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!
Cells migrate collectively by intermittent bursts of activity
30.09.2016 | Aalto University
The structure of the BinAB toxin revealed: one small step for Man, a major problem for mosquitoes!
30.09.2016 | CNRS (Délégation Paris Michel-Ange)
Heavy construction machinery is the focus of Oak Ridge National Laboratory’s latest advance in additive manufacturing research. With industry partners and university students, ORNL researchers are designing and producing the world’s first 3D printed excavator, a prototype that will leverage large-scale AM technologies and explore the feasibility of printing with metal alloys.
Increasing the size and speed of metal-based 3D printing techniques, using low-cost alloys like steel and aluminum, could create new industrial applications...
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...
Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.
Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
30.09.2016 | Event News
29.09.2016 | Event News
28.09.2016 | Event News
30.09.2016 | Materials Sciences
30.09.2016 | Earth Sciences
30.09.2016 | Life Sciences