|Scientists Develop Method to Track Immune System
Enzyme in Live Animals
Scientists supported by the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes
of Health have created two mouse strains that will permit researchers
to trace, in a live animal, the activity of an enzyme believed
to play a crucial role both in the normal immune response as well
as autoimmunity and B cell tumor development. Their report appears
in the Journal of Experimental Medicine.
The enzyme, known as activation-induced cytidine deaminase or
AID (which has no relation to the AIDS virus), is expressed by
B cells, which are produced in the bone marrow and are responsible
for making antibodies that attack foreign invaders such as viruses
and bacteria. The enzyme enables the cells to respond with precision
to the almost limitless types of invaders the body may encounter.
Unfortunately, it also has a down side.
B cells constantly scan the body for foreign invaders, explains
Rafael Casellas, Ph.D., an investigator in NIAMS’ Molecular Immunology
and Inflammation Branch and lead author of the paper. As B cells
encounter foreign antigens from viruses, bacteria or allergens,
they migrate to germinal centers — specialized microenvironments
in tonsils, spleen and lymph nodes. Within germinal centers, B
cells divide extensively and express the AID enzyme, which causes
random mutations and recombination in the cells’ immunoglobulin
(antibody) genes. For the most part, these genetic changes are
beneficial because they enable B lymphocytes to attack and stop
the invader. In some cases, however, AID-dependent alterations
in the genetic material of B cells can also lead to unwanted results
such as autoimmunity and development of B cell tumors, as in the
case of Burkitt lymphoma.
“It becomes crucial that we comprehend how AID is regulated during
the normal immune response as well as in tumorigenesis and autoimmunity,” says
Casellas. The problem with understanding how AID is regulated or
deregulated is that there has not been an easy way to visualize
the enzyme’s action in a living animal — until now.
To address this issue, Dr. Casellas and his colleagues created
transgenic mice that had a green fluorescent protein derived from
jellyfish fused to the AID enzyme. In these transgenic animals,
B cells express the tagged enzyme during the immune response. In
a second mouse strain, Casellas and coworkers expressed permanently
a yellow fluorescent protein in the progeny of germinal center
B cells. “Thanks to these new mouse models, we can track in live
animals whenever the AID enzyme is active as well as the result
of that activity,” says Casellas. Scientists can also cross these
new mouse strains with mice predisposed to B-cell tumors or autoimmunity
to see differences in enzyme expression in health and disease.
NIAMS Director Stephen I. Katz. M.D., Ph.D., believes these new
tools have great potential to help solve some mysteries of the
immune system, such as the causes of B-cell tumors and autoimmunity. “The
better we understand these problems,” he says, “the closer we come
to better treatments for them and eventually, perhaps, ways to
this picture of intestinal villi from one of the new
mouse strains, plasma cells are tagged with yellow (green-appearing)
This work was also supported by the National Cancer Institute.
The mission of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), a part of the Department of Health and
Human Services’ National Institutes of Health, is to support research
into the causes, treatment and prevention of arthritis and musculoskeletal
and skin diseases; the training of basic and clinical scientists
to carry out this research; and the dissemination of information
on research progress in these diseases. For more information about
NIAMS, call the information clearinghouse at (301) 495-4484 or
(877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
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