Lupus Study Reveals Possible Drug Target

The findings were reported in the May 1, 2003, issue of Nature.

The researchers discovered how Tall-1, a protein implicated in lupus, binds to its main receptor, Baff-R. The Tall-1 molecule is an important regulator of the immune system. It spurs B cells to mature and produce antibodies, one of the body's main defense mechanisms. Mice engineered to make too much Tall-1 develop lupus-like symptoms.

Structural studies showed that Baff-R sits on Tall-1 in a saddle-like manner. Tall-1 has a small hump with valleys on each side. Baff-R sits on the hump with its two binding domains extending into the valleys on Tall-1. A small section of the Baff-R receptor is crucial for binding the Tall-1 molecule and spurring B cells to mature. Preventing this binding would prevent the B cell maturation that contributes to lupus and other autoimmune diseases.

"This fragment is a good candidate for drug development because we believe such a small molecule would be easy to synthesize and to get into the body where it could bind to and neutralize Tall-1,” said Gongyi Shang, Ph.D., assistant professor in the integrated department of immunology at National Jewish Medical and Research Center (Denver, CO, USA) and the University of Colorado Health Sciences Center (Denver, USA).



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National Jewish Medical and Research Center
University of Colorado Health Sciences Center