Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

B cells produce antibodies 'when danger calls, but not when it whispers'

16.05.2014

The specialized immune cells only act when specific threshold is reached

The immune system's B cells protect us from disease by producing antibodies, or "smart bullets," that specifically target invaders such as pathogens and viruses while leaving harmless molecules alone. But how do B cells determine whether a threat is real and whether to start producing these weapons?


Mutations in the B cell's key molecular circuit in chickens, shown in green, resulted in ambiguity about whether the threshold, where the 0 line is, had been reached. Without these mutations, there were no such ambiguities, as the blue dots show.

Credit: Japan's RIKEN Center for Integrative Medical Sciences

An international team of life scientists shows in the May 16 issue of the journal Science how and why these cells respond only to true threats.

"It is critical for B cells to respond either fully or not at all. Anything in between causes disease," said the study's senior author, Alexander Hoffmann, a professor of microbiology, immunology and molecular genetics in the UCLA College of Letters and Science. "If B cells respond wimpily when there is a real pathogen, you have immune deficiency, and if they respond inappropriately to something that is not a true pathogen, then you have autoimmune disease."

The antibodies produced by B cells attack antigens — molecules associated with pathogens, microbes and viruses. A sensor on the cell's surface is meant to recognize a specific antigen, and when the sensor encounters that antigen, it sends a signal that enables the body's army of B cells to respond rapidly. However, there may be similar molecules nearby that are harmless. The B cells should ignore their signals — something they fail to do in autoimmune diseases.

So how do the B cells decide whether to start producing antibodies?

"These immune cells are somewhat hard of hearing, which is appropriate because the powerful and potentially destructive immune responses should jump into action only when danger calls, not when it whispers," said Hoffmann.

The B cells make their response only when a rather high threshold is reached, Hoffmann and his colleagues report. A small or moderate signal — from a harmless molecule, for instance — gets no response, which reduces the risk of false alarms.

"It's like your car'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.

###

Co-authors of the study included Mariko Okada-Hatakeyama, a professor at Japan's RIKEN Center, and Marcelo Behar, a postdoctoral scholar in Hoffmann's laboratory who has now accepted a position as an assistant professor at the University of Texas, Austin.

Funding sources for the research included federal grants to Hoffmann by the National Cancer Institute and National Institute of Allergy and Infectious Diseases (grants R01CA141722, R01AI083453), both part of the National Institutes of Health, and funding to Okada-Hatakeyama from the Cell Innovation Program of Japan's Ministry of Education, Culture, Sports, Science and Technology, and the Japan Society for the Promotion of Science.

Hoffmann's research: Correcting cellular miscommunication

Many diseases are related to miscommunication in cells, Hoffmann said. In other research, he and colleagues showed for the first time that it is possible to correct a certain type of cellular miscommunication — one involving the connection of receptors to genes controlled during inflammation — without severe side effects. That research, federally funded by the NIH, was published in the journal Cell on Oct. 10, 2013.

Hoffmann and his colleagues may be able to develop therapeutic strategies that do not simply inhibit or shut down faulty communication lines in diseased cells but actually correct the misunderstanding. (They have already accomplished this with cells in a Petri dish. Their next step is to see if this can be done in an animal, and then in a human.)

Stuart Wolpert | Eurek Alert!

Further reports about: Cell RIKEN autoimmune immune mutations pathogens produce producing threshold viruses

More articles from Life Sciences:

nachricht Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>