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!
The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie
How protein islands form
15.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
Researchers from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, the Italian Space Agency (ASI), and the Instituto Geofisico--Escuela Politecnica Nacional (IGEPN) of Ecuador, showed an increasing volcanic danger on Cotopaxi in Ecuador using a powerful technique known as Interferometric Synthetic Aperture Radar (InSAR).
The Andes region in which Cotopaxi volcano is located is known to contain some of the world's most serious volcanic hazard. A mid- to large-size eruption has...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
16.08.2017 | Physics and Astronomy
16.08.2017 | Materials Sciences
16.08.2017 | Interdisciplinary Research