New Genetic Clue to Lupus Is Found

A newly discovered immune-system molecule may work against therapies targeting autoimmune disease

By Jenni Laidman

Genetic variations mean that some people have activating Fc receptors on their B cells (red) and are more likely to develop autoimmune diseases. Image: Robert Kimberly, University of Alabama at Birmingham

It was a Reese's Peanut Butter Cup moment in genetic evolution: The end of one gene fused to the beginning of another and, voil, a new, composite gene was born. In most people the two-component gene does not work. But in a small percentage the gene functions and puts its possessors at increased risk for lupus and potentially other autoimmune diseases, in which the immune system attacks the bodys own tissues, says a team of researchers at the University of Alabama at Birmingham.

If the Birmingham researchers are right, the gene could be a clue to improving therapy for autoimmune diseases. At least one prominent researcher has roundly criticized the putative lupus link, however.

In a paper published December 18 in Science Translational Medicine, the Alabama researchers said that working copies of the fused gene disrupt a tidy feedback loop that the immune system uses to regulate the production of antibodiesmolecules that are key players in immune responses to disease-causing microorganisms.

In many autoimmune disorders antibodies run amok, targeting not invading microbes, but a persons organs. Cells known as B lymphocytes, or B cells, secrete the antibodies, and so the B cells make an attractive target for therapies to control autoimmune conditions. Many scientists have focused specifically on manipulating a molecule on B cells that, when bound by antibodies, normally tells the B cells, Stop! No more antibodies! In a healthy immune system, activation of this moleculeknown as Fc gamma RIIb, or the IIb receptor for shortmakes antibody production self-limiting: more antibodies means that more B cells close the antibody tap.

The Alabama team found that, when functional, the Reeses Cup gene causes B cells to manufacture a previously undetected moleculeFc gamma RIIc. When that molecule is activated by an antibody it countermands the IIb stop order, telling B cells to secrete more antibodies. In people with the fusion gene that encodes the IIc receptor molecule, antibodies are just as likely to engage IIc as IIb and thus induce B cells to overproduce antibodies. "We believe this is going to change the way people think about feedback and B cells," Robert Kimberly, co-author of the Science Translational Medicine paper, told Scientific American in a telephone interview.. "The way feedback is depicted in the textbook is incomplete."

The researchers demonstrated the contrarian role of the IIc molecules in studies of both mice and in human and mouse cells in culture. When mice B cells, which don't normally make the IIc molecule, were genetically altered to produce IIc, they generated more antibodies than the B cells of unaltered littermates. Human B cells that had at least one copy of the functioning fusion gene expressed the IIc molecule. Further, the researchers reported, people who carried two copies of the gene that makes IIc had an early immune response to an anthrax vaccine that was two and a half times greater than those without the IIc molecule. Because the vaccine induced antibody production, the rise was another a sign that IIc amps up antibody production. To make the link to IIc and lupus, the researchers compared the genetic profiles of 1,425 people with lupus with the same number without and found that those with the working copies of the IIc-encoding gene had at a 20 percent increased odds of contracting lupusa risk factor the researchers said was equivalent to other established genetic effects for lupus. Up until now, it was assumedgoing back decadesthat there was only a brake on the B cell, Kimberly says. But the expression of IIc counterbalances that brake and gives the B cell a feed-forward signal rather than a feedback.

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New Genetic Clue to Lupus Is Found