New Genetic Clue to Lupus Is Found

A newly discovered immune-system molecule may work against therapies targeting autoimmune disease
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Genetic variations mean that some people have activating Fc receptors on their B cells (red) and are more likely to develop autoimmune diseases.
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, voilà, 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 body’s 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 antibodies—molecules that are key players in immune responses to disease-causing microorganisms.

In many autoimmune disorders antibodies run amok, targeting not invading microbes, but a person’s 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 molecule—known as Fc gamma RIIb, or the IIb receptor for short—makes antibody production self-limiting: more antibodies means that more B cells close the antibody tap.

The Alabama team found that, when functional, the Reese’s Cup gene causes B cells to manufacture a previously undetected molecule—Fc 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 lupus—a risk factor the researchers said was equivalent to other established genetic effects for lupus. “Up until now, it was assumed—going back decades—that 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.”

How is it that the fused gene is silent in most people but gives rise to the feed-forward IIc receptor in some? Usually, the Reese’s Cup gene includes three nucleotides—DNA code letters—that serve as a stop sign, preventing the gene from making the IIc receptor molecule. But in 7 to 15 percent of the population a change in a single nucleotide of this stop sign eliminates its inhibitory effect.

The receptor was not discovered in B cells before, Kimberly says, because the part of it that lies outside the B cell membrane is identical to the IIb receptor. Only the intracellular part of this membrane-spanning protein, which tells the cell how to respond to antibody binding, differs. This difference explains why antibodies can bind readily to both receptors, but with opposite results.

But Jeffrey Ravetch, the Rockefeller University researcher who discovered the existence of Fc receptors and has spent the last several decades characterizing them, says the Science Translational Medicine paper proves nothing. “It’s technically flawed. The conclusions that they draw are not supported by the data they show. It’s lacking controls,” Ravetch told Scientific American in a telephone interview. He criticized nearly every method the researchers used, including the kinds of cells examined in cell-culture studies and the “on switch” the researchers used to activate the genes encoding Fc receptors in laboratory mice as well as the lack of quantitative data showing the amount of gene activity. “If you want to take a swing at the fences, you’d better be prepared to defend yourself,” Ravetch says. “As the authors are well aware, this is a topic for drug development, and those are very important efforts looking at endogenous brakes on the immune system to rein in uncontrolled immune response. If you’re going to take that swing, you want to get it right.”

Kimberly disagrees with Ravetch's objection, saying both the mouse and human data was quantitative, and noted that because mice don't make the IIc receptor, it was impossible to use the mouse's own "on switch" to activate the receptor, as Ravetch contends.

If the Alabama team’s result holds up, it could, they say, help to explain not only why some people overproduce antibodies that are bad for them, but also why some with autoimmune disorder do not respond to treatments meant to bind to and activate the inhibitory IIb receptors. If the drugs also activate IIc receptors, they could pump up antibody production as much as they dampened it. “There are always patients who don’t respond to any therapy,” says Jeffrey Edberg, a co-author on the paper. “That’s been one of the biggest issues in the field—to try to figure out why some people respond and others don’t.”

But whether the work will end up helping people with autoimmune disorders remains an open question. Bassil Dahiyat, president and CEO of Xencor, which has engineered antibodies to interact with the IIb receptor, points out that in studies of patients with lupus and rheumatoid arthritis the company has so far seen nothing to indicate that its engineered antibodies are causing B cells to make more antibodies. Rather, across the board, they see strong B cell suppression, he notes.

Still, if IIc receptor does play a role in B cell antibody production, then testing for its activity could potentially help Xencor and other gene therapy companies that are targeting B cells determine the best candidates for treatment with their products.

“Wouldn’t it be fantastic if we could see which patients would respond to different drugs?” Dahiyat says. That would be an important tool, he adds. “It’s fantastic to see these pieces come together.”

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