Using high-throughput sequencing, investigators make a surprising discovery about the immune system.
As elite soldiers of the body’s immune response, B cells serve as a vast standing army ready to recognize and destroy invading antigens, including infections and cancer cells. To do so, each new B cell comes equipped with its own highly specialized weapon, a unique antibody protein that selectively binds to specific parts of the antigen. The key to this specialization is the antigen-binding region that tailors each B cell to a particular antigen, determining whether B cells survive boot camp and are selected for maturation and survival, or wash out and die.
Now, using high-throughput sequencing technology and computational and systems biology, investigators from Beth Israel Deaconess Medical Center (BIDMC) have discovered that B cells can be selected for survival independent of their antigen binding regions. Described online this week in the journal Proceedings of the National Academy of Sciences (PNAS), the findings add a surprising new dimension to the understanding of antibody repertoires – each individual’s complement of millions of B cells -- and the potential for shaping these repertoires to better fight disease.
“B cells play essential roles in vaccination, infection, autoimmunity, aging and cancer,” explains senior author Ramy Arnaout, MD, DPhil, an investigator in the Department of Pathology at BIDMC and Assistant Professor of Pathology at Harvard Medical School whose work focuses on the emerging field of high-throughput multimodality immunology, also known as immunomics. “We were surprised and excited to find that B cell survival could be influenced by a non-antigen-binding region of the antibody, specifically the ‘elbow’ region that connects the antigen-binding regions to the signaling domain.”
Each new B cell makes its own unique antibody by mixing and matching from a set of a few hundred genes, taking one each from subsets called V, D and J. The most diverse part of an antibody is the region where the three genes come together, a stretch called the third complementarity-determining region, or CDR3.
“CDR3 is thought to be the single most important determinant of antigen binding,” explains Arnaout. As a result, in understanding how the body fights infections and in developing new vaccines, immunologists have primarily focused their attention on CDR3, while considering other parts of the antibody, including the elbow region, to play secondary roles.
In their new study, Arnaout and colleagues sequenced 2.8 million VDJ-recombined heavy-chain genes from immature and mature B-cell subsets in mice. “We initially wanted to ask how selection on CDR3 changed antibody repertoires during B-cell maturation,” says Arnaout. But, unexpectedly, during the course of the investigation, they found they were instead focused on the antibody’s ‘elbow’ region.”
They found that B cells for which antibodies use V genes that encode ‘looser’ elbows were more likely to mature, regardless of their CDR3 sequence. This effect was both distinct from, and larger than previously described maturation-associated changes in CDR3 in the mice. Furthermore, it had a unique source: Differences in the V genes were hard-coded into the genome, as opposed to the mixed-and-matched combination of V, D and J genes that typically differs from B cell to B cell.
“This discovery was a little like going to watch a concert pianist perform and being mesmerized by her fingers only to realize that music was also coming from her elbows,” says Arnaout. “It was something of a shock.”
One explanation for how this “loose elbow” promotes survival relates to the bending process of the antibody. “B-cell selection and maturation depend on signaling,” he explains. “Antigen binding is the signal, but for it to get to the cell it has to go through the elbow. It, therefore, makes sense that previous experiments have found that disrupting the elbow abolishes signaling without affecting antigen binding. We think a loose elbow might affect how the cell perceives binding, which then determines whether the B-cell soldiers are able to divide and form an elite antigen-fighting platoon, or turn in their weapons and retreat.”
Ultimately, the authors write, “This discovery adds a surprising new dimension to the understanding of antibody repertoires and might one day help us shape them ourselves.”
Coauthors include BIDMC investigators Joseph Kaplinsky (first author) and Anthony Li and New York University Medical Center investigators Amy Sun, Maryaline Coffre and Sergei B. Koralov (co-senior author.) Coffre and Koralov were supported by a grant from the Beckman Foundation.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.
The BIDMC health care team includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Health Care, Commonwealth Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.
Bonnie Prescott | newswise
Cnidarians remotely control bacteria
21.09.2017 | Christian-Albrechts-Universität zu Kiel
Immune cells may heal bleeding brain after strokes
21.09.2017 | NIH/National Institute of Neurological Disorders and Stroke
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
21.09.2017 | Physics and Astronomy
21.09.2017 | Life Sciences
21.09.2017 | Health and Medicine