A more complicated network than generally accepted may control maturation of B cells in the immune system

November 22, 2012, RIKEN
Fluorescently labeled early B cell progenitors. Credit: 2012 Wooseok Seo, RIKEN Research Center for Allergy and Immunology

The process of blood cell development, known as hematopoiesis, gives rise to numerous different immune cell subtypes. Each of these in turn matures through a stepwise process governed by the action of transcription factors—specialized proteins that coordinate activation and deactivation of specific target genes. 

Antibody-secreting B lymphocytes develop via a well-studied mechanism, but research from Ichiro Taniuchi's team at the RIKEN Center for Allergy and Immunology in Yokohama injects new complexity into this model. The current mechanism involves three —E2A, Ebf1 and Pax5—that progressively set the stage for maturation of functional B lymphocytes. "Not only does this trio of transcription factors function sequentially, but each one is also responsible for the expression of the next," explains Wooseok Seo, a researcher in Taniuchi's laboratory and lead author of the study. "E2A is required for the expression of Ebf1, and so on."

Seo and Taniuchi were studying another transcription factor, Runx1, which is a critical component of blood cell development. Without Runx1, hematopoiesis cannot take place. The researchers therefore decided to study its role in B cell development by engineering a genetically modified mouse that expresses Runx1 in every cell except early stage B cell precursors.

Without Runx1, these cells stalled early in development, at essentially the same stage where Ebf1 exerts its effects. Seo and colleagues determined that Runx1, in partnership with the Cbfβ protein, normally binds to the promoter sequence that regulates Ebf1 production. Interestingly, Ebf1 has two distinct promoters; and, Runx1-Cbfβ and E2A each bind a different promoter of Ebf1. "Our hypothesis is that E2A and Runx1 might be distinctive, but not necessarily exclusive, in their mode of function," says Seo.

In the absence of Runx1, Ebf1 gene activity is drastically reduced, preventing downstream induction of the 'final step' in B . However, Runx1 also appears to activate a 'positive feedback' loop by switching on the gene encoding its upstream activator, E2A, thereby accelerating the process of B cell differentiation. Without Runx1, therefore, none of the three differentiation factors are properly expressed. 

These findings suggest that earlier models of this process may be greatly oversimplified. "We propose that the simple hierarchy model of this trio of transcriptional factors for development might not be true, and suggest a more complicated network," says Seo. He and his colleagues are now exploring the mechanisms Runx1 employs to control , and how these enable it to exert such a potent influence on hematopoietic development.

Explore further: Study examines role of microglial cells as both defenders and fighters in the nervous system

More information: Seo, W., Ikawa, T., Kawamoto, H. & Taniuchi, I. Runx1–Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1. The Journal of Experimental Medicine 209, 1255–1262 (2012). jem.rupress.org/content/early/ … em.20112745.abstract

Related Stories

Study examines role of microglial cells as both defenders and fighters in the nervous system

October 16, 2012
(Medical Xpress)—In many pathologies of the nervous system, there is a common event - cells called microglia are activated from surveillant watchmen into fighters.  Microglia are the immune cells of the nervous system, ...

Inherited DNA change explains overactive leukemia gene

May 25, 2012
A small inherited change in DNA is largely responsible for overactivating a gene linked to poor treatment response in people with acute leukemia.

Disappearance of genetic material allows tumor cells to grow

August 4, 2011
Malignant Sézary syndrome is characterized by the reproduction of a special type of white blood cells in the skin of male and female patients. In contrast to most other skin lymphomas, patients with Sézary syndrome ...

Recommended for you

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

Scientists unleash power of genetic data to identify disease risk

January 16, 2018
Massive banks of genetic information are being harnessed to shed new light on modifiable health risks that underlie common diseases.

Blood-vessel-on-a-chip provides insight into new anti-inflammatory drug candidate

January 15, 2018
One of the most important and fraught processes in the human body is inflammation. Inflammatory responses to injury or disease are crucial for recruiting the immune system to help the body heal, but inflammation can also ...

Molecule produced by fat cells reduces obesity and diabetes in mice

January 15, 2018
UC San Francisco researchers have discovered a new biological pathway in fat cells that could explain why some people with obesity are at high risk for metabolic diseases such as type 2 diabetes. The new findings—demonstrated ...

Obese fat becomes inflamed and scarred, which may make weight loss harder

January 12, 2018
The fat of obese people becomes distressed, scarred and inflamed, which can make weight loss more difficult, research at the University of Exeter has found.

0 comments

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.