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B cells produce antibodies 'when danger calls, but not when it whispers'
Date:5/15/2014

ar's airbag, which won't be deployed unless you really need it," Hoffmann said. "You can imagine that if the airbag were poorly designed and if you brake very hard or have a slight accident, it could deploy slowly and be useless. You want it to deploy fully or not at all. That is what the B cell does when deciding whether it confronts something that is truly pathogenic or harmless. No B cell responds partially."

We have billions of B cells, and each one creates this threshold through a molecular circuit involving two molecules. One of these molecules, known as CARMA1, activates the other, IKKb, which further activates the first one.

"Positive feedback between the two causes infinite growth, and once you trigger it, there is no way to turn it off until the smart bullets are shot," said Hoffmann, whose research aims to understand and decode the language of cells. "But a second feature of positive feedback is that it can create a threshold only above which this runaway activation occurs."

He and his colleagues developed mathematical equations based on the molecular circuit and were then able to simulate, virtually, B cell responses. The team's resulting predictions were tested experimentally by their collaborators at the Laboratory for Integrated Cellular Systems at Japan's RIKEN Center for Integrative Medical Sciences. In one part of the study, the researchers made specific mutations in IKKb so that it could not signal back to CARMA1. They also made mutations in CARMA1 to prevent it from receiving the signal from IKKb. In both cases, the B cells responded partially, some of the time, like a weakly inflating airbag.

"It became a gray-zone response rather than a black-and-white response," said Hoffmann, who constructs mathematical models of biology.

The research could lead to better diagnosis of disease if patients with an autoimmune disorder, such as lupus, have a defect in this molecular circuit.


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Contact: Stuart Wolpert
swolpert@support.ucla.edu
310-206-0511
University of California - Los Angeles
Source:Eurekalert  

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