Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Newly Identified B-Cell Selection Process Adds to Our Understanding of Antibody Diversity

11.06.2014

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.”

... more about:
»Antibody »B-cell »BIDMC »CDR3 »elbow »genes

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

Further reports about: Antibody B-cell BIDMC CDR3 elbow genes

More articles from Life Sciences:

nachricht Moth takes advantage of defensive compounds in Physalis fruits
26.08.2016 | Max-Planck-Institut für chemische Ökologie

nachricht Designing ultrasound tools with Lego-like proteins
26.08.2016 | California Institute of Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Streamlining accelerated computing for industry

PyFR code combines high accuracy with flexibility to resolve unsteady turbulence problems

Scientists and engineers striving to create the next machine-age marvel--whether it be a more aerodynamic rocket, a faster race car, or a higher-efficiency jet...

Im Focus: X-ray optics on a chip

Waveguides are widely used for filtering, confining, guiding, coupling or splitting beams of visible light. However, creating waveguides that could do the same for X-rays has posed tremendous challenges in fabrication, so they are still only in an early stage of development.

In the latest issue of Acta Crystallographica Section A: Foundations and Advances , Sarah Hoffmann-Urlaub and Tim Salditt report the fabrication and testing of...

Im Focus: Piggyback battery for microchips: TU Graz researchers develop new battery concept

Electrochemists at TU Graz have managed to use monocrystalline semiconductor silicon as an active storage electrode in lithium batteries. This enables an integrated power supply to be made for microchips with a rechargeable battery.

Small electrical gadgets, such as mobile phones, tablets or notebooks, are indispensable accompaniments of everyday life. Integrated circuits in the interiors...

Im Focus: UCI physicists confirm possible discovery of fifth force of nature

Light particle could be key to understanding dark matter in universe

Recent findings indicating the possible discovery of a previously unknown subatomic particle may be evidence of a fifth fundamental force of nature, according...

Im Focus: Wi-fi from lasers

White light from lasers demonstrates data speeds of up to 2 GB/s

A nanocrystalline material that rapidly makes white light out of blue light has been developed by KAUST researchers.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

The energy transition is not possible without Geotechnics

25.08.2016 | Event News

New Ideas for the Shipping Industry

24.08.2016 | Event News

A week of excellence: 22 of the world’s best computer scientists and mathematicians in Heidelberg

12.08.2016 | Event News

 
Latest News

Symmetry crucial for building key biomaterial collagen in the lab

26.08.2016 | Health and Medicine

Volcanic eruption masked acceleration in sea level rise

26.08.2016 | Earth Sciences

Moth takes advantage of defensive compounds in Physalis fruits

26.08.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>