2008 Articles and Releases

Immune Systems in Overdrive

Are children who mount very robust responses to immune challenges predisposed to autoimmune diseases such as lupus and juvenile rheumatoid arthritis?  Dr. Barak Cohen is probing genetic variation in the immune response to find out. His research may lead to better treatments for children with these types of disorders.

The immune system works around the clock to fend off bacteria, viruses and other foreign invaders. But for people with an autoimmune disease, including rheumatoid arthritis, lupus or type 1 diabetes, the immune system functions in overdrive and mistakenly attacks the body’s own cells.

Why the body would turn on itself remains a mystery. But Barak Cohen, Ph.D., suspects that clues to explain the immune system’s misfiring lie within a patient’s own DNA.

“We think there may be common genetic variations that predispose certain people to autoimmune diseases,” says Cohen, assistant professor of genetics at Washington University School of Medicine. “Our ultimate goal is to find those variations.”

But rather than study patients who suffer from autoimmune diseases, Cohen and his colleagues have taken a radically different approach.  With a grant from the Children’s Discovery Institute, they are probing individual immune cells derived from large families to determine the normal range of genetic variation in the immune response.

“Our contention is that you can’t understand what goes wrong in autoimmune diseases until you understand the normal range of human genetic variation,” Cohen explains. “One way to understand what’s normal is to study variation found in large multi-generation families.”

Cohen is relying on blood samples collected from some 450 individuals from 30 large families. Each family has grandparents, parents and children.

The key cells that make up the immune system are T cells and B cells. B cells make antibodies that are specific to an immune challenge.  The researchers are using B cell lines from blood samples donated by the family members.  They have set out to measure molecular properties of the cells that will likely be influenced by underlying genetics.

“It’s much more precise to measure molecular traits of cells than to measure symptoms of disease such as blood pressure or cholesterol, which can vary considerably depending on whether the patient has exercised recently or ate a high-fat meal for dinner last night,” Cohen says. “But if you pick up a cell and measure that cell’s response to a stimulus, it is very exact.”

Cohen will measure whether there is a genetic component to how many receptors are on the surface of B cells, how robustly the cells respond to an immune challenge and other traits. “We’ll try to find the genetic determinants that lead some people to respond robustly to an immune challenge and others to respond normally or even weakly,” he says.

“Our hypothesis is that those who mount a very, very robust response to an immune challenge may be predisposed to autoimmune diseases,” Cohen says.

Once Cohen and his group have determined the normal range of genetic variations that underlie an immune response, they will investigate whether children with autoimmune diseases have variants outside this range. They will determine if variations at the higher end of normal are more common among children with B-cell autoimmune diseases, such as lupus, juvenile rheumatoid arthritis, and an inflammation of the muscles known as dermatomyocytis.

Eventually, Cohen says, identifying genetic variations in the immune response may lead to specific therapies that can neutralize the effects of those variations to treat autoimmune diseases more effectively.

By Caroline Arbanas

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