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Lupus Research Update: 2008 Volume 1

Volume 1, 2008 - Online Edition | In This Issue


ALR Funded International Consortium Identifies Genes Linked to Lupus >
The Faces of Lupus: Eddie Kennison, Kansas City Chiefs >
Meet the Investigator — Mary K. Crow, M.D., Named Chair of Scientific Advisory Board >
Research Results — A New Clue in the Survival of Autoimmune B Cells >
Research Results — Narrowing Down a Lupus-Related Gene >
Research Results — Finding Hidden Clues to Children's Lupus Nephritis >
Research Results — Finding Ways to a Safer Pregnancy for Women with Lupus >
Drug Research and Development News >
Leaving a Legacy >

Research Results — A New Clue in the Survival of Autoimmune B Cells

It's well known that inflammation is a key contributor to the symptoms and tissue damage caused by lupus. Numerous mediators play a role in this inflammation, and identifying which ones and how they operate is an important step in finding ways to treat that inflammation. Alliance for Lupus Research grantee Richard Bucala M.D., Ph.D.,a professor of medicine and rheumatology at Yale University School of Medicine, and his team focus on one such chemical, the inflammatory cytokine called macrophage migration inhibitory factor (MIF). They want to know, why MIF levels so high in people with lupus and just how do these high MIF levels relate to disease manifestations.Richard Bucala M.D., Ph.D.

In a paper published in the February 2008 issue of the Journal of Biological Chemistry, Dr. Bucala and his team focused on the role of MIF in B lymphocytes, immune system cells that produce autoantibodies, including the anti-DNA and anti-nuclear antibodies that are the hallmark of lupus. These antibodies are not only used to diagnose lupus, but directly cause tissue damage. Ordinarily, B cells producing such anti-self antibodies should be destroyed or die off; in people with lupus, they survive.

In their paper, Dr. Bucala and his team report that MIF promotes B cells survival, which may be particularly significant for B cells producing damaging autoantibodies. By uncovering the biochemical pathway by which MIF supports B cell survival, the researchers have identified new targets for intervention. In fact, there are already several anti-MIF therapeutics in preclinical development that could disrupt MIF action. Dr. Bucala's group is involved in identifying such potential therapies, particularly those that can be taken orally and don't require injections.

The next step, he said, is to examine B cell function in mouse models of lupus and in people with lupus to see whether inhibiting the MIF pathway can reduce autoantibody production. The goal is not to entirely suppress MIF, because it is needed for various other functions, but to suppress the overproduction seen in people with lupus.

The other area of investigation is to examine how differing forms of the MIF gene contributes to high MIF expression. "High-expression MIF alleles (a form of the MIF gene) have been associated with autoimmune diseases like rheumatoid arthritis, scleroderma and asthma," said Dr. Bucala. "We're currently looking at the association between the MIF gene and lupus, including the incidence of lupus and disease manifestations such as kidney damage."

The idea is that individuals with high-expression MIF alleles might be more prone to developing lupus; or, if they developed lupus because of a confluence of environmental and genetic factors, they might have more severe disease manifestations.

This, in turn, suggests that there may be people with lupus with an MIF-dependent form of the disease who would be most likely to benefit from MIF-directed therapies. "And that makes the design of clinical trials more efficient and cost effective because we could just select those people that have a high-expressing MIF gene for the studies," said Dr. Bucala.

Yael Gore, Diana Starlets, Shirly Becker-Herman, Utako Kaneyuki, Lin Leng, Richard Bucala and Idit Shachar Macrophage Migration Inhibitory Factor (MIF) Induces B Cell Survival by Activation of a CD74/CD44 Receptor Complex. Journal of Biological Chemistry, Feb 2008.

Just the Facts

What the study showed:
Macrophage migration inhibitory factor (MIF) contributes to the survival of B cells that produce the autoantibodies responsible for lupus.

What it means:
Reducing MIF levels could, in turn, reduce the number of autoantibody-producing B cells, which are implicated in inflammation and damage during the disease. This suggests a possible target for more individualized and effective treatments for lupus flares.

What's next:
Inhibiting MIF expression in a mouse model of lupus to see if that changes the manifestation of the disease.

ALR funding:
$1.4 million


1.5 million

people in the U.S. have Lupus.

100 million

dollars committed to lupus research by the Alliance for Lupus Research.


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