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January 15, 2003


 



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 immunity.

SAP recently was identified as the gene responsible for a lethal human genetic disease, X-linked lymphoproliferative disease.

"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 the virus.

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 manageable infections.

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.

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