School of Medicine Researchers Learn More About a Key Enzyme Involved in Allergy and Cancer

By Sathya Achia Abraham

An international research team has learned how a key enzyme critically regulates the development of a category of antibody-producing B cells, setting the stage for development of target drugs that may one day treat diseases ranging from allergy to cancer.

Researchers from the Virginia Commonwealth University School of Medicine, Jagiellonian University in Krakow, Poland; Juntendo University School of Medicine in Tokyo, Japan; the University of Michigan; and Stony Brook University School of Medicine in New York, have been studying a proteolytic enzyme called ADAM10, which can inhibit cell signaling pathways.

ADAM10 works by cleaving many cell receptors off the cell membrane, so the receptor cannot respond to signals from other cells. However, it can activate some signaling pathways by cleaving receptors into smaller signaling molecules.

In a study published online in the February issue of The Journal of Experimental Medicine, the team reported that ADAM10 is necessary for the development of marginal zone B cells, or MZBs, that reside in the spleen and initiate immune responses to blood-borne pathogens in a mouse model. Development of MZBs depends on signals through the Notch2 receptor.

Further experiments showed that ADAM10 is required for the initiation of Notch2 signaling. They also found that ADAM10 cleaves CD23 - another receptor found on B cells that regulates allergic reactions, according to David R. Gibb, first author on the paper and an M.D./Ph.D. candidate in the VCU School of Medicine.

Gibb said that deleting ADAM10 in the mouse model prevented CD23 cleavage, which may have a significant impact on antibody production following exposure to environmental allergens.

“Excessive Notch signaling is a characteristic of many cancers, including B cell leukemia and lymphoma. Thus, our report identifies ADAM10 as a potential drug target for the treatment of patients with these types of cancer,” Gibb said.

“Moreover, because signaling through CD23 decreases allergic reactions, blocking ADAM10 with pharmaceuticals could represent a novel therapy for allergic patients,” he said.

“This study is the first demonstration that ADAM10 is a critical regulator of B cell development. Additionally, although many regulators of Notch2 signaling have been previously described, progress in using these findings for therapeutic purposes has been restricted by a lack of understanding of signal activation,” said Gibb.

Daniel Conrad, Ph.D., professor in the VCU Department of Microbiology and Immunology, directed the research conducted at VCU. Conrad has been investigating a basic mechanism involved in allergic disease since the 1970s. In previous work published in a 2006 issue of Nature Immunology, VCU was part of a team that demonstrated, for the first time, the role of ADAM10 in allergy. They found that ADAM10 triggers a chain of events that results in enhanced allergic reactions. Specifically, it was able to release a major allergy regulatory protein from the surface of cells and thereby promote a stronger allergic response.

Conrad is a member of the Asthma and Allergic Disease Research Center at VCU, which is funded by the National Institutes of Health. Additional funding for this work was from the American Heart Association, Crohn’s and Colitis Foundation of America, the Veteran’s Administration Merit Award and the Polish Ministry of Scientific Research.