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
“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
“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