Emory Vaccine Research Center Study in Nature Identifies
Specific Gene Required for Long-term Immunity
ATLANTA -- In a study in the Jan. 16 issue of Nature, scientists
at the Emory Vaccine Research Center show that a gene called SAP is
required to generate long-term immunity.
By measuring the immune responses
of "knockout" mice genetically engineered to lack SAP, researchers found
that the geneís absence impairs the immune systemís "memory," namely
its ability to recognize and react to infection. This finding has implications
for research in vaccines, which by definition must engender long-term
SAP recently was identified
as the gene responsible for a lethal human genetic disease, X-linked
"There are only a few known
lethal immunodeficiencies in humans, and a defect in the SAP gene is
one of them," said first author Shane Crotty, PhD.. "So this gene is
clearly important for immune responses. Our work now shows that the
SAP gene is a central player in long-term antibody responses, and indicates
that manipulation of SAP may have therapeutic benefits in generating
better antibody responses."
Dr. Crotty and his colleagues
compared the immune responses of the knockout mice against those of
genetically normal control mice. When infected with a virus, in this
case lymphocytic choriomeningitis virus, both sets of mice mounted initial
immune responses of similar magnitude. After the initial response subsided,
however, the SAP-negative mice failed to produce significant numbers
of either virus-specific plasma cells or memory B-cells, both of which
are crucial components of long-term immunity.
In the Nature paper,
the investigators commented that it is unusual to find that a gene affects
long-term but not short-term immunity.
"What is so interesting about
this gene is that it controls the generation of long-term memory, but
itís not important for short-term immune responses.. We havenít seen
a gene that does this before," said Rafi Ahmed, PhD, VRC Director and
senior author of the study.
The researchers were able
to pinpoint the effect of the absence of SAP on the CD4+ T-cells of
the immune system. These cells were present in normal or even increased
numbers in the SAP-negative mice as compared to the control mice. However,
in SAP-negative mice the CD4+ T-cells apparently failed to stimulate
the production of memory B-cells and plasma cells, which in turn are
necessary to produce antiviral antibodies.
When the immune system encounters
an unfamiliar pathogen, such as a virus, it mounts a strong initial
response aimed at eliminating the invader from the body. This acute
initial response consists of a rapid proliferation of certain types
of immune system cells, plasma cells, which produce antibodies to destroy
Following this initial response,
the immune system produces smaller numbers of plasma cells and memory
B-cells that remain in the body long after the infection is cleared.
These long-lived cells are responsible for "remembering" that particular
virus and quickly rousing the immune system should it reappear. They
are crucial to long-term immunity, and, therefore, to the success of
a vaccine; a vaccine that fails to generate long-term immune memory
does not protect against infection.
People with SAP mutations
often present with immunological abnormalities and chronic infections.
Many of the deaths among people with X-linked lymphoproliferative disease
result from infection with Epstein-Barr virus. The VRC study suggests
that this may be due to the inability of SAP-negative individuals to
sustain long-term immunity against Epstein-Barr virus.
Dr. Ahmedís research at Emory
focuses on identifying ways to manipulate specific components of the
immune system. The goal is to learn how to turn on or off certain functions
as needed, to combat cancerous tumors or prevent rejection of a transplanted
organ, for instance, while maintaining the protective benefits of the
immune system. Current therapies generally involve the wholesale destruction
of the immune system, leaving patients dangerously vulnerable to ordinarily
Future investigations into
SAP will focus on identifying precisely how it affects the ability of
CD4+ T-cells to stimulate the production of long-lived plasma cells
and memory B-cells.
In addition to Drs. Crotty
and Ahmed, the authors of the study were Ellen N.. Kersh, PhD, of the
VRC, and Jennifer Cannons, PhD, and Pamela L. Schwartzberg, MD, PhD,
of the National Human Genome Research Institute of the National Institutes
of Health. The study was funded by the National Institutes of Health.