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 and lupus.

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.

Or both.

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.

September 25, 2003