Development of Systemic Lupus Erythematosus Linked to X Chromosome Gene

Lupus is a difficult to diagnose autoimmune disease that is characterized by fever, skin lesions, joint pain or arthritis, and anemia. It generally affects the kidneys, spleen, and various other organs.

SLE can occur in both males and females of all ages, but 90% of patients are women, primarily women in their childbearing years. This gender oriented tendency inspired investigators at the University of Texas Southwestern Medical Center (Dallas, USA) to seek causative factors somewhere on the X chromosome.

In the current study, published in the March 27, 2009, online edition of the journal the Proceedings of the [U.S.] National Academy of Sciences (PNAS), they focused on the X chromosome gene IRAK1 (interleukin-1 receptor associated kinase-1), which had been shown to have an association with SLE in earlier studies. This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced up regulation of the transcription factor NF-kappa B.

This study evaluated genetic data from 759 people who developed lupus as children, 5,337 patients who developed it as adults, and 5,317 healthy controls. Each group comprised four ethnicities: European-Americans, African-Americans, Asian-Americans and Hispanic-Americans. In addition, the investigators worked with a line of SLE-susceptible mice that had been genetically engineered to lack IRAK1.

Results of the human genetic study showed a definite link between IRAK1 and SLE in the patients exhibiting disease symptoms. In the mouse study, IRAK1 deficiency eliminated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity" associated with SLE.

"This first demonstration of an X chromosome gene as a disease susceptibility factor in human lupus raises the possibility that the gender difference in rates may in part be attributed to sex chromosome genes," said senior author Dr. Chandra Mohan, professor of internal medicine at the University of Texas Southwestern Medical Center. "The extensive involvement of IRAK1 in the regulation of the immune response renders its association with lupus a prime candidate for careful genetic and functional analysis. Our work also shows that blocking IRAK1 action shuts down lupus in an animal model. Though many genes may be involved in lupus, we only have very limited information on them."

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University of Texas Southwestern Medical Center