A new test shows a strikingly large percentage of antibody-producing immune cells don’t pass muster
BY LYNN LOVE
By the standards of even the laxest schools, 45
out of 100 is a failing grade. So it doesn’t seem to say much
for the human immune system that B cells, responsible for producing
tiny Y-shaped molecules called antibodies, are lucky to score half
that on a “standardized aptitude test” developed in the
laboratory of Rockefeller’s Michel Nussenzweig.
Antibodies are the immune system’s first
line of defense against viruses and other potentially harmful
antigens from outside the body. But when antibodies mistakenly
identify the body’s own tissues as harmful, they can trigger
an immune attack. The result: diseases such as rheumatoid arthritis
Nussenzweig’s research, published in Science, shows that
between 55 and 75 percent of the B cells developing in the bone
marrow and blood of healthy adults generate antibodies that are
prone to this self-destructive behavior. The research represents
the first time a group of immunologists has measured the immunity
aptitude of developing B cells.
“Until now, there has been no measurement
of the immune system that helps researchers determine precisely how
and when auto-reactivity occurs,” says Nussenzweig. “This
gives us a way to compare early auto-reactive B cells in healthy
adults to those of people with autoimmune disorders.”
The six-person research team, led by Hedda
Wardemann and Eric Meffre in Nussenzweig’s Laboratory of
Molecular Immunology, tested the early B cells’ aptitude by
analyzing the antibodies they produce. They cloned antibodies from
single B cells in different stages of development, then activated
those antibodies in test tubes and measured their biochemical
tendencies toward auto-reactivity.
That a large percentage of early B cells show
auto-reactive capacity doesn’t surprise Nussenzweig.
“The immune system’s responsibility for recognizing
antigens is vast, and B cells must possess an almost unlimited
capacity from the very beginning,” says Nussenzweig. When the
body demands such great diversity, the error rate can be high.
To compensate, the body has a series of
checkpoints that serve to weed out bad B cells before they fully
mature. “In the past 20 years, immunologists have learned
there are three mechanisms by which auto-reactive B cells are
removed from the system,” says Wardemann. Her research has
identified two of them – receptor editing and anergy –
that quell the overzealous B cells before they enter duty in the
immune system. Receptor editing enables B cells to reshuffle genes
to preserve the cell’s ability to function. Anergy allows B
cells to inactivate themselves without dying. Both mechanisms help
to avert autoimmunity.
Wardemann and Meffre want to learn whether
autoimmune reactions result from a failure in one of those
checkpoint systems or whether normal B cells somehow become
auto-reactive after passing the checkpoints.
The lab’s newest study addresses this
issue by comparing early B cells isolated from the blood of people
with lupus with those from a healthy population. Differences
between the two groups of cells could yield clues about what makes
developing B cells go bad.