If you're a Caucasian male, your chances of getting lupus are slim. However, your odds double or triple if you're Native American , African American, Hispanic, or Asian. If you're a woman, your odds are 10-15 times higher than those of Caucasian men. In fact, 90% of lupus victims are women. To add insult to injury, lupus is a leading cause of kidney disease, stroke and premature cardiovascular disease in women of childbearing age. Scientists don't know the reasons for lupus' selective attacks. However, thanks to the relentless work of researchers like JAX Professor Derry Roopenian, Ph.D.,, the mysterious pathogenesis of lupus is being unraveled.
In a study using lupus-prone JAX® Mice strain BXSB/MpJ (000740), Roopenian, postdoctoral fellow Jason Bubie, and colleagues at the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases have shown that interleukin 21 (IL21) plays a key role in the pathogenesis of lupus (Bubier et al. 2009).
What is lupus?
Technically known as systemic lupus erythematosus (SLE), lupus is a chronic autoimmune disease — a disease in which the body is attacked by its own immune system. Unlike other autoimmune diseases, such as type 1 diabetes, in which an errant immune system attacks only certain tissues, SLE is a systemic disease in which abnormal antibodies attack a variety of tissues and organs, including the skin, joints, blood and kidneys, resulting in unexplained fever, extreme fatigue and sometimes severe renal disease.
Approximately 500,000 to 1.5 million Americans have been diagnosed with lupus and more than 16,000 develop the disease each year. For most people, lupus symptoms are mild, affecting only a few organs, but, for others, the symptoms are life-threatening. The genetic basis of lupus has been difficult to determine; only 5% of people diagnosed with lupus have a close relative who already has or may develop the disease, and only about 5% of children whose parents have lupus develop the disease. Lupus is typically diagnosed in people between ages 15 and 44. (S.L.E. Lupus Foundation).
Lupus and the Yaa mutation
Among the mice used to study lupus are those bearing the Y chromosome-accelerated autoimmunity and lymphoproliferation (Yaa) allele. JAX distributes two strains carrying this mutation: B6.SB-Yaa/J (000483) and BXSB/MpJ. The mutant Yaa allele is the result of a duplication of at least 17 genes on the X chromosome, including toll-like receptor 7 (Tlr7), and their translocation to the Y chromosome. This translocation results in the doubling of expression of these genes in male mice. Typically, BXSB/MpJ males spontaneously develop a severe autoimmune disease characterized by enlarged lymph nodes and spleens, hemolytic anemia, hypergammaglobulinemia, monocytosis and immune complex glomerulonephritis. In contrast, BXSB/MpJ females, which have only one transcriptionally active copy of their X chromosome, and BXSB.B6-Yaa+/J (000742) mice (BXSB mice that lack the Yaa duplication) only develop an attenuated form of autoimmune disease.
Lupus and interleukin 21
Roopenian has been researching lupus in mouse models for over a decade. In 2009, he and his research team sought to determine the role of IL21 in the pathogenesis of lupus. IL21 is a pleiotropic cytokine expressed on several different T cell types (primarily CD4 T cells) and induces multiple T and B cell-mediated immune responses. Its role in lupus was suspected because Roopenian and his collaborators had determined that BXSB/MpJ mice have abnormally high levels of IL21 transcripts and serum protein; recent studies had suggested that allelic variation in the Il21 gene is a risk factor for human SLE. Wondering what might happen if BXSB/MpJ mice were rendered IL21-deficient, Roopenian bred it to an IL21 receptor (Il21r)-deficient stock and produced BXSB.129 Il21rtm1Wjl mice, mice with the Yaa mutation but unable to respond to IL21. These mice grew up healthy, developing none of the abnormalities characteristic of SLE.
A ray of hope
These findings are a ray of hope for lupus victims. Conventional therapies for lupus don't cure the disease. They merely mask its symptoms and produce harsh side effects. More effective therapies are likely if the basic molecular and cellular mechanisms involved in lupus' pathology are dissected in human patients and mouse models such as the BXSB/MpJ mouse. Roopenian's research helps pave the way for the development of effective protein-based therapies, including monoclonal antibodies that target key molecular lupus pathways, such as interleukin 21 signaling. Said Roopenian: "Our findings provide strong clues about how SLE occurs and a clear indication of the importance of interleukin 21 signaling in lupus-like diseases. They suggest that interrupting interleukin 21 signaling events may prove to be an effective therapeutic option for human SLE."
Reference
Bubier JA, Sproule TJ, Foreman O, Spolski R, Shaffer DJ, Morse HC 3rd, Leonard WJ, Roopenian DC. 2009. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci U S A 106:1518-23.