lupus and could possibly lead to methods for treating the underlying causes, as well as the symptoms, of this troubling disease.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Jacob CO, Zhu J, Armstrong DL, Yan M, Han J, Zhou XJ, Thomas JA, Reiff A, Myones BL, Ojwang JO, Kaufman KM, Klein-Gitelman M, McCurdy D, Wagner-Weiner L, Silverman E, Ziegler J, Kelly JA, Merrill JT, Harley JB, Ramsey-Goldman R, Vila LM, Bae SC, Vyse TJ, Gilkeson GS, Gaffney PM, Moser KL, Langefeld CD, Zidovetzki R, Mohan C. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2009 Apr 14; 106(15): 6256-61. Epub 2009 Mar 27. PMCID: PMC2669395.