Study finds that microbes influence B-cell development in the gut

August 21, 2013, Children's Hospital Boston
Immunohistochemical section of small intestinal mucosa showing TdT+ pro-B cells stained in brown. Credit: Duane Wesemann

Gut bacteria exert a dramatic, systemic effect on the development of the immune system's B-lymphocytes, according to a new mouse study by researchers at Boston Children's Hospital. While influences of gut bacteria on T-lymphocytes have been noted before, this is the first time that researchers have documented early B-cell development in the gut and that microbes influence this process.

The study team—led by Duane Wesemann, MD, PhD, and Frederick Alt, PhD, of Boston Children's Hospital's Program in Cellular and Molecular Medicine (PCMM)—reported their findings online Aug. 21 in Nature.

Starting at birth, the immune system programs immature B-cells to produce antibodies against a wide array of potentially pathogenic by shuffling genes for different antibody components. This shuffling process, called V(D)J recombination, depends on a factor called RAG, which results in an immense number of B-cells that collectively are able to respond to a diverse repertoire of antigens that the immune system has yet to encounter.

V(D)J recombination programs each individual B-cell to produce a single kind of antibody that will work against a single antigen. Because this shuffling process is random, some newly generated B-cells make self-reactive receptors. If this happens, the cells continue the RAG-mediated shuffling, a process called editing, which replaces a self-reactive receptor with one that is not self-reactive.

Several recent studies focused on T-cells have suggested that gut microbes have a range of effects on the immune system.

"We were looking at B-cells in the gut because we had previous data suggesting that certain B-cell lymphomas arise from cells that undergo editing in gut-associated lymphoid tissues," says Alt, director of the Boston Children's PCMM, and the Charles A. Janeway Professor of Pediatrics at Harvard Medical School. "However, we didn't expect to also find an active process of early B-cell development and antibody diversification going on in the gut."

The team found that immature B-cells within the lamina propria portion of the gut were actively shuffling antibody genes, as measured by RAG levels and V(D)J recombination intermediates. In fact, the level of gene shuffling within gut B-cells was similar to that in B-cells developing in the bone marrow, suggesting there also was primary B-cell development in the gut. These results stand counter to current dogma on B-cell development in mice and humans.

"Sheep, rabbits and chickens develop their primary B-cell repertoire in the gut," says Wesemann. "Previously, primary antibody diversification had only been demonstrated in the bone marrow of humans and mice; so the finding that the process also occurs in the mouse gut was surprising."

"It could be that the gut serves as another location for primary B-cell development in the mouse in addition to the bone marrow," Alt adds. "Others have found immature B-cells in the lamina propria in humans, which based on our mouse studies suggests that gut B-cell development also might occur in humans."

When the team looked more closely, they saw that the diversity of the B-cell repertoire in the gut differed markedly from that in the bone marrow, as measured by sequencing- shuffled antibody genes in B-cells from both locations. The level of shuffling was the same, but the nature of the actual rearrangements differed dramatically between the two sites. The study also showed that at least some of the repertoire differences may have been generated by editing in gut B-cells.

A striking aspect of the discovery was that the amount of gene shuffling occurring in immature B-cells from weaning-age young mice changed dramatically depending on whether the mice were colonized with normal intestinal bacteria or were raised in a germ-free environment. Immature B-cells from mice with colonized intestines exhibited significantly more developing B-cells than those from germ-free animals, findings that held true in the gut, and spleen.

Overall, the study suggests that not only regulate T-cell activities but also influence those of B-cells.

Explore further: Researchers find gut bacteria teaches immune cells to see them as friendly

More information:

Related Stories

Researchers find gut bacteria teaches immune cells to see them as friendly

September 22, 2011
(Medical Xpress) -- Most people know that the gut (human or otherwise) has bacteria in it that helps in the proper digestion of food. But how these bacteria manage to evade destruction by the immune system has been a mystery. ...

How to achieve a well-balanced gut

August 8, 2013
Creating an environment that nurtures the trillions of beneficial microbes in our gut and, at the same time, protects us against invasion by food-borne pathogens is a challenge. A study published on August 8 in PLOS Pathogens ...

NIH team describes protective role of skin microbiota

July 26, 2012
A research team at the National Institutes of Health has found that bacteria that normally live in the skin may help protect the body from infection. As the largest organ of the body, the skin represents a major site of interaction ...

Researchers identify key player in the genesis of human intestinal immunity

June 20, 2013
The trillions of harmful bacteria that populate the human gut represent a continuous threat to our health. Proper intestinal immune function creates a protective barrier between us and the extensive microbial ecosystem in ...

New findings may help overcome hurdle to successful bone marrow transplantation

May 28, 2013
Blood diseases such as leukemia, multiple myeloma, and myelodysplasia can develop from abnormal bone marrow cells and a dysfunctional bone marrow microenvironment that surrounds these cells. Until now, researchers have been ...

Thymus teaches immune cells to ignore vital gut bacteria

April 29, 2013
The tiny thymus teaches the immune system to ignore the teeming, foreign bacteria in the gut that helps you digest and absorb food, researchers say.

Recommended for you

Forces from fluid in the developing lung play an essential role in organ development

January 23, 2018
It is a marvel of nature: during gestation, multiple tissue types cooperate in building the elegantly functional structures of organs, from the brain's folds to the heart's multiple chambers. A recent study by Princeton researchers ...

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.


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.