First atlas of B-cell clones in body forms new foundation for infectious disease research

August 29, 2017
A model of the human body showing distinct B cell clonal networks in the gastrointestinal tract and in the blood-rich organs such as bone marrow, spleen, and lung. Credit: Alexander H. Farley

A new "anatomic atlas" of how B cells - the immune system's producer of antibodies - link up to form networks has been charted by researchers from the Perelman School of Medicine at the University of Pennsylvania. This map will be an important resource for researchers and clinicians studying infectious diseases, the microbiome, vaccine responses, and tissue-specific immunity. Their findings appear in Nature Biotechnology.

"Our bodies are filled with B-cell clones," said senior author Nina Luning Prak, MD, PhD, an associate professor of Pathology and Laboratory Medicine. B cells are diverse in the number of distinct their genes can encode. Immunologists estimate there are about 100 billion different types of antibodies per person.

"We dubbed our study 'Blood & Guts,' when we started to see that B-cell clone populations partition into two broad networks," Prak said. "There are large networks in the gut (the jejunum, ileum, and colon) and different networks in blood-rich regions such as blood, bone marrow, spleen, and lung. We essentially discovered and mapped the B-cell clonal geography of the human body." They did this with the help of consented human who allowed their tissues to be used for research purposes, in addition to transplantation.

When B cells are in response-to-invader mode, they undergo what is termed a "clonal expansion," which can occur in a variety of tissues. These populations are simply collections of cells that can all be traced back to the same parent B cell.

B cells combat infection locally, activating specific T cells and molecules that influence nearby immune cells within specific tissues. On the whole, the distribution and movement of B-cell clones influences how infections are controlled throughout the body. Past animal studies have found that these specifics, which differ tissue by tissue, are important for building up protective immunity and keeping the helpful bacteria species in the microbiome happy. However, researchers did not know the lay of the B-cell landscape, so to speak, until now.

The team also found more memory B cells, with their associated uber-diverse antibodies, in the gut network group. These gastrointestinal populations were more related genetically compared to the blood-rich tissue groups.

"Presumably, this is because the gut is one of the organs that is constantly bombarded by stimuli from the environment—whether the stimuli that drive these B-cell clones are derived from the microbiome or other pathogens is not yet known," Prak said. The greater interconnection among B cells that share similar antibodies in the gut could be the body's way of coordinating immune responses across large distances along the gastrointestinal tract, she suggests.

To make the map, the investigators sequenced a region of the B-cell gene that encodes an antibody component called the heavy-chain variable domain. This part of the antibody is generated by multiple rearrangements in the gene and contributes to the vast diversity of antibodies that humans generate over a lifetime. These antibody gene shuffles were analyzed using DNA from the seven tissue types and blood from the organ donors.

The computational analysis of the B-cell lineages, with over 38 million gene rearrangements, required the development of new and visualization tools. Prak says it took the group, which included members of her lab and a team of computational biologists led by Uri Hershberg at Drexel University, two-and-a-half years to complete the meticulous sequencing and data analysis to plot the map.

Co-author Donna Farber, from Columbia University, directed the organ donor tissue program for acquiring the tissue samples. "The donors, the research surgeons who performed the tissue acquisition, and the organ procurement organization, LiveOnNY, were all critical for being able to carry out this work," Prak said.

She likens tracing each line of B cells through the body to the Verizon guy in the commercial moving from spot to spot asking, "Can you hear me now?" In this analogy, the Verizon guy stands in a particular tissue asking whether a cell from a given collection of related B is present. Each B-cell clonal lineage is like a cell phone network. The geographic regions covered by the each network are the tissues and the entire planet Earth is the body of a single person.

Prak's team traced over 933,000 B-cell lineages and replicated their results using the tissues from the six organ donors. "In the case of our research, we have the equivalent of data from six different Earths," she said.

"That's a lot of testing—millions of Verizon commercials' worth. Our fantasy for the future is to create organ-specific immune monitoring assays. If we can define features of the antibody repertoire that are unique to particular tissues, we may be able to monitor tissue-specific immune responses using blood-based clinical lab tests."

Such tests might be used to monitor immune responses to vaccines or inappropriate antibody responses in organ-specific autoimmune diseases; however, the first step towards that is knowing the location of B-cell clones.

The B-cell clonal network data can be accessed and analyzed further using the team's computational framework for analysis, ImmuneDB. Continuously updated applications for data analysis and visualization of B-cell data are also available here and here.

Explore further: New type of blood cells work as indicators of autoimmunity

Related Stories

New type of blood cells work as indicators of autoimmunity

August 14, 2017
A team from Instituto de Medicina Molecular Lisboa, led by Luis Graça, has analyzed blood samples from patients with Sjögren syndrome, an autoimmune disease that affects the mucous membranes and moisture-secreting glands ...

First ever 'atlas' of T cells in human body

December 20, 2012
By analyzing tissues harvested from organ donors, Columbia University Medical Center (CUMC) researchers have created the first ever "atlas" of immune cells in the human body. Their results provide a unique view of the distribution ...

Team tracks rare T cells in blood to better understand annual flu vaccine

February 17, 2017
For most vaccines to work the body needs two cell types - B cells and T helper cells - to make antibodies. B cells are the antibody factories and the T helper cells refine the strength and accuracy of antibodies to home and ...

Immune system cell clones created before birth may last for decades

July 6, 2017
Key immune system cells produced before birth may survive well into adulthood, according to new research published in PLOS Computational Biology.

HDAC3 role in B-cell development

August 4, 2017
Histone deacetylases (HDACs) are enzymes that modulate gene expression and have important roles in development and disease. HDAC inhibitors are active against lymphoma, and understanding the roles of specific HDACs is important ...

Recommended for you

Antibody protects against Zika and dengue, mouse study shows

September 25, 2017
Brazil and other areas hardest hit by the Zika virus - which can cause babies to be born with abnormally small heads - are also home to dengue virus, which is spread by the same mosquito species.

Gene immunotherapy protects against multiple sclerosis in mice

September 21, 2017
A potent and long-lasting gene immunotherapy approach prevents and reverses symptoms of multiple sclerosis in mice, according to a study published September 21st in the journal Molecular Therapy. Multiple sclerosis is an ...

New academic study reveals true extent of the link between hard water and eczema

September 21, 2017
Hard water damages our protective skin barrier and could contribute to the development of eczema, a new study has shown.

Exposure to pet and pest allergens during infancy linked to reduced asthma risk

September 19, 2017
Children exposed to high indoor levels of pet or pest allergens during infancy have a lower risk of developing asthma by 7 years of age, new research supported by the National Institutes of Health reveals. The findings, published ...

Cholesterol-like molecules switch off the engine in cancer-targeting 'Natural Killer' cells

September 18, 2017
Scientists have just discovered how the engine that powers cancer-killing cells functions. Crucially, their research also highlights how that engine is fuelled and that cholesterol-like molecules, called oxysterols, act as ...

MicroRNA helps cancer evade immune system

September 18, 2017
The immune system automatically destroys dysfunctional cells such as cancer cells, but cancerous tumors often survive nonetheless. A new study by Salk scientists shows one method by which fast-growing tumors evade anti-tumor ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.