Structures from the human immune system's oldest branch shed light on a range o...( PHILADELPHIA How molecules of the o...),Health

PHILADELPHIA How molecules of the oldest branch of the human immune system have interconnected has remained a mystery. Now, two new structures, both involving a central component of an enzyme important to the complement system of the immune response, reveal how this system fights invading microbes while avoiding problems of the body attacking itself.

The structures may pave the way to more efficient therapeutics for such complement-mediated diseases as age-related macular degeneration, rheumatoid arthritis, or systemic lupus erythematosus, as well as give insight into the pathogenesis of other immune and inflammatory diseases.

The complement system, an evolutionarily old arm of the immune system, comprises a network of proteins that "complement" the work of antibodies in destroying foreign invaders. They serve as a rapid defense mechanism in most species, from primitive sponges to humans. When complement proteins are triggered into action by a microbe, the proteins ultimately form a complex enzyme called C3 convertase, initiating a cascade of immune and inflammatory reactions. In order to avoid self-attack, regulatory proteins such as factor H bind with C3b, a central component of C3, to help the immune system recognize the body's own tissue and keep complement in check.

Researchers at the University of Pennsylvania School of Medicine, in collaboration with colleagues at Utrecht University in the Netherlands, have determined the structure of C3 convertase and of the C3b fragment in complex with factor H. The work appears this month in two companion papers in Nature Immunology.

"Research on the complement system has waited more than 30 years for these structures," says senior author John Lambris, PhD, the Dr. Ralph and Sallie Weaver Professor of Research Medicine at Penn.

In the case of the C3 convertase structure, the researchers were able to make crystals by stabilizing the convertase complex with an inhibit
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